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Sample records for non-antiarrhythmic drugs prolonging

  1. Drug-induced QT interval prolongation: mechanisms and clinical management

    PubMed Central

    Nachimuthu, Senthil; Assar, Manish D.

    2012-01-01

    The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies. PMID:25083239

  2. Topical Drug Formulations for Prolonged Corneal Anesthesia

    PubMed Central

    Wang, Liqiang; Shankarappa, Sahadev A.; Tong, Rong; Ciolino, Joseph B.; Tsui, Jonathan H.; Chiang, Homer H.; Kohane, Daniel S.

    2013-01-01

    Purpose Ocular local anesthetics (OLA’s) currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect on the duration of corneal anesthesia of the site-1 sodium channel blocker tetrodotoxin (TTX), applied with either proparacaine or the chemical permeation enhancer OTAB. The effect of test solutions on corneal healing was also studied. Methods Solutions of TTX, proparacaine, and OTAB, singly or in combination were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet-Bonnet esthesiometer, and the duration of corneal anesthesia calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo following corneal debridement. Results Combination of TTX and proparacaine resulted in corneal anesthesia that was 8–10 times longer in duration than that from either drug administered alone, while OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed following co-administration of TTX and proparacaine. Conclusion Co-administration of TTX and proparacaine significantly prolonged corneal anesthesia but in view of delayed corneal re-epithelialization, caution is suggested in use of the combination. PMID:23615270

  3. Drug-induced QT interval prolongation and torsades de pointes

    PubMed Central

    Tisdale, James E.

    2016-01-01

    Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval–prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration. Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide. Other important pharmacokinetic interactions include antidepressants (bupropion, duloxetine, fluoxetine, paroxetine) interacting with flecainide, quinidine or thioridazine. Pharmacists play an important role in minimizing the risk of drug-induced QTc interval prolongation and TdP through knowledge of drugs that are associated with a known or possible risk of TdP, individualized assessment of risk of drug-induced QTc interval prolongation, awareness of drug interactions most likely to result in TdP and attention to dose reduction of renally eliminated QTc interval-prolonging drugs in patients with kidney disease. Treatment of hemodynamically stable TdP consists of discontinuation of the offending drug(s), correction of electrolyte abnormalities and administration of intravenous magnesium sulfate 1 to 2 g. PMID:27212965

  4. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine.

    PubMed

    Park, Young-Min

    2012-12-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy.

  5. Polyvinylpyrrolidone induced artefactual prolongation of activated partial thromboplastin times in intravenous drug users with renal failure.

    PubMed

    Kristoffersen, A H; Bjånes, T K; Jordal, S; Leh, S; Leh, F; Svarstad, E

    2016-05-01

    Essentials Prolonged activated partial thromboplastin times (APTT) were found in drug users with renal failure. An oral methadone solution containing polyvinylpyrrolidone (PVP) had been injected intravenously. Spiking normal plasma with increasing concentrations of PVP resulted in artifically prolonged APTT. APTT prolongation may indicate PVP deposits as underlying cause in patients with renal failure.

  6. Unusually Prolonged Presentation of Designer Drug Encephalopathy Responsive to Steroids.

    PubMed

    Albadareen, Rawan; Thornton, Stephen; Heshmati, Arezou; Gerona, Roy; Lowry, Jennifer

    2015-07-01

    The availability and use of novel psychoactive substances has risen dramatically over the last decade. The unpredictability of their toxicity constitutes a real challenge. We report a case of an adolescent who developed prolonged encephalopathy after ingesting "Hot Molly," which was found to contain the novel psychoactive substance, methylenedioxybenzylpiperazine when analyzed by high resolution mass spectrometry assay. This is the first case of human toxicity from methylenedioxybenzylpiperazine ingestion in the medical literature confirmed by body fluid analysis presenting with significant and prolonged encephalopathy. The prolonged course may be due to CYP2D6 inhibition from a combination of the methylenedioxyphenyl moiety and the patient's ultrarapid metabolizer pharmacokinetics. The response to high dose corticosteroids suggests a possible inflammatory effect that warrants further investigation.

  7. Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes

    PubMed Central

    Antzelevitch, Charles

    2008-01-01

    Torsade de pointes (TdP) is a life-threatening arrhythmia that develops as a consequence of a reduction in the repolarization reserve of cardiac cells leading to amplification of electrical heterogeneities in the ventricular myocardium as well as to the development of early after depolarization-induced triggered activity. Electrical heterogeneities within the ventricles are due to differences in the time course of repolarization of the three predominant cell types that make up the ventricular myocardium, giving rise to transmural voltage gradients and a dispersion of repolarization that contributes to the inscription of the electrocardiographic T wave. A number of non-antiarrhythmic drugs and antiarrhythmic agents with class III actions and/or the various mutations and cardiomyopathies associated with the long QT syndrome reduce net repolarizing current and amplify spatial dispersion of repolarization, thus creating the substrate for re-entry. This results in a prolongation of the QT interval, abnormal T waves, and development of TdP. Agents that prolong the QT interval but do not cause an increase in transmural dispersion of repolarization (TDR) do not induce TdP, suggesting that QT prolongation is not the sole or optimal determinant for arrhythmogenesis. This article reviews recent advances in our understanding of these mechanisms, particularly the role of TDR in the genesis of drug-induced TdP, and examines how these may guide us towards development of safer drugs. PMID:17766323

  8. Prolonged drug-induced myoclonus: is it related to palonosetron?

    PubMed

    Chaw, Sook Hui; Chan, Lucy; Lee, Pui Kuan; Bakar, Jaseemuddeen A; Rasiah, Raveenthiran; Foo, Li Lian

    2016-12-01

    We report a case of drug-induced myoclonus possibly related to palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist which was administered as a prophylaxis for postoperative nausea and vomiting in a 28-year-old female. The recurrent episodes of myoclonus jerk involving the head, neck and shoulder persisted for a period of 4 days. The patient also exhibited an episode of severe bradycardia leading to hypotension 7 h after surgery. To our knowledge, this is the first report presenting these adverse events potentially associated with the use of palonosetron.

  9. Despite Federal Legislation, Shortages Of Drugs Used In Acute Care Settings Remain Persistent And Prolonged.

    PubMed

    Chen, Serene I; Fox, Erin R; Hall, M Kennedy; Ross, Joseph S; Bucholz, Emily M; Krumholz, Harlan M; Venkatesh, Arjun K

    2016-05-01

    Early evidence suggests that provisions of the Food and Drug Administration Safety and Innovation Act of 2012 are associated with reductions in the total number of new national drug shortages. However, drugs frequently used in acute unscheduled care such as the care delivered in emergency departments may be increasingly affected by shortages. Our estimates, based on reported national drug shortages from 2001 to 2014 collected by the University of Utah's Drug Information Service, show that although the number of new annual shortages has decreased since the act's passage, half of all drug shortages in the study period involved acute care drugs. Shortages affecting acute care drugs became increasingly frequent and prolonged compared with non-acute care drugs (median duration of 242 versus 173 days, respectively). These results suggest that the drug supply for many acutely and critically ill patients in the United States remains vulnerable despite federal efforts.

  10. Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

    PubMed Central

    Chain, Anne SY; Dubois, Vincent FS; Danhof, Meindert; Sturkenboom, Miriam CJM; Della Pasqua, Oscar

    2013-01-01

    Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID:23351036

  11. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

    PubMed Central

    Shah, Rashmi R

    2013-01-01

    Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure–response (E–R) analysis may be more sensitive than simple changes in QTc interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT studyfrom one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E–R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn. PMID:22882246

  12. Prolongation of QT interval in isolated feline hearts by antipsychotic drugs.

    PubMed

    Drici, M D; Wang, W X; Liu, X K; Woosley, R L; Flockhart, D A

    1998-12-01

    Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG) recordings, a phenomenon which, when severe, may facilitate the occurrence of complex ventricular arrhythmias such as torsade de pointes. However, the effects of these drugs on the cardiac repolarization process have not been evaluated extensively. This study was designed to examine the potency of five antipsychotic drugs in lengthening the QT interval of the perfused feline heart: haloperidol, risperidone, sertindole, clozapine, and olanzapine. The hearts were infused with increasing concentrations of drugs (0.1-20 micromol/L) for 40-minute intervals at each concentration. ECG recordings were made, with signals amplified and data recorded on a strip chart recorder. Four representative beats from each set of three signal recordings were chosen for QT interval measurement. Our data indicated that all tested drugs prolonged the QT interval in a concentration-dependent manner (p < 0.01). Haloperidol and risperidone were significantly more potent than sertindole, clozapine, and olanzapine (p < 0.001). At a concentration of 0.5 micromol/L over a 40-minute infusion interval, haloperidol lengthened the interval by 26.2+/-0.7%, risperidone by 19.4+/-2.2%, and sertindole by 8.9+/-3.5% (p < 0.05 compared with baseline); clozapine and olanzapine were less potent. Although species differences may limit extrapolation of our findings to humans, the cardiac potassium channels of felines clearly resemble those of humans. This model may serve as the basis for further studies of drug-induced prolongation of the QT interval and precipitation of ventricular arrhythmias.

  13. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    SciTech Connect

    Cros, C.; Skinner, M.; Moors, J.; Lainee, P.; Valentin, J.P.

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  14. QT interval prolongation: preclinical and clinical testing arrhythmogenesis in drugs and regulatory implications.

    PubMed

    Giorgi, Mariano A; Bolaños, Ricardo; Gonzalez, Claudio Daniel; Di Girolamo, Guillermo

    2010-01-01

    The assessment about the proarrhythmic risk associated with a particular drug is a major requirement for drugs under development, since many drugs have been withdrawn from market or got under strict pharmacological vigilance because of such a risk. Predicting the development of a life-threatening arrhythmia is a hard task but, in the case of TdP ("Torsades de Pointes"), there are some useful markers. Among them, the prolongation of the QT interval and its heart rate correction (QTc) are the most remarkable. Actually, QT prolongation is considered the surrogate marker of TdP from the clinical and regulatory standpoint. ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The regulatory information about preclinical safety evaluation is contained in ICH S7B. Both guidelines have been a matter of intense debate. False negative and false positive results have been found within the preclinical and clinical field. There still are grey areas in which further research would be necessary. Improvement of tools that may contribute to complement the data from the human ether-a-go-go-related gene HERG channel and QT/QTc studies, such as concentration-QT relationship (CQT) studies and other innovative techniques, will be more than welcome.

  15. Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs

    PubMed Central

    Burnham, M P; Sharpe, P M; Garner, C; Hughes, R; Pollard, C E; Bowes, J

    2014-01-01

    Background and Purpose Prolongation of the cardiac QRS complex is linked to increased mortality and may result from drug-induced inhibition of cardiac sodium channels (hNaV1.5). There has been no systematic evaluation of preclinical and marketed drugs for their additional potential to cause QRS prolongation via gap junction uncoupling. Experimental Approach Using the human cardiac gap junction connexin 43 (hCx43), a dye transfer ‘parachute’ assay to determine IC50 values for compound ranking was validated with compounds known to uncouple gap junctions. Uncoupling activity (and hNaV1.5 inhibition by automated patch clamp) was determined in a set of marketed drugs and preclinical candidate drugs, each with information regarding propensity to prolong QRS. Key Results The potency of known gap junction uncouplers to uncouple hCx43 was ranked (according to IC50) as phorbol ester>digoxin>meclofenamic acid>carbenoxolone>heptanol. Among the drugs associated with QRS prolongation, 29% were found to uncouple hCx43 (IC50 < 50 μM), whereas no uncoupling activity was observed in drugs not associated with QRS prolongation. In preclinical candidate drugs, hCx43 and hNaV1.5 IC50 values were similar (within threefold). No consistent margin over preclinical Cmax (free) was apparent for QRS prolongation associated with Cx43 inhibition. However, instances were found of QRS prolonging compounds that uncoupled hCx43 with significantly less activity at hNaV1.5. Conclusion and Implications These results demonstrate that off-target uncoupling activity is apparent in drug and drug-like molecules. Although the full ramifications of Cx inhibition remain to be established, screening for hCx43 off-target activity could reduce the likelihood of developing candidate drugs with a risk of causing QRS prolongation. PMID:24328991

  16. Inorganically modified diatomite as a potential prolonged-release drug carrier.

    PubMed

    Janićijević, Jelena; Krajišnik, Danina; Calija, Bojan; Dobričić, Vladimir; Daković, Aleksandra; Krstić, Jugoslav; Marković, Marija; Milić, Jela

    2014-09-01

    Inorganic modification of diatomite was performed with the precipitation product of partially neutralized aluminum sulfate solution at three different mass ratios. The starting and the modified diatomites were characterized by SEM-EDS, FTIR, thermal analysis and zeta potential measurements and evaluated for drug loading capacity in adsorption batch experiments using diclofenac sodium (DS) as a model drug. In vitro drug release studies were performed in phosphate buffer pH6.8 from comprimates containing: the drug adsorbed onto the selected modified diatomite sample (DAMD), physical mixture of the drug with the selected modified diatomite sample (PMDMD) and physical mixture of the drug with the starting diatomite (PMDD). In vivo acute toxicity testing of the modified diatomite samples was performed on mice. High adsorbent loading of the selected modified diatomite sample (~250mg/g in 2h) enabled the preparation of comprimates containing adsorbed DS in the amount near to its therapeutic dose. Drug release studies demonstrated prolonged release of DS over a period of 8h from both DAMD comprimates (18% after 8h) and PMDMD comprimates (45% after 8h). The release kinetics for DAMD and PMDMD comprimates fitted well with Korsmeyer-Peppas and Bhaskar models, indicating that the release mechanism was a combination of non-Fickian diffusion and ion exchange process.

  17. The assessment of potential for QT interval prolongation with new pharmaceuticals: impact on drug development.

    PubMed

    Gralinski, M R

    2000-01-01

    Few examinations of a single physiological variable can end the development of a putative new pharmaceutical. Prolongation of the electrocardiographic QT interval is one of these tests. Recognizing the removal of several approved and widely used medicines, worldwide regulatory authorities have raised a heightened awareness on the submission of data surrounding the ventricular repolarization process. This review will discuss the anatomy and physiology surrounding the generation of the electrocardiographic QT interval and the consequences of its alteration. In addition, relevant models of preclinical safety and general guidelines for clinical examination in this area are discussed along with the impact of incorporating these assays into the drug development process.

  18. Prolonged drug delivery system of an antifungal drug by association with polyamidoamine dendrimers

    PubMed Central

    Jose, Jobin; Charyulu, R Narayana

    2016-01-01

    Introduction: The potent antifungal agent amphotericin B (AmB) is not freely soluble in water. The clinical use of AmB is limited by nephrotoxicity and poor water solubility. Polyamidoamine (PAMAM) dendrimer offers an identical carrier for drug binding that has the capacity to attach and discharge drugs in numerous ways. Materials and methods: In this research work, we explored the potential of PAMAM dendrimers to improve the solubility of AmB. Results and discussion: The experimental results indicated that the solubility of AmB was greatly enhanced in the presence of PAMAM dendrimer solutions. Results indicated that the solubility of AmB enhanced with increase in dendrimer generations as well as concentration. In vitro release studies of AmB in the presence of the third generation of PAMAM dendrimers was performed by the dialysis method. Our research work revealed that binding of drug into dendrimers led to sustained release of AmB in vitro. Conclusion: Based on the stability studies, it was concluded that the drug dendrimer complex should be stored in a dark place at a cool temperature. PMID:27051632

  19. On the relationship between block of the cardiac Na+ channel and drug-induced prolongation of the QRS complex

    PubMed Central

    Harmer, AR; Valentin, J-P; Pollard, CE

    2011-01-01

    BACKGROUND AND PURPOSE Inhibition of the human cardiac Na+ channel (hNav1.5) can prolong the QRS complex and has been associated with increased mortality in patients with underlying cardiovascular disease. The safety implications of blocking hNav1.5 channels suggest the need to test for this activity early in drug discovery in order to design out any potential liability. However, interpretation of hNav1.5 blocking potency requires knowledge of how hNav1.5 block translates into prolongation of the QRS complex. EXPERIMENTAL APPROACH We tested Class I anti-arrhythmics, other known QRS prolonging drugs and drugs not reported to prolong the QRS complex. Their block of hNav1.5 channels (as IC50 values) was measured in an automated electrophysiology-based assay. These IC50 values were compared with published reports of the corresponding unbound (free) plasma concentrations attained during clinical use (fCmax) to provide an IC50 : fCmax ratio. KEY RESULTS For 42 Class I anti-arrhythmics and other QRS prolonging drugs, 67% had IC50 : fCmax ratios <30. For 55 non-QRS prolonging drugs tested, 72% had ratios >100. Finally, we determined the relationship between the IC50 value and the free drug concentration associated with prolongation of the QRS complex in humans. For 37 drugs, QRS complex prolongation was observed at free plasma concentrations that were about 15-fold lower than the corresponding IC50 at hNav1.5 channels. CONCLUSIONS AND IMPLICATIONS A margin of 30- to 100-fold between hNav1.5 IC50 and fCmax appears to confer an acceptable degree of safety from QRS prolongation. QRS prolongation occurs on average at free plasma levels 15-fold below the IC50 at hNav1.5 channels. LINKED ARTICLE This article is commented on by Gintant et al., pp. 254–259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01433.x PMID:21480866

  20. Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients

    PubMed Central

    Schächtele, Simone; Tümena, Thomas; Gaßmann, Karl-Günter; Fromm, Martin F.; Maas, Renke

    2016-01-01

    Background Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited. Objective This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs. Methods In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria–Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs). Results Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions. Conclusion In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs

  1. Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

    SciTech Connect

    Nozaki, Yumiko; Honda, Yayoi; Tsujimoto, Shinji; Watanabe, Hitoshi; Kunimatsu, Takeshi; Funabashi, Hitoshi

    2014-07-01

    Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.

  2. Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance

    PubMed Central

    Vargas, Hugo M; Bass, Alan S; Koerner, John; Matis-Mitchell, Sherri; Pugsley, Michael K; Skinner, Matthew; Burnham, Matthew; Bridgland-Taylor, Matthew; Pettit, Syril; Valentin, Jean-Pierre

    2015-01-01

    Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960–2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes. PMID:26031452

  3. Antipsychotic drugs and QTc prolongation: the potential role of CYP2D6 genetic polymorphism.

    PubMed

    Dorado, Pedro; Berecz, Roland; Peñas-Lledó, Eva M; Llerena, Adrián

    2007-02-01

    Although the most common, and usually serious, side effects of first-generation (or typical) antipsychotic drugs, such as Parkinsonism, dystonias and tardive dyskinesia, were known from early times, their cardiovascular safety was not properly in the focus of treatment management. The growing evidence of these drug-related cardiac changes and the appearance of potentially fatal dysrhythmias have increased the interest on their safety profile. Thus, the introduction of the new second-generation (atypical) antipsychotic drugs put emphasis on the preregistration evaluation of the potential cardiac side effects and electrocardiogram predictors (QT interval lengthening). In spite of this, these drugs do not appear to be exempt from these potential risks. The present review summarizes up-to-date knowledge about the cardiac safety of antipsychotic drugs, and analyses the role of drug metabolic processes (CYP2D6 genetic polymorphism) in the complex pathophysiology of the phenomenon. In addition, some recommendations are formulated.

  4. Extensively Drug-Resistant Tuberculosis: Report and Literature Review on Two Cases Requiring Prolonged Treatment

    PubMed Central

    Matos-Tocasca, Martha; De la Cruz-Ku, Gabriel; Auccacusi, Erick; Fernandez-Salas, Diego; García-Ahuanari, Tatiana; Valcarcel-Valdivia, Bryan

    2016-01-01

    Case series Patient: Female, 28 • Male, 20 Final Diagnosis: Extensively drug-resistant tuberculosis Symptoms: Cough productive • dyspnea • hemoptysis • respiratory failure • weight loss Medication: — Clinical Procedure: — Specialty: Pulmonology Objective: Unusual clinical course Background: Extensively drug-resistant tuberculosis (XDR-TB) is a global problem due to the high morbidity and mortality it causes. Peru is one of the countries with the highest numbers of cases of XDR-TB, which increase every year. Case Report: We present the case of two siblings who developed XDR-TB, underwent surgery twice, and were in individualized treatment for more than 6 years. Finally they achieved remission of symptoms, despite not having standardized treatment schemes during their diagnosis period. Conclusions: Extensively drug-resistant tuberculosis can be cured with a treatment that involves both medical care and patient actions to achieve remission of the disease. PMID:27807339

  5. Commentary on: “Levofloxacin‐Induced QTc Prolongation Depends on the Time of Drug Administration”

    PubMed Central

    Johannesen, L

    2016-01-01

    Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization? PMID:27647678

  6. Risk assessment and experimental design in the development of a prolonged release drug delivery system with paliperidone

    PubMed Central

    Iurian, Sonia; Turdean, Luana; Tomuta, Ioan

    2017-01-01

    This study focuses on the development of a drug product based on a risk assessment-based approach, within the quality by design paradigm. A prolonged release system was proposed for paliperidone (Pal) delivery, containing Kollidon® SR as an insoluble matrix agent and hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), or sodium carboxymethyl cellulose as a hydrophilic polymer. The experimental part was preceded by the identification of potential sources of variability through Ishikawa diagrams, and failure mode and effects analysis was used to deliver the critical process parameters that were further optimized by design of experiments. A D-optimal design was used to investigate the effects of Kollidon SR ratio (X1), the type of hydrophilic polymer (X2), and the percentage of hydrophilic polymer (X3) on the percentages of dissolved Pal over 24 h (Y1–Y9). Effects expressed as regression coefficients and response surfaces were generated, along with a design space for the preparation of a target formulation in an experimental area with low error risk. The optimal formulation contained 27.62% Kollidon SR and 8.73% HPMC and achieved the prolonged release of Pal, with low burst effect, at ratios that were very close to the ones predicted by the model. Thus, the parameters with the highest impact on the final product quality were studied, and safe ranges were established for their variations. Finally, a risk mitigation and control strategy was proposed to assure the quality of the system, by constant process monitoring. PMID:28331293

  7. The conventional antihistamine drug cyproheptadine lacks QT-interval-prolonging action in halothane-anesthetized guinea pigs: comparison with hydroxyzine.

    PubMed

    Kobayashi, Kazuko; Omuro, Naoki; Takahara, Akira

    2014-01-01

    Antihistamines are known to belong to the chemical class that may induce long QT syndrome. Among them, cyproheptadine has been shown to exert multifaceted actions on the ventricular repolarization phase; namely, shortening of the action potential duration at supra-therapeutic concentrations of 2 - 8 μM and prolongation of the QT interval at ≥ 10 μM. Since information is limited regarding the in vivo electrophysiological effects of cyproheptadine, we assessed it using the halothane-anesthetized guinea-pig model, which was compared with effects of another antihistamine drug, hydroxyzine. Sub-therapeutic to therapeutic doses of hydroxyzine at 1 and 10 mg/kg, i.v. prolonged the QT interval and duration of monophasic action potential, whereas therapeutic to supra-therapeutic doses of cyproheptadine at 0.1 and 1 mg/kg, i.v. hardly affected the indices of ventricular repolarization. These results suggest that cyproheptadine may be categorized into antihistamines with little effect on the ventricular repolarization.

  8. Risk assessment and experimental design in the development of a prolonged release drug delivery system with paliperidone.

    PubMed

    Iurian, Sonia; Turdean, Luana; Tomuta, Ioan

    2017-01-01

    This study focuses on the development of a drug product based on a risk assessment-based approach, within the quality by design paradigm. A prolonged release system was proposed for paliperidone (Pal) delivery, containing Kollidon(®) SR as an insoluble matrix agent and hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), or sodium carboxymethyl cellulose as a hydrophilic polymer. The experimental part was preceded by the identification of potential sources of variability through Ishikawa diagrams, and failure mode and effects analysis was used to deliver the critical process parameters that were further optimized by design of experiments. A D-optimal design was used to investigate the effects of Kollidon SR ratio (X1), the type of hydrophilic polymer (X2), and the percentage of hydrophilic polymer (X3) on the percentages of dissolved Pal over 24 h (Y1-Y9). Effects expressed as regression coefficients and response surfaces were generated, along with a design space for the preparation of a target formulation in an experimental area with low error risk. The optimal formulation contained 27.62% Kollidon SR and 8.73% HPMC and achieved the prolonged release of Pal, with low burst effect, at ratios that were very close to the ones predicted by the model. Thus, the parameters with the highest impact on the final product quality were studied, and safe ranges were established for their variations. Finally, a risk mitigation and control strategy was proposed to assure the quality of the system, by constant process monitoring.

  9. An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens.

    PubMed

    Nagai, Noriaki; Mano, Yu; Ito, Yoshimasa

    2016-01-01

    Disulfiram (DSF) is a dimer of diethyldithiocarbamate (DDC) that we previously added to a solution of 2-hydroxypropyl-β-cyclodextrin (DSF solution). We found that the instillation of this DSF solution delayed lens opacification in a hereditary cataractous ICR/f rat. In this study, we attempted to design an ophthalmic formulation containing DSF nanoparticles for use as a lens targeted drug delivery system (nano-DSF suspension), and investigated the changes in drug content in the lens after the instillation of DSF solution or nano-DSF suspension. The nano-DSF suspension was prepared by a bead mill method to yield a mean particle size of nano-DSF of 181 nm. Following the instillation of 1.4% DSF solution or the nano-DSF suspension, DDC was detected only in the aqueous humor and lens; in both, the area under the curve (AUC) and mean residence time (MRT) for the nano-DSF suspension were higher than for the DSF solution. In addition, we found that the DDC residence time in the cortex and nucleus of the lens was higher than in the capsule-epithelium. Although DDC was not detected in the cortex and nucleus of lenses following the instillation of the 1.4% DSF solution, the instillation of a 1.4% nano-DSF suspension led to the accumulation of DDC in both areas. In conclusion, it is possible that the instillation of a nano-DSF suspension can supply more DDC into the aqueous humor and lens than a conventional formulation, and these findings provide information significant for the prevention of cataracts and the design of a lens targeted drug delivery system.

  10. Tolerability and Plasma Drug Level Monitoring of Prolonged Subcutaneous Teicoplanin Treatment for Bone and Joint Infections

    PubMed Central

    Bennis, Youssef; Diouf, Momar; Saroufim, Carlo; Brunschweiler, Benoit; Rousseau, Florence; Joseph, Cédric; Hamdad, Farida; Ait Amer Meziane, Mohamed; Routier, Simon; Schmit, Jean-Luc

    2016-01-01

    Teicoplanin is a key drug for the treatment of multiresistant staphylococcal bone and joint infections (BJI), yet can only be administered via a parenteral route. The objective of this study was to evaluate the safety and tolerability of subcutaneous (s.c.) teicoplanin for that indication over 42 days. Thirty patients with Gram-positive cocci BJI were included. Once the target of 25 to 40 mg/liter trough serum concentration was achieved, treatment was switched from an intravenous to an s.c. route. No discontinuation of teicoplanin related to injection site reaction and no severe local adverse event were observed. On multivariate analysis, better tolerability was observed at the beginning of treatment, in patients over 70 years old, and for dosages less than 600 mg. In conclusion, we recommend s.c. administration of teicoplanin when needed. PMID:27458228

  11. [Consequences of prolonged use of psychoactive drugs. Substitute natural treatment and individual psychotherapy].

    PubMed

    Cugurra, F

    1994-10-01

    The history of psychopharmacology shows the differences existing between various groups of substances, natural, and more recent synthetic ones. At present, benzodiazepine anxiolytic agents are being singled out for their abuse and addiction potential. There has been a return to and widespread use of traditional natural therapies and more modern psychotherapy. Patients are more than every wary of synthetic agents. The production of herbal substances is nowdays organized on an industrial scale. The properties of "alternative" herbal agents are illustrated that have been known for centuries and are now studied with the methods of biochemistry. A large number of studies are concerned in several countries with the actions of traditional plants. The WHO encourages this tendency which in some countries has attained official status in schools of medicine, and amounts to a marked reduction in the cost of health. Nevertheless, the past and present importance of the research on synthetic drugs (antibiotics, and even psychoactive substances) cannot be denied. The attention of science in this field is aimed at finding new molecules that are possibly free of addictive properties but are effective in behavioral therapy. A recent example is buspirone. Finally, a psychotherapeutic method is briefly described. In his comment and conclusions the author poses important questions concerning the organization of medical and pharmaceutic studies in the near future.

  12. A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

    PubMed

    Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Raymond; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

    2017-02-17

    Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve

  13. Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets.

    PubMed

    Devjak Novak, S; Šporar, E; Baumgartner, S; Vrečer, F

    2012-07-01

    The key physicochemical properties of functional excipients should be identified, and the influence of their variability on the properties of the final dosage form should be evaluated during the development phase. Excipients produced by different manufacturers and/or by different manufacturing processes should have comparable properties. Hydroxypropyl methylcellulose (HPMC) with a high molecular weight is a functional excipient often used in solid matrix systems with prolonged release of active pharmaceutical ingredients (API). This study investigates whether HPMC manufactured by two manufacturers using different chemical procedures differs in particle-size distribution, particle shape, particle morphology, chemical composition, and dissolution of diclofenac sodium as a model drug. NIR spectroscopy was introduced and calibration models were developed to detect physical differences among HPMC batches from two different origins. The physical differences between HPMC samples were additionally confirmed with scanning electron microscopy (SEM), gas chromatography (GC) measurements, and dissolution testing of hydrophilic matrix tablets. Our results prove that, even if HPMC polymers manufactured from two different sources comply with the pharmacopeial specification, they significantly differ in physicochemical properties and thus influence the properties of the formulated dosage forms.

  14. Polymeric drugs with prolonged sustained delivery of specific anti-aggregant agents for platelets: kinetic analysis of the release mechanism.

    PubMed

    Gallardo, Alberto; Rodríguez, Gema; Fernández, Mar; Aguilar, María Rosa; San Román, Julio

    2004-01-01

    The in vitro aqueous behaviour of a metacryloyloxyethyl [2-(acetyloxy)-4-(trifluoromethyl)]benzoate (THEMA)/N,N'-dimethylacrylamide (DMA) copolymer with a THEMA molar content of 39% (labeled THDMA39) has been investigated. This composition has been selected to achieve a system able to keep both the non-water solubility during the release and the resorbability (and the water solubility) after the completion of the drug release. This copolymer exhibited, at pH 7.4, a constant release during several months, very interesting for a long term treatments required for the application of some cardiovascular devices. A kinetic model has been developed to explain the pseudo-zero-order kinetics of the release process. This model, which considers (from the aqueous studies) a linear increase with time of the amount of water present in the polymeric matrix, has been able to fit adequately the experimental data.

  15. Impact of Prolonged Cannabinoid Excretion in Chronic Daily Cannabis Smokers’ Blood on Per Se Drugged Driving Laws

    PubMed Central

    Bergamaschi, Mateus M.; Karschner, Erin L.; Goodwin, Robert S.; Scheidweiler, Karl B.; Hirvonen, Jussi; Queiroz, Regina H.C.; Huestis, Marilyn A.

    2013-01-01

    BACKGROUND Cannabis is the illicit drug most frequently reported with impaired driving and motor vehicle accidents. Some “per se” laws make it illegal to drive with any amount of drug in the body, while others establish blood, saliva, or urine concentrations above which it is illegal to drive. The persistence of Δ9-tetrahydrocannabinol (THC) in chronic daily cannabis smokers’ blood is unknown. METHODS Thirty male chronic daily cannabis smokers resided on a secure research unit for up to 33 days, with daily blood collection. Samples were processed in an ice bath during sample preparation to minimize cannabinoid adsorption onto precipitant material. We quantified THC by 2-dimensional GC-MS. RESULTS Of the 30 participants, 27 were THC-positive on admission, with a median (range) concentration of 1.4 μg/L (0.3–6.3). THC decreased gradually; only 1 of 11 participants was negative at 26 days, 2 of 5 remained THC-positive (0.3 μg/L) for 30 days, and 5.0% of participants had THC ≥1.0 μg/L for 12 days. Median 11-hydroxy-THC concentrations were 1.1 μg/L on admission, with no results ≥1.0 μg/L 24 h later. 11-Nor-9-carboxy-THC (THCCOOH) detection rates were 96.7% on admission, decreasing slowly to 95.7% and 85.7% on days 8 and 22, respectively; 4 of 5 participants remained THCCOOH positive (0.6–2.7 μg/L) after 30 days, and 1 remained positive on discharge at 33 days. CONCLUSIONS Cannabinoids can be detected in blood of chronic daily cannabis smokers during a month of sustained abstinence. This is consistent with the time course of persisting neurocognitive impairment reported in recent studies. PMID:23449702

  16. In vivo evaluation of a biodegradable donut-shaped minitablet for prolonged posterior segment drug delivery in the rabbit eye model.

    PubMed

    Choonara, Yahya E; Pillay, Viness; Danckwerts, Michael Paul; Carmichael, Trevor R; Meyer, Leith C R; Du Toit, Lisa C; Naylor, Simon; Wanblad, Carla

    2011-05-01

    This study focused on the in vivo evaluation of a biodegradable ganciclovir-loaded donut-shaped minitablet (DSMT) for controlled drug delivery in the New Zealand white albino rabbit eye model. Specialized tablet tooling was used to manufacture a poly(lactic-co-glycolic acid) DSMT device that was implanted into 18 rabbits through the pars plana/peripheral retina of the right eyes of each rabbit. The left eyes were used as controls. Possible adverse effects on ocular tissues were assessed by histomorphology, slit-lamp biomicroscopy, intraocular pressure (IOP) measurements, and indirect ophthalmoscopy. The ex vivo microenvironmental vitreous pH was also monitored. Rabbits were euthanized at predetermined intervals and the residual devices, vitreous humor, and ocular tissue were retrieved and stored appropriately until further analysis. The DSMT was well tolerated up to 72 days and was still visible in the superotemporal quadrant of the eye. The mean IOP range (6-8 mmHg; N = 18) and changes in vitreous pH (7.25 ± 0.01; N = 3) correlated with baseline measurements. The DSMT displayed constant ganciclovir release at a rate of 2.02 μ g/h maintained within the 50% effective dose for human cytomegalovirus retinitis (N = 3). The design simplicity and application of the biodegradable DSMT device may provide a superior alternative for prolonged rate-controlled intraocular drug delivery.

  17. Effect of patient characteristics on the yield of prolonged baseline head-up tilt testing and the additional yield of drug provocation.

    PubMed Central

    Fitzpatrick, A. P.; Lee, R. J.; Epstein, L. M.; Lesh, M. D.; Eisenberg, S.; Sheinman, M. M.

    1996-01-01

    OBJECTIVE: To define the value of tilt testing and hte additional yield of drug provocation over prolonged baseline tilt in different patient subgroups. (Many different protocols are in use for head-up tilt testing in heterogeneous groups of patients. Not all patients in reported series have recurrent syncope, and there is often a wide age range and a variable incidence of structural heart disease.) DESIGN: In a prospective study, baseline 60 degrees head-up tilt testing was undertaken for 45 minutes, initially without drug provocation. Patients who remained symptom free were given intravenous isoprenaline (isoproterenol) and further tilting or edrophonium (10 mg bolus) during tilt, in an order determined randomly before the start of the test. If they were symptom free after the first drug, they were given the other drug. A positive test was recorded when syncope or pre-syncope occurred with a rapid fall (> 30%) in blood pressure. The impact on tilt result of the type of symptoms, presence of significant structural heart disease (SHD), presence of a non-cardiovascular cause of sudden diminished consciousness (SDC), and age was then assessed by subgroup analysis. PATIENTS: 145 patients (73 female, mean age 51 (25), range 8-94) with one or more episodes of pre-syncope or syncope. RESULTS: 39 patients (27%, 21 female, age 49 (25) years) had positive tests and 106 (73%, 52 female, age 52 (25) years) negative tests. 27 (69%) had a positive test during baseline tilt at 20.5 (10.8) minutes, five (13%) with isoprenaline infusion, and seven (18%) with edrophonium bolus. Patients with recurrent syncope rather than single syncopal episodes or single or recurrent pre-syncope were more likely to have a positive tilt test (41% v 17%, P < 0.005) and patients with SHD or SDC (69/14 patients) were much less likely than patients without (16% v 42%, P < 0.0001). The yield of positive tests was similar if patients were below (26%) or above (27%) the mean age (50 years). When multiple

  18. CD4+Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZBxNZW) F1 lupus mice

    PubMed Central

    2013-01-01

    Introduction The ability to ameliorate murine lupus renders regulatory T cells (Treg) a promising tool for the treatment of systemic lupus erythematosus (SLE). In consideration to the clinical translation of a Treg-based immunotherapy of SLE, we explored the potential of CD4+Foxp3+ Treg to maintain disease remission after induction of remission with an established cyclophosphamide (CTX) regimen in lupus-prone (NZBxNZW) F1 mice. As a prerequisite for this combined therapy, we also investigated the impact of CTX on the biology of endogenous Treg and conventional CD4+ T cells (Tcon). Methods Remission of disease was induced in diseased (NZBxNZW) F1 mice with an established CTX regimen consisting of a single dose of glucocorticosteroids followed by five day course with daily injections of CTX. Five days after the last CTX injection, differing amounts of purified CD4+Foxp3+CD25+ Treg were adoptively transferred and clinical parameters, autoantibody titers, the survival and changes in peripheral blood lymphocyte subsets were determined at different time points during the study. The influence of CTX on the numbers, frequencies and proliferation of endogenous Treg and Tcon was analyzed in lymphoid organs by flow cytometry. Results Apart from abrogating the proliferation of Tcon, we found that treatment with CTX induced also a significant inhibition of Treg proliferation and a decline in Treg numbers in lymphoid organs. Additional adoptive transfer of 1.5 × 106 purified Treg after the CTX regimen significantly increased the survival and prolonged the interval of remission by approximately five weeks compared to mice that received only the CTX regimen. The additional clinical amelioration was associated with an increase in the Treg frequency in the peripheral blood indicating a compensation of CTX-induced Treg deficiency by the Treg transfer. Conclusions Treg were capable to prolong the interval of remission induced by conventional cytostatic drugs. This study provides

  19. The biological effect of prolonged radiation and ways of selecting new anti-radiation drugs effective in this kind of radiation injury

    NASA Technical Reports Server (NTRS)

    Rogozkin, V. D.; Chertkov, K. S.; Nikolov, I.

    1974-01-01

    The basic characteristics of prolonged radiation - increased tolerance of radiation injury - are attributed to cellular kinetics; as dose rate is reduced, the population rate is not disturbed, particularly that of stem cells which makes it possible for the organism to tolerate higher radiation loads. It is concluded that this effect makes approved radio protectors, whose effect contains an established cytostatic component, unsuitable for prolonged radiation. It is better to correct the stem pool formation process by either accelerating the proliferation of cells or limiting the effect of stimuli causing cells to lose colony forming properties.

  20. Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations.

    PubMed

    Brvar, Nina; Mateović-Rojnik, Tatjana; Grabnar, Iztok

    2014-10-01

    This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation.

  1. Microsphere-integrated drug-eluting stents: PLGA microsphere integration in hydrogel coating for local and prolonged delivery of hydrophilic antirestenosis agents.

    PubMed

    Indolfi, Laura; Causa, Filippo; Giovino, Concetta; Ungaro, Francesca; Quaglia, Fabiana; Netti, Paolo Antonio

    2011-05-01

    The development of a novel generation of drug-eluting stent (DES) relies upon the idea to obtain very flexible platforms able to overcome some issues associated to available devices and widen their field of application, especially to the currently emerging biotech therapeutics. Here, we propose a new concept of DES named microsphere-integrated drug-eluting stent (MIDES) composed of drug eluting biodegradable poly(D,L-lactide-co-glycolide) microspheres--encapsulating an hydrophilic model molecule (dextran)--fully integrated in a poly(2-hydroxy-ethyl-methacrylate) coating. By implementing a modified spray-coating technique, we have been able to achieve a thin (10 μm), smooth, and homogeneous hydrogel surface embedding underneath a population of two different microparticles formulations--Dex502H and Dex506. The amount of drug can be tailored, resulting in a dextran loading as high as 1.4 μg/cm, by simply reiteration of coating layer deposition making the MIDES a custom-made device where the release kinetics can be further modified by opportunely choosing microsphere properties. DES use is nowadays restricted to delivery of hydrophobic pharmaceuticals; release of hydrophilic therapeutics from MIDES can, however, be finely controlled by specifically engineering biodegradable microspheres. By varying polymer resomer, we obtained a tunable release rate in the first month of delivery. Depending on the microspheres properties release profile changes drastically moving from a biphasic release, in the case of Dex502H, with a burst of about 20% in the first day to a more sustained release for Dex506 particles. As proof of principle, we also demonstrated that MIDES approach can allows the delivery of two different agents opening up the way to a multitherapy in restenosis treatment.

  2. Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii.

    PubMed

    Durante-Mangoni, Emanuele; Del Franco, Mariateresa; Andini, Roberto; Bernardo, Mariano; Giannouli, Maria; Zarrilli, Raffaele

    2015-07-01

    The spread of extensively drug-resistant (XDR) gram-negative bacteria has boosted colistin use, with a resultant selection of colistin-resistant, often pandrug-resistant strains. Whether acquisition of further resistance mechanisms translates into a reduced virulence is the subject of active research. In this report, we describe clinical features of an immunocompromised patient who developed infection due to colistin-resistant Acinetobacter baumannii while on long-term colistin therapy. We analyzed phenotypic and genotypic characteristics, molecular mechanisms of colistin resistance, and in vitro and in vivo fitness of sequential colistin-sensitive and colistin-resistant strains isolated from the patient. Both colistin-sensitive and colistin-resistant strains were XDR and showed identical ST78 genotype. At variance with prior reports on colistin-resistant strains of A. baumannii, resistance to colistin due to P233S mutation in PmrB sensor kinase did not associate with any measurable reduction in strain fitness, growth characteristics, and virulence.

  3. Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

    PubMed Central

    Vexler, Vladimir; Yu, Li; Pamulapati, Chandrasena; Garrido, Rosario; Grimm, Hans Peter; Sriraman, Priya; Bohini, Sandhya; Schraeml, Michael; Singh, Usha; Brandt, Michael; Ries, Stefan; Ma, Han; Klumpp, Klaus; Ji, Changhua

    2013-01-01

    CD81 is an essential receptor for hepatitis C virus (HCV). K21 is a novel high affinity anti-CD81 antibody with potent broad spectrum anti-HCV activity in vitro. The pharmacokinetics (PK), pharmacodynamics and liver distribution of K21 were characterized in cynomolgus monkeys after intravenous (i.v.) administration of K21. Characteristic target-mediated drug disposition (TMDD) was shown based on the PK profile of K21 and a semi-mechanistic TMDD model was used to analyze the data. From the TMDD model, the estimated size of the total target pool at baseline (Vc • Rbase) is 16 nmol/kg and the estimated apparent Michaelis-Menten constant (KM) is 4.01 nM. A simulation using estimated TMDD parameters indicated that the number of free receptors remains below 1% for at least 3 h after an i.v. bolus of 7 mg/kg. Experimentally, the availability of free CD81 on peripheral lymphocytes was measured by immunostaining with anti-CD81 antibody JS81. After K21 administration, a dose- and time-dependent reduction in free CD81 on peripheral lymphocytes was observed. Fewer than 3% of B cells could bind JS81 3 h after a 7 mg/kg dose. High concentrations of K21 were found in liver homogenates, and the liver/serum ratio of K21 increased time-dependently and reached ~160 at 168 h post-administration. The presence of K21 bound to hepatocytes was confirmed by immunohistochemistry. The fast serum clearance of K21 and accumulation in the liver are consistent with TMDD. The TMDD-driven liver accumulation of the anti-CD81 antibody K21 supports the further investigation of K21 as a therapeutic inhibitor of HCV entry. PMID:23924796

  4. Prolonged Antibiotic Use Tied to Precancerous Colon Growths

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_164445.html Prolonged Antibiotic Use Tied to Precancerous Colon Growths Drugs that ... 2017 TUESDAY, April 4, 2017 (HealthDay News) -- Taking antibiotics for an extended period in early to middle ...

  5. Early Clinical Experience with a Polymer-Free Biolimus A9 Drug-Coated Stent in DES-Type Patients Who Are Poor Candidates for Prolonged Dual Anti-Platelet Therapy

    PubMed Central

    Kinnaird, Tim; Butt, Mehmood; Abdul, Fairoz; Yazji, Khaled; Hailan, Ahmed; Gallagher, Sean; Ossei-Gerning, Nicholas; Chase, Alexander; Choudhury, Anirban; Smith, David; Anderson, Richard

    2016-01-01

    Introduction Prolonged dual anti-platelet therapy (DAPT) may cause excess bleeding in certain patients. The biolimus-A9 drug-coated stent (BA9-DCS) has a rapid drug-elution profile allowing shortened DAPT. Data were gathered on the early experience implanting this stent in drug-eluting stent eligible patients deemed to be at high risk of bleeding. Background and Methods The demographics, procedural data and clinical outcomes were gathered prospectively for 249 patients treated with a BA9-DCS stent at 2 UK centres, and compared to a cohort of patients treated in the same period with drug-eluting stents (PCI-DES). Results Operator-defined BA9-DCS indications included warfarin therapy, age, and anaemia. Patients receiving a BA9-DCS were older (71.6±11.8 vs. 64.8±11.6yrs, p<0.001), more often female (38.2 vs. 26.8%, P<0.001), and more likely to have comorbidity including chronic kidney disease or poor LV function than PCI-DES patients. The baseline Mehran bleed risk score was also significantly higher in the BA9-DCS group (19.4±8.7 vs. 13.1±5.8, p<0.001). Of the BA9-DCS cohort, 95.5% of patients demonstrated disease fitting NICE criteria for DES placement. The number of lesions treated (1.81±1.1 vs. 1.58±0.92, p = 0.003), total lesion length (32.1±21.7 vs. 26.1±17.6mm, p<0.001), number of stents used (1.93±1.11 vs. 1.65±1.4, p = 0.007) and total stent length (37.5±20.8 vs. 32.4±20.3, p<0.01) were greater for BA9-DCS patients. DAPT was prescribed for 3.3±3.9 months for BA9-DCS patients and 11.3±2.4 months for PCI-DES patients (p<0.001). At follow up of 392±124 days despite the abbreviated DAPT course stent related event were infrequent with ischemia-driven restenosis PCI (2.8 vs. 3.4%, p = 0.838), and stent thrombosis (1.6 vs. 2.1%, p = 0.265) rates similar between the BA9-DCS ad PCI-DES groups. After propensity scoring all clinical end-points were similar between both cohorts. Conclusions This early experience using polymer-free BA9 drug-coated stents in

  6. Management of children with prolonged diarrhea

    PubMed Central

    Giannattasio, Antonietta; Guarino, Alfredo; Lo Vecchio, Andrea

    2016-01-01

    Prolonged diarrhea is usually defined as acute-onset diarrhea lasting 7 days or more, but less than 14 days. Its trend has been declining in recent years because of improvement in the management of acute diarrhea, which represents the ideal strategy to prevent prolonged diarrhea. The pathogenesis of prolonged diarrhea is multifactorial and essentially based on persistent mucosal damage due to specific infections or sequential infections with different pathogens, host-related factors including micronutrient and/or vitamin deficiency, undernutrition and immunodeficiency, high mucosal permeability due to previous infectious processes and nutrient deficiency with consequential malabsorption, and microbiota disruption. Infections seem to play a major role in causing prolonged diarrhea in both developing and developed areas. However, single etiologic pathogens have not been identified, and the pattern of agents varies according to settings, host risk factors, and previous use of antibiotics and other drugs. The management of prolonged diarrhea is complex. Because of the wide etiologic spectrum, diagnostic algorithms should take into consideration the age of the patient, clinical and epidemiological factors, and the nutritional status and should always include a search for enteric pathogens. Often, expensive laboratory evaluations are of little benefit in guiding therapy, and an empirical approach may be effective in the majority of cases. The presence or absence of weight loss is crucial for driving the initial management of prolonged diarrhea. If there is no weight loss, generally there is no need for further evaluation. If weight loss is present, empiric anti-infectious therapy or elimination diet may be considered once specific etiologies have been excluded. PMID:26962439

  7. Physiology of prolonged bed rest

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.

    1988-01-01

    Bed rest has been a normal procedure used by physicians for centuries in the treatment of injury and disease. Exposure of patients to prolonged bed rest in the horizontal position induces adaptive deconditioning responses. While deconditioning responses are appropriate for patients or test subjects in the horizontal position, they usually result in adverse physiological responses (fainting, muscular weakness) when the patient assume the upright posture. These deconditioning responses result from reduction in hydrostatic pressure within the cardiovascular system, virtual elimination of longitudinal pressure on the long bones, some decrease in total body metabolism, changes in diet, and perhaps psychological impact from the different environment. Almost every system in the body is affected. An early stimulus is the cephalic shift of fluid from the legs which increases atrial pressure and induces compensatory responses for fluid and electrolyte redistribution. Without countermeasures, deterioration in strength and muscle function occurs within 1 wk while increased calcium loss may continue for months. Research should also focus on drug and carbohydrate metabolism.

  8. Deciding about treatments that prolong life

    MedlinePlus

    Palliative care - treatments that prolong life; Palliative care - life support; End-of-life-treatments that prolong life; Ventilator - treatments that prolong life; Respirator - treatments that prolong life; Life-support - treatments ...

  9. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  10. Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

    PubMed Central

    Lee, Hae Won; Lim, Mi-sun; Seong, Sook Jin; Seo, Jeong Ju; Kim, Eun-Jung; Kang, Wonku; Yoon, Young-Ran

    2013-01-01

    Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography–mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5′-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose. PMID:23593245

  11. Cetirizine and loratadine: minimal risk of QT prolongation.

    PubMed

    2010-02-01

    Some antihistamines, such as mizolastine and ebastine, can prolong the QT interval and provoke severe cardiac arrhythmias. This review examines the effects of two widely used antihistamines, cetirizine and loratadine, on the QT interval. As of mid 2009 very few clinical data had been published on the risk of QT prolongation with cetirizine or loratadine. The very rare reported cases of torsades de pointes linked to loratadine mainly appear to involve drug interactions, especially with amiodarone and enzyme inhibitors. We found no reports of QT prolongation attributed to desloratadine, the main metabolite of loratadine. Two cases of QT prolongation with cetirizine have been published, one of which involved overdose and renal failure. The reports are too vague to conclude that cetirizine was implicated. We found no reports of QT prolongation attributed to levocetirizine. Cetirizine is a metabolite of hydroxyzine, another antihistamine. In the 1960s, a study of patients with psychosis showed a risk of QT prolongation. A case of recurrent syncope with QT prolongation has since been reported, along with rare cases of cardiac arrhythmia. In practice, cetirizine and loratadine are first-line antihistamines. However, caution is needed in certain circumstances. In particular, it is best that patients who have risk factors for torsades de pointes or who are taking certain enzyme inhibitors avoid using loratadine. It is best to avoid using cetirizine in cases of renal failure.

  12. Inhibition in Prolonged Work Tasks.

    ERIC Educational Resources Information Center

    van der Ven, A. H. G. S.; And Others

    1989-01-01

    A new model is presented that explains reaction time fluctuations in prolonged work tasks. The model extends the so-called Poisson-Erlang model and accounts for long-term trend effects in the reaction time curve. The model is consistent with Spearman's hypothesis that inhibition increases during work and decreases during rest. (TJH)

  13. Physiology Of Prolonged Bed Rest

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    1991-01-01

    Report describes physiological effects of prolonged bed rest. Rest for periods of 24 hours or longer deconditions body to some extent; healing proceeds simultaneously with deconditioning. Report provides details on shifts in fluid electrolytes and loss of lean body mass, which comprises everything in body besides fat - that is, water, muscle, and bone. Based on published research.

  14. QTc interval prolongation in patients with HIV and AIDS.

    PubMed Central

    Sani, Mahmoud U.; Okeahialam, Basil N.

    2005-01-01

    A higher prevalence of QT prolongation has been reported among HIV/AIDS patients, possibly related to drugs prescribed for them or to an acquired form of long QT syndrome. A prolonged QTc is a predictor of cardiovascular mortality. We set out to study this interval in a group of AIDS patients. One-hundred consecutive AIDS patients admitted into the Jos University Teaching Hospital and who satisfied the inclusion criteria were recruited. All were evaluated for symptomatology of cardiovascular disease and had a 12-lead surface electrocardiogram recording. QT interval, taken from the onset of the QRS complex to the end of the T wave, was corrected for heart rate. Eighty HIV-negative, healthy persons and 78 HIV-positive, asymptomatic subjects were used as controls. Forty-five percent of the AIDS patients had prolonged QTc interval. Prolonged QTc was present in 28% of HIV-positive controls and 10% of HIV-negative controls. The mean QTc interval differs significantly between the AIDS patients and the two control groups. From our study, Nigerian HIV-positive asymptomatic subjects have higher prevalence of QTc prolongation compared to HIV-negative subjects and, as they move to AIDS, the prevalence of QTc prolongation increases. This makes for increased cardiovascular mortality. PMID:16396057

  15. Bilateral Scapulohumeral Ankylosis after Prolonged Mechanical Ventilation

    PubMed Central

    Schreinemakers, J. Rieneke; van Noort, Arthur; Rademakers, Maarten V.

    2016-01-01

    This case demonstrates a rarely reported bilateral scapulohumeral bony ankylosis. A young woman developed extensive heterotopic ossifications (HOs) in both shoulder joints after being mechanically ventilated for several months at the intensive care unit in a comatose status. She presented with a severe movement restriction of both shoulder joints. Surgical resection of the bony bridges was performed in 2 separate sessions with a significant improvement of shoulder function afterwards. No postoperative complications, pain, or recurrence of HOs were noted at 1-year follow-up. Mechanical ventilation, immobilization, neuromuscular blockage, and prolonged sedation are known risk factors for the development of HOs in the shoulder joints. Relatively early surgical resection of the HOs can be performed safely in contrary to earlier belief. Afterwards, nonsteroidal anti-inflammatory drugs and/or radiation therapy can be possible treatment modalities to prevent recurrence of HOs. PMID:27583120

  16. Prolonged cholestasis and ductopenia associated with tenoxicam.

    PubMed

    Trak-Smayra, Viviane; Cazals-Hatem, Dominique; Asselah, Tarik; Duchatelle, Veronique; Degott, Claude

    2003-07-01

    Cholestatic liver diseases leading to progressive destruction of intra-hepatic bile ducts and ductopenia encompass multiple etiologies. Pathophysiology and natural history of drug-induced cholangiopathies remain unclear. We report a case of prolonged ductopenia attributed to Tenoxicam (Tilcotil o--a non-steroidal anti-inflammatory drug of the oxicam family) ingested at therapeutic dose. A 36 year-old male patient was admitted for jaundice and Lyell syndrome starting 1 week after the ingestion of Tenoxicam. Liver biopsy showed cholestasis, non-suppurative cholangitis and polymorphous inflammatory infiltrate of the portal tracts (round cells, macrophages an eosinophils). Treatment with ursodesoxycholic acid and cholestyramine was instituted and the patient was asymptomatic 1 year after. Three years later mild biological cholestasis persisted and ductopenia was evidenced on liver biopsy. In this report we found that: (1) The toxicity of tenoxicam was probably mediated by an immunoallergic mechanism (Lyell syndrome and eosinophils on histology); (2) ductopenia was secondary to inflammatory cholangitis. Factors responsible for this chronic evolution are still unknown (genetic predisposition, vascular factors, etc.); and (3) the presence of ductopenia contrasted with the "clinical recovery" of the disease suggesting accessory bile drainage by cholangioles or partial reconstruction of the biliary tree.

  17. Prolonged and tunable residence time using reversible covalent kinase inhibitors

    PubMed Central

    Bradshaw, J. Michael; McFarland, Jesse M.; Paavilainen, Ville O.; Bisconte, Angelina; Tam, Danny; Phan, Vernon T.; Romanov, Sergei; Finkle, David; Shu, Jin; Patel, Vaishali; Ton, Tony; Li, Xiaoyan; Loughhead, David G.; Nunn, Philip A.; Karr, Dane E.; Gerritsen, Mary E.; Funk, Jens Oliver; Owens, Timothy D.; Verner, Erik; Brameld, Ken A.; Hill, Ronald J.; Goldstein, David M.; Taunton, Jack

    2015-01-01

    Drugs with prolonged, on-target residence time often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here, we demonstrate progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Utilizing an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrate biochemical residence times spanning from minutes to 7 days. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK more than 18 hours after clearance from the circulation. The inverted cyanoacrylamide strategy was further utilized to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating generalizability of the approach. Targeting noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates “residence time by design”, the ability to modulate and improve the duration of target engagement in vivo. PMID:26006010

  18. Moving frames and prolongation algebras

    NASA Technical Reports Server (NTRS)

    Estabrook, F. B.

    1982-01-01

    Differential ideals generated by sets of 2-forms which can be written with constant coefficients in a canonical basis of 1-forms are considered. By setting up a Cartan-Ehresmann connection, in a fiber bundle over a base space in which the 2-forms live, one finds an incomplete Lie algebra of vector fields in the fields in the fibers. Conversely, given this algebra (a prolongation algebra), one can derive the differential ideal. The two constructs are thus dual, and analysis of either derives properties of both. Such systems arise in the classical differential geometry of moving frames. Examples of this are discussed, together with examples arising more recently: the Korteweg-de Vries and Harrison-Ernst systems.

  19. Use of in vitro methods to predict QT prolongation

    SciTech Connect

    Hammond, T.G. . E-mail: tim.hammond@astrazeneca.com; Pollard, C.E.

    2005-09-01

    The inhibition of the hERG-encoded potassium channel can lead to prolongation of the cardiac action potential-manifested as a prolongation of the QT interval on the ECG. Although QT interval prolongation is not dangerous per se, in a small percentage of cases, it is associated with a potentially fatal arrhythmia: Torsades de Pointes (TdP). This channel type is pharmacologically promiscuous, so many compounds have caused QT interval prolongation in man and this has led to drugs being withdrawn from the market following evidence of TdP. From a drug discovery perspective, focusing as early as possible on screening out hERG activity is important. Retrospective analysis of hERG potency versus clinical incidence of TdP suggests provisional safety margins that could be used as target values by medicinal chemists. Large safety margins will not always be possible; however, and in such circumstances, if the risk-benefit ratio still favours developing the compound, a pre-clinical assessment of the likelihood that any QT interval prolongation will or will not lead to TdP in man may be important. An isolated rabbit heart model of arrhythmia shows promise in this respect, based on a comparison of clinical data with that obtained from this assay. Specific regulatory guidance on this topic is still in the draft form but the pre-clinical document (ICH S7B) contains a largely useful perspective on how an integrated risk assessment could be formed using in vitro and in vivo assays. The role of this document is evolving however, since the draft clinical guideline (E14) suggests that irrespective of the pre-clinical data, a thorough clinical ECG study will be required at some point during development.

  20. Frequency and cause of transient QT prolongation after surgery.

    PubMed

    Joyce, Daniel D; Bos, J Martijn; Haugaa, Kristina H; Tarrell, Robert F; Morlan, Bruce W; Caraballo, Pedro J; Ackerman, Michael J

    2015-11-15

    Patients undergoing surgery are often exposed to QT-inciting factors that may increase the risk for complications. We evaluated the clinical characteristics and outcomes of patients with QTc ≥500 ms within the first 24 hours after surgery as identified by an institution-wide electrocardiogram alert system. From November 2010 to June 2011, 470 patients exhibited an electrocardiographically isolated QTc ≥500 ms. QT prolongation after surgery was the setting for >1 of every 10 QTc alerts (59 patients). We determined the presence of QT prolonging medical conditions, drugs, electrolyte abnormalities, and the surgical patient's clinical outcome. The average preoperative QTc of the 59 patients demonstrating perioperative QT prolongation was 463 ± 56 ms with a postoperative QTc increase of 54 ± 37 ms. Most patients (n = 48, 83%) had ≥1 known QT-inciting factor before surgery. Compared with presurgical findings, there was a significant increase in pro-QTc score after surgery (1.8 ± 1.5 vs 3.5 ± 2.0, p <0.01) indicating a greater burden of perioperative QT-inciting factors. In conclusion, nearly all cases of QT prolongation could be explained by known etiologic or iatrogenic factors suggesting that maladaptive cardiac repolarization is most likely not a transient, postoperative stress response and may be avoided by altering clinical management.

  1. Prolonged-release melatonin for children with neurodevelopmental disorders.

    PubMed

    De Leersnyder, Hélène; Zisapel, Nava; Laudon, Moshe

    2011-07-01

    Previous studies demonstrated the efficacy and safety of prolonged-release melatonin in children and adolescents with neurodevelopmental and behavioral disorders. The long-term effectiveness and safety of prolonged-release melatonin treatment were assessed in 88 children (42 girls and 46 boys) with neurodevelopmental disorders. These patients participated in a compassionate-use program with the drug Circadin (2 mg; Neurim Pharmaceuticals, Tel Aviv, Israel) in France, and received treatment in the context of regular care by a specialized physician. The study involved a structured questionnaire for the parents, comprising a combination of multiple-choice and numeric questions addressing sleep onset/offset, sleep quality problems, and mood. The dose of melatonin ranged from 4-6 mg, and treatment duration ranged from 6-72 months. Within 3 months, sleep latency with prolonged-release melatonin decreased by 44.0% (P < 0.001), sleep duration increased by 10.1% (P < 0.001), the number of awakenings decreased by 75% (P < 0.001), and sleep quality improved by 75%, compared with baseline (P < 0.001). No serious adverse events or treatment-related comorbidities were reported. Prolonged-release melatonin remains a safe, effective therapy for the long-term treatment of sleep disorders in children with neurodevelopmental disorders.

  2. [A case of prolonged paroxysmal sympathetic hyperactivity].

    PubMed

    Yamamoto, Akiko; Ide, Shuhei; Iwasaki, Yuji; Kaga, Makiko; Arima, Masataka

    2016-03-01

    We report the case of a 4-year-old girl who presented with paroxysmal sympathetic hyperactivity (PSH), after developing severe hypoxic-ischemic-encephalopathy because of cardiopulmonary arrest. She showed dramatic paroxysmal sympathetic activity with dystonia. She was treated with wide variety of medications against PSH, which were found to be effective in previous studies. Among them, morphine, bromocriptine, propranolol, and clonidine were effective in reducing the frequency of her attacks while gabapentin, baclofen, dantrolene, and benzodiazepine were ineffective. Though the paroxysms decreased markedly after the treatment, they could not be completely controlled beyond 500 days. Following the treatment, levels of plasma catecholamines and their urinary metabolites decreased to normal during inter- paroxysms. However, once a paroxysm had recurred, these levels were again very high. This case study is considered significant for two rea- sons. One is that PSH among children have been rarely reported, and the other is that this case of prolonged PSH delineated the transition of plasma catecholamines during the treatment. The excitatory: inhibitory ratio (EIR) model proposed by Baguley was considered while dis- cussing drug sensitivity in this case. Accumulation of similar case studies will help establish more effective treatment strategies and elucidate the pathophysiology of PSH.

  3. Prolonged-release hard gelatin capsules of furosemide for the treatment of dogs.

    PubMed

    Smal, J; Haapala, O; Marvola, M; Kuusela, S; Happonen, I

    1995-02-01

    The object of this study was to examine whether prolonged-release hard gelatin capsule formulations could be developed for dogs. Different viscosity grades of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used to control drug release. Furosemide was chosen because of its wide use in the management of heart failure in dogs. In vitro, selecting different viscosity grades allowed good control of drug release, whereas in vivo the difference between formulations was clearly smaller. Although all formulations gave prolonged release, both inter- and intra-individual variation in the plasma concentration-time curves was high. It is difficult to develop prolonged-release formulations for drugs such as furosemide with highly variable pharmacokinetic properties. However, hard gelatin capsules containing hydrophilic polymers could still be a suitable choice for some drugs.

  4. The Effect of Ethanol on the Release of Opioids from Oral Prolonged-Release Preparations

    PubMed Central

    Walden, Malcolm; Nicholls, Fiona A.; Smith, Kevin J.; Tucker, Geoffrey T.

    2007-01-01

    Recent experience has prompted the US FDA to consider whether ethanol ingestion may modify the release characteristics of prolonged-release formulations, where dose dumping may be an issue for patient safety. The influence of ethanol on the in vitro release of opioid drugs from some prolonged-release formulations utilizing different release technologies was examined. Results indicated that the prolonged-release mechanisms remained intact under the testing conditions, although one product showed initial sensitivity to ethanol in its release characteristics. Nevertheless, in this case, extrapolation of the findings to likely outcome in vivo indicated no risk of dose-dumping. It is proposed that prolonged-release medicinal products should be tested during development to ensure robustness to the effects of ethanol on drug release. PMID:17882730

  5. Flakka-Induced Prolonged Psychosis

    PubMed Central

    2016-01-01

    In South Florida, there has been a highly addictive new synthetic drug flooding the streets for people looking for a cheap high. Alpha-PVP, better known as Flakka, is an illegal substance that sells on the streets for as little as $5 a hit and delivers an instant high that can last from hours to days with lingering effects for weeks after it has been ingested. Although people use Flakka for its potential euphoric high, symptoms are known to easily escalate into frightening delusions, paranoid psychosis, extreme agitation, and a multitude of other altered mental states. According to the National Institute on Drug Abuse, Florida appears to be the nation's hot spot for reports of Flakka. In this case report, a 17-year-old female with no prior psychiatric diagnosis presents to the hospital under a 72-hour involuntary placement for altered mental status with agitation and psychotic behaviors. After multiple days of symptomatic treatment with benzodiazepines and antipsychotics, the patient became coherent enough to give a history of a “friend” putting Flakka in her food at school as a joke. Although she continues to have residual symptoms including psychomotor agitation and slowing of cognition, she was alert, oriented, and able to be discharged home with proper follow-up. PMID:27418996

  6. Flakka-Induced Prolonged Psychosis.

    PubMed

    Crespi, Craig

    2016-01-01

    In South Florida, there has been a highly addictive new synthetic drug flooding the streets for people looking for a cheap high. Alpha-PVP, better known as Flakka, is an illegal substance that sells on the streets for as little as $5 a hit and delivers an instant high that can last from hours to days with lingering effects for weeks after it has been ingested. Although people use Flakka for its potential euphoric high, symptoms are known to easily escalate into frightening delusions, paranoid psychosis, extreme agitation, and a multitude of other altered mental states. According to the National Institute on Drug Abuse, Florida appears to be the nation's hot spot for reports of Flakka. In this case report, a 17-year-old female with no prior psychiatric diagnosis presents to the hospital under a 72-hour involuntary placement for altered mental status with agitation and psychotic behaviors. After multiple days of symptomatic treatment with benzodiazepines and antipsychotics, the patient became coherent enough to give a history of a "friend" putting Flakka in her food at school as a joke. Although she continues to have residual symptoms including psychomotor agitation and slowing of cognition, she was alert, oriented, and able to be discharged home with proper follow-up.

  7. [Patient safety: prescription of drugs that prolong the QT interval].

    PubMed

    Hernández-Arroyo, María Jesús; Díaz-Madero, Alfonso; Menacho-Miguel, David

    2015-09-01

    Objetivo: conocer la prescripcion de farmacos con riesgo conocido de prolongar el intervalo QT en un area de salud, informar a los medicos responsables de los factores de riesgo asociados a su aparicion y mejorar la seguridad del paciente. Métodos: estudio descriptivo transversal y observacional de prevalencia. Se incluyeron 4.964 pacientes de un area de salud en tratamiento con farmacos con riesgo conocido en un mes. Se identificaron farmacos de riesgo, interacciones y factores predisponentes. Se proporciono a cada medico los pacientes con farmacos con riesgo conocido, las recomendaciones y la encuesta para conocer mas factores de riesgo, su utilidad y su actitud clinica. Se realizo un analisis estadistico descriptivo. Resultados: el 3,2% de los pacientes del area estaban tratados con farmacos con riesgo conocido. El 64,0% eran mujeres, 57,5% mayores de 65 anos, y el 39,6% presentaban interacciones. El numero medio de factores de riesgo por paciente fue 1,78. Los farmacos con riesgo conocido mas frecuentes fueron antidepresivos (41,2%) y antibioticos (40,4%). El 25,4% de los medicos devolvio la encuesta informando de la actitud clinica en 1.073 pacientes: se retiro el farmaco con riesgo conocido en 289, se redujo la dosis en 113 y se realizo electrocardiograma en 398. Los medicos identificaron otros factores de riesgo: problema cardiaco (17,9%) e hiper/hipotiroidismo (8,8%). Conclusiones: la prevalencia detectada en la prescripcion de farmacos que prolongan el intervalo QT es relevante teniendo en cuenta que los pacientes tenian ademas otros factores de riesgo. Su identificacion permite mejorar la calidad de la atencion y la seguridad del paciente.

  8. Cyclodextrin modified PLLA parietal reinforcement implant with prolonged antibacterial activity.

    PubMed

    Vermet, G; Degoutin, S; Chai, F; Maton, M; Flores, C; Neut, C; Danjou, P E; Martel, B; Blanchemain, N

    2017-02-12

    The use of textile meshes in hernia repair is widespread in visceral surgery. Though, mesh infection is a complication that may prolong the patient recovery period and consequently presents an impact on public health economy. Such concern can be avoided thanks to a local and extended antibiotic release on the operative site. In recent developments, poly-l-lactic acid (PLLA) has been used in complement of polyethyleneterephthalate (Dacron®) (PET) or polypropylene (PP) yarns in the manufacture of semi-resorbable parietal implants. The goal of the present study consisted in assigning drug reservoir properties and prolonged antibacterial effect to a 100% PLLA knit through its functionalization with a cyclodextrin polymer (polyCD) and activation with ciprofloxacin. The study focused i) on the control of degree of polyCD functionalization of the PLLA support and on its physical and biological characterization by Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC) and cell viability, ii) on the understanding of drug/meshes interaction using mathematic model and iii) on the correlation between drug release studies in phosphate buffer saline (PBS) and microbiological evaluation of meshes and release medium against E. coli and S. aureus. All above mentioned tests highlighted the contribution of polyCD on the improved performances of the resulting antibacterial implantable material.

  9. Prolonged Prevention of Retinal Degeneration with Retinylamine Loaded Nanoparticles

    PubMed Central

    Puntel, Anthony; Maeda, Akiko; Golczak, Marcin; Gao, Song-Qi; Yu, Guanping; Palczewski, Krzysztof; Lu, Zheng-Rong

    2015-01-01

    Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially all-trans-retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of all-trans-retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4−/−Rdh8−/− (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration. PMID:25617130

  10. Prolonged partial epilepsy: a case report

    SciTech Connect

    Wilson, M.A.

    1980-11-01

    The case study of a patient with prolonged partial epilepsy is presented. There was a discrepancy between the extent of the abnormality seen on the radionuclide angiogram and that seen on the static brain scan.

  11. QT Prolongation due to Graves' Disease

    PubMed Central

    Deol, Nisha; Tolly, Renee; Manocha, Rohan; Naseer, Maliha

    2017-01-01

    Hyperthyroidism is a highly prevalent disease affecting over 4 million people in the US. The disease is associated with many cardiac complications including atrial fibrillation and also less commonly with ventricular tachycardia and fibrillation. Many cardiac pathologies have been extensively studied; however, the relationship between hyperthyroidism and rate of ventricular repolarization manifesting as a prolonged QTc interval is not well known. Prolonged QTc interval regardless of thyroid status is a risk factor for cardiovascular mortality and life-threatening ventricular arrhythmia. The mechanism regarding the prolongation of the QT interval in a hyperthyroid patient has not been extensively investigated although its clinical implications are relevant. Herein, we describe a case of prolonged QTc in a patient who presented with signs of hyperthyroidism that was corrected with return to euthyroid status. PMID:28154763

  12. QTc Prolongation in Patients Acutely Admitted to Hospital for Psychosis and Treated with Second Generation Antipsychotics

    PubMed Central

    Kroken, Rune A.; Løberg, Else-Marie; Jørgensen, Hugo A.

    2013-01-01

    QTc interval prolongation is a side effect of several antipsychotic drugs, with associated risks of torsade de pointes arrhythmias and sudden cardiac death. There is an ongoing debate of whether or not electrocardiogram (ECG) assessments should be mandatory in patients starting antipsychotic drugs. To investigate QTc prolongation in a clinically relevant patient group 171 adult patients acutely admitted to an emergency ward for psychosis were consecutively recruited. ECGs were recorded at baseline and then at discharge or after 6 weeks at the latest (discharge/6 weeks), thus reflecting the acute phase treatment period. The mean QTc interval was 421.1 (30.4) ms at baseline and there was a positive association between the QTc interval and the agitation score whereas the QTc interval was inversely associated with the serum calcium level. A total of 11.6% had abnormally prolonged QTc intervals and another 14.3% had borderline prolongation. At discharge/6 weeks, the corresponding proportions were reduced to 4.2% and 5.3%, respectively. The reduction of the proportion with prolonged QTc intervals reached statistical significance (chi-square exact test: P = 0.046). The finding of about one-quarter of the patients with borderline or prolonged QTc intervals could indicate mandatory ECG recordings in this population. This trial is registered with ClinicalTrials.gov ID: NCT00932529. PMID:24490070

  13. Prolonged morphine administration alters protein expression in the rat myocardium

    PubMed Central

    2011-01-01

    Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day) for 10 days. Proteins from the plasma membrane- and mitochondria-enriched fractions or cytosolic proteins isolated from left ventricles were run on 2D gel electrophoresis, scanned and quantified with specific software to reveal differentially expressed proteins. Results Nine proteins were found to show markedly altered expression levels in samples from morphine-treaded rats and these proteins were identified by mass spectrometric analysis. They belong to different cell pathways including signaling, cytoprotective, and structural elements. Conclusions The present identification of several important myocardial proteins altered by prolonged morphine treatment points to global effects of this drug on heart tissue. These findings represent an initial step toward a more complex view on the action of morphine on the heart. PMID:22129148

  14. Prolongation structures of nonlinear evolution equations

    NASA Technical Reports Server (NTRS)

    Wahlquist, H. D.; Estabrook, F. B.

    1975-01-01

    A technique is developed for systematically deriving a 'prolongation structure' - a set of interrelated potentials and pseudopotentials - for nonlinear partial differential equations in two independent variables. When this is applied to the Korteweg-de Vries equation, a new infinite set of conserved quantities is obtained. Known solution techniques are shown to result from the discovery of such a structure: related partial differential equations for the potential functions, linear 'inverse scattering' equations for auxiliary functions, Backlund transformations. Generalizations of these techniques will result from the use of irreducible matrix representations of the prolongation structure.

  15. Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy

    PubMed Central

    Maxwell, Nicole M; Nevin, Remington L; Stahl, Stephen; Block, Jerald; Shugarts, Sarah; Wu, Alan H B; Dominy, Stephen; Solano-Blanco, Miguel Alonso; Kappelman-Culver, Sharon; Lee-Messer, Christopher; Maldonado, Jose; Maxwell, Andrew J

    2015-01-01

    Key Clinical Message Susceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication. PMID:26185633

  16. Effect of prolonged freezing of semen on exosome recovery and biologic activity.

    PubMed

    Welch, Jennifer L; Madison, Marisa N; Margolick, Joseph B; Galvin, Shannon; Gupta, Phalguni; Martínez-Maza, Otoniel; Dash, Chandravanu; Okeoma, Chioma M

    2017-03-24

    Exosomes are important vehicles of intercellular communication that shape host responses to physiologic, tumorigenic, and pathogenic conditions. The composition and function of exosomes are dynamic and depends on the state and condition of the cellular source. In prior work, we found that semen exosomes (SE) from healthy donors who do not use illicit drugs potently inhibit HIV-1. Following semen donation, specimens are either used immediately or frozen for use at a later time. It has been shown that short-term freezing of semen has no effect on SE-mediated HIV-1 inhibition. However, the effect of illicit drugs and prolonged freezing on SE bioactivity is unknown. Here, we show preservation of SE physical properties, (morphology, concentration, intensity/size) irrespective of illicit drug use or duration of semen freezing. Interestingly, illicit drugs and prolonged freezing decreased the levels of SE-bound CD63/CD9 and acetylcholinesterase activity respectively. Furthermore, we show differential effects of illicit drug use and prolonged freezing on SE-mediated HIV-1 inhibition. Our results highlight the importance of the source of SE and condition of semen storage on SE content and function. In-depth evaluation of donor drug-use and duration of semen storage on SE cargo and bioactivity will advance our understanding of SE composition and function.

  17. Effect of prolonged freezing of semen on exosome recovery and biologic activity

    PubMed Central

    Welch, Jennifer L.; Madison, Marisa N.; Margolick, Joseph B.; Galvin, Shannon; Gupta, Phalguni; Martínez-Maza, Otoniel; Dash, Chandravanu; Okeoma, Chioma M.

    2017-01-01

    Exosomes are important vehicles of intercellular communication that shape host responses to physiologic, tumorigenic, and pathogenic conditions. The composition and function of exosomes are dynamic and depends on the state and condition of the cellular source. In prior work, we found that semen exosomes (SE) from healthy donors who do not use illicit drugs potently inhibit HIV-1. Following semen donation, specimens are either used immediately or frozen for use at a later time. It has been shown that short-term freezing of semen has no effect on SE-mediated HIV-1 inhibition. However, the effect of illicit drugs and prolonged freezing on SE bioactivity is unknown. Here, we show preservation of SE physical properties, (morphology, concentration, intensity/size) irrespective of illicit drug use or duration of semen freezing. Interestingly, illicit drugs and prolonged freezing decreased the levels of SE-bound CD63/CD9 and acetylcholinesterase activity respectively. Furthermore, we show differential effects of illicit drug use and prolonged freezing on SE-mediated HIV-1 inhibition. Our results highlight the importance of the source of SE and condition of semen storage on SE content and function. In-depth evaluation of donor drug-use and duration of semen storage on SE cargo and bioactivity will advance our understanding of SE composition and function. PMID:28338013

  18. Prolonged blood circulation of methotrexate by modulation of liposomal composition.

    PubMed

    Hong, M S; Lim, S J; Lee, M K; Kim, Y B; Kim, C K

    2001-01-01

    Prolonged circulation by liposomal incorporation has been shown to enhance the therapeutic efficacy of drugs in many cases. The purpose of this study was to investigate whether the prolonged circulation of methotrexate (MTX) can be achieved by modulating the liposomal compositions. Various compositions of liposomes were prepared with 2:1 of phosphatidylcholine (PC) and cholesterol (CH) with or without distearoylphosphatidyl-ethanolamine-N-poly(ethyleneglycol) 2000 (DSPE-PEG). The MTX encapsulation efficiency depended on the type of PC used. It also appeared to increase by inclusion of DSPE-PEG. The size of liposomes decreased by the inclusion of DSPE-PEG. The inclusion of DSPE-PEG lowered the plasma-induced release of MTX from EggPC/CH and DPPC/CH liposomes, suggesting its enhancement effect on the liposomal stability. After intravenous injection to rats, the pharmacokinetics and biodistribution of MTX were significantly changed by liposomal incorporation and also by the composition of liposomes. The total body clearance of MTX incorporated in EggPC/CH, DPPC/CH, EggPC/CH/DSPE-PEG, and DPPC/CH/DSPE-PEG liposomes decreased 4.4-, 14.9-, 24.5-, and 53.1-fold, compared with that of free MTX. The ratio of MTX concentration in blood to liver and spleen after injection of DPPC/CH, EggPC/CH/DSPE-PEG, and DPPC/CH/DSPE-PEG liposomes was 5.4-, 8.5-, and 13.5-fold higher than that of EggPC/CH liposomes. Furthermore, the accumulation of MTX in the kidney, one of the organs in which MTX exhibits its toxicity, was significantly lowered by liposomal incorporation, especially by DSPE-PEG-containing liposomes. Taken together, DPPC/CH/DSPE-PEG liposomes most effectively prolonged the blood circulation, and reduced hepatosplenic and kidney uptake of MTX. DPPC/CH/DSPE-PEG liposomes may have potential as an efficient delivery system for MTX.

  19. Carotid Baroreflex Function During Prolonged Exercise

    NASA Technical Reports Server (NTRS)

    Raven, P. B.

    1999-01-01

    Astronauts are often required to work (exercise) at moderate to high intensities for extended periods while performing extra-vehicular activities (EVA). Although the physiologic responses associated with prolonged exercise have been documented, the mechanisms involved in blood pressure regulation under these conditions have not yet been fully elucidated. An understanding of this issue is pertinent to the ability of humans to perform work in microgravity and complies with the emphasis of NASA's Space Physiology and Countermeasures Program. Prolonged exercise at a constant workload is know to result in a progressive decrease in mean arterial pressure (MAP) concomitant with a decrease in stroke volume and a compensatory increase in heart rate. The continuous decrease in MAP during the exercise, which is related to the thermoregulatory redistribution of circulating blood volume to the cutaneous circulation, raises the question as to whether there is a loss of baroreflex regulation of arterial blood pressure. We propose that with prolongation of the exercise to 60 minutes, progressive increases on central command reflect a progressive upward resetting of the carotid baroreflex (CBR) such that the operating point of the CBR is shifted to a pressure below the threshold of the reflex rendering it ineffectual in correcting the downward drift in MAP. In order to test this hypothesis, experiments have been designed to uncouple the global hemodynamic response to prolonged exercise from the central command mediated response via: (1) continuous maintenance of cardiac filling volume by intravenous infusion of a dextran solution; and (2) whole body surface cooling to counteract thermoregulatory cutaneous vasodialation. As the type of work (exercise) performed by astronauts is inherently arm and upper body dependent, we will also examine the physiologic responses to prolonged leg cycling and arm ergometry exercise in the supine positions with and without level lower body negative

  20. Association Among Sociodemograhic Factors, Work Ability, Health Behavior, and Mental Health Status for Young People After Prolonged Unemployment.

    PubMed

    Lappalainen, Kirsi; Manninen, Pirjo; Räsänen, Kimmo

    2017-02-01

    The purpose of this study was to explore the associations of prolonged unemployment, health, and work ability among young workers using data from the 2008-2010 Occupational Health Counselling project in Kuopio, Eastern Finland. The total sample for this study was 190 young unemployed adults. The questionnaire included the Work Ability Index (WAI), the Beck Depression Inventory, the Alcohol Use Disorders Identification Test, and the Occupational Health Counselling Survey. Multivariate analyses revealed that men had a higher prevalence of prolonged unemployment than women. Using drugs for purposes other than treatment was associated independently with an increased prevalence of prolonged unemployment. Low WAI scores were associated with a higher prevalence of prolonged unemployment. This study showed that attention should be paid to male workers, those who have poor or moderate work ability and workers who use drugs. Young unemployed workers should be recognized at an early stage. A comprehensive, flexible network of community resources is essential to support young unemployed adults.

  1. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis.

    PubMed

    Guglielmetti, Lorenzo; Jaspard, Marie; Le Dû, Damien; Lachâtre, Marie; Marigot-Outtandy, Dhiba; Bernard, Christine; Veziris, Nicolas; Robert, Jérôme; Yazdanpanah, Yazdan; Caumes, Eric; Fréchet-Jachym, Mathilde

    2017-03-01

    Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24 weeks. There are scarce data on patients treated with this drug outside clinical trials.All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30 days of bedaquiline were included in a multicentre observational cohort.Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361 days and 33 patients (73%) received prolonged (>190 days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500 ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment.Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort.

  2. Prolonged treatment of refractory status epilepticus in a child.

    PubMed

    Sahin, M; Riviello, J J

    2001-02-01

    Barbiturate anesthesia, which is commonly used for refractory status epilepticus, is an effective treatment, but with many significant complications. The relationship between the duration of this extreme therapy and the ultimate outcome of refractory status epilepticus has not been well studied. We report a 7-year-old girl who presented with refractory status epilepticus secondary to presumed encephalitis with a focal lesion on cranial magnetic resonance imaging. She was treated for 70 days with high-dose antiepileptic drugs and recovered with a residual seizure disorder. This case suggests that, if the status epilepticus is due to a reversible cause such as encephalitis, neurologic recovery may occur despite this very prolonged course of extreme therapy.

  3. Acute prolongation of myocardial refractoriness by sotalol.

    PubMed Central

    Bennett, D H

    1982-01-01

    Sotalol, a beta adrenoceptor antagonist, was given intravenously to 15 patients with accessory atrioventricular pathways during intracardiac electrophysiological studies. Eleven patients had the Wolff-Parkinson-White syndrome and four patients had concealed left sided accessory pathways. Four patients were restudied while receiving oral sotalol. In contrast to the actions typical of beta blocking agents, intravenous sotalol prolonged the effective refractory periods of the ventricles and accessory pathways and reduced the ventricular response to atrial fibrillation in the patients with the Wolff-Parkinson-White syndrome. Similar results were obtained with oral administration. These findings support the observation that sotalol, unlike other beta blocking agents. causes acute prolongation of the myocardial action potential and suggest that this action might be of therapeutic use. PMID:7082500

  4. Status of vestibular function after prolonged bedrest

    NASA Astrophysics Data System (ADS)

    Burgeat, M.; Toupet, M.; Loth, D.; Ingster, I.; Guell, A.; Coll, J.

    6 young, healthy, male volunteers were submitted to one week of head down (-4°) bedrest. This position simulates the cerebral hemodynamic conditions in weightlessness. Measurements of vestibular equilibrium and of oculomotor system function were made before and after the prolonged bedrest. Analysis of the results indicates that vestibular responses, as measured by the maximal speed of the slow phase of the provoked nystagmus (caloric and sinusoidal rotatory stimulations), are decreased after prolonged bedrest. This statistically significant diminution requires confirmation with a greater number of cases. The reflex conflicting or interacting with the cervico-ocular and optokinetic reflexes on the one hand and the foveal vision on the other, is one of several possible explanations for the observed changes.

  5. Severe bradycardia and prolonged hypotension in ciguatera.

    PubMed

    Chan, Thomas Yan Keung

    2013-06-01

    Ciguatera results when ciguatoxin-contaminated coral reef fish from tropical or subtropical waters are consumed. The clinical features that present in affected persons are mainly gastrointestinal, neurological, general, and much less commonly, cardiovascular. We report the case of a 50-year-old man who developed the characteristic combination of acute gastrointestinal and neurological symptoms after the consumption of an unidentified coral reef fish head. In addition to those symptoms, he developed dizziness, severe bradycardia (46 bpm) and prolonged hypotension, which required the administration of intravenous atropine and over three days of intravenous fluid replacement with dopamine infusion. Patients with ciguatera can develop severe bradycardia and prolonged hypotension. Physicians should recognise the possible cardiovascular complications of ciguatera and promptly initiate treatment with intravenous atropine, intravenous fluid replacement and inotropic therapy if such complications are observed.

  6. SALIVARY ANTIMICROBIAL PROTEIN RESPONSE TO PROLONGED RUNNING

    PubMed Central

    Kuennen, M.; Gourley, C.; Schneider, S.; Dokladny, K.; Moseley, P.

    2013-01-01

    Introduction Prolonged exercise may compromise immunity through a reduction of salivary antimicrobial proteins (AMPs). Salivary IgA (IgA) has been extensively studied, but little is known about the effect of acute, prolonged exercise on AMPs including lysozyme (Lys) and lactoferrin (Lac). Objective To determine the effect of a 50-km trail race on salivary cortisol (Cort), IgA, Lys, and Lac. Methods 14 subjects: (6 females, 8 males) completed a 50km ultramarathon. Saliva was collected pre, immediately after (post) and 1.5 hrs post race (+1.5). Results Lac concentration was higher at +1.5 hrs post race compared to post exercise (p < 0.05). Lys was unaffected by the race (p > 0.05). IgA concentration, secretion rate, and IgA/Osm were lower +1.5 hrs post compared to pre race (p < 0.05). Cort concentration was higher at post compared to +1.5 (p < 0.05), but was unaltered from pre race levels. Subjects finished in 7.81±1.2 hrs. Saliva flow rate did not differ between time points. Saliva Osm increased at post (p < 0.05) compared to pre race. Conclusions The intensity could have been too low to alter Lys and Lac secretion rates and thus, may not be as sensitive as IgA to changes in response to prolonged running. Results expand our understanding of the mucosal immune system and may have implications for predicting illness after prolonged running. PMID:24744458

  7. Prolonging life: legal, ethical, and social dilemmas.

    PubMed

    Paulson, Steve; Comfort, Christopher P; Lee, Barbara Coombs; Shemie, Sam; Solomon, Mildred Z

    2014-11-01

    The ability of modern medicine to prolong life has raised a variety of difficult legal, ethical, and social issues on which reasonable minds can differ. Among these are the morality of euthanasia in cases of deep coma or irreversible injury, as well as the Dead Donor Rule with respect to organ harvesting and transplants. As science continues to refine and develop lifesaving technologies, questions remain as to how much medical effort and financial resources should be expended to prolong the lives of patients suspended between life and death. At what point should death be considered irreversible? What criteria should be used to determine when to withhold or withdraw life-prolonging treatments in cases of severe brain damage and terminal illness? To explore these complex dilemmas, Steve Paulson, executive producer and host of To the Best of Our Knowledge, moderated a discussion panel. Pediatrician Sam Shemie, hospice medical director Christopher P. Comfort, bioethicist Mildred Z. Solomon, and attorney Barbara Coombs Lee examined the underlying assumptions and considerations that ultimately shape individual and societal decisions surrounding these issues. The following is an edited transcript of the discussion that occurred November 12, 2013, 7:00-8:30 PM, at the New York Academy of Sciences in New York City.

  8. Drugs and Air Operations

    DTIC Science & Technology

    2001-06-01

    schedules. Sleep 1998;21:79-90. 21. Bishop C, Roehrs T, Rosenthal L, Roth T. Alerting effects of methylphenidate under basal 12. Newhouse PA, Penetar DM...drug effects on performance and behaviour after prolonged sleep deprivation: A 22. Roehrs T, Papineau K, Rosenthal L, Roth T. comparison of amphetamine

  9. Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes.

    PubMed

    Gluais, Pascale; Bastide, Michèle; Caron, Jacques; Adamantidis, Monique

    2002-05-31

    Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1-3 microM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03-0.3 microM) reduced significantly the current density of the delayed rectifier current and at 30 microM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.

  10. QT Prolongation and Life Threatening Ventricular Tachycardia in a Patient Injected With Intravenous Meperidine (Demerol®).

    PubMed

    Song, Mi Kyoung; Bae, Eun Jung; Baek, Jae Suk; Kwon, Bo Sang; Kim, Gi Beom; Noh, Chung Il; Choi, Jung Yun; Park, Sung Sup

    2011-06-01

    QT prolongation is a serious adverse drug effect, which is associated with an increased risk of Torsade de pointes and sudden death. Many drugs, including both cardiac and non-cardiac drugs, have been reported to cause prolongation of QT interval. Although meperidine has not been considered proarrhythmic, we present a unique case of a 16-year-old boy without an underlying cardiac disease, who developed polymorphic ventricular tachycardia, ventricular fibrillation and QT prolongation after an intravenous meperidine injection. He had no mutation in long QT syndrome genes (KCNQ1, KCNH2, and SCN5A), but single nucleotide polymorphisms were reported, including H558R in SCNA5A and K897T in KCNH2.

  11. Prolonged fatigue in Ukraine and the United States: Prevalence and risk factors

    PubMed Central

    Friedberg, Fred; Tintle, Nathan; Clark, Jake; Bromet, Evelyn J.

    2015-01-01

    Background Prolonged, severe, unalleviated fatigue may be disabling whether it occurs on its own or in conjunction with medical or psychiatric conditions. This paper compares the prevalence and correlates of prolonged fatigue in general population samples in Ukraine versus the U.S. Methods Population surveys were conducted in 2002 in both Ukraine (Ukraine World Mental Health [WMH] Survey) and the U.S. (National Comorbidity Survey-Replication; NCS-R). Both surveys administered the Composite International Diagnostic Interview (CIDI 3.0), which contained modules assessing: neurasthenia (prolonged fatigue); mood, anxiety, and alcohol/drug use disorders; chronic medical conditions; and demographic characteristics. Multivariable logistic regression was used to examine risk factors in each country. Results The lifetime prevalence of prolonged fatigue was higher in Ukraine (5.2%) than the U.S. (3.7%). In both countries, one-fifth of individuals with prolonged fatigue had no medical or DSM-IV psychiatric condition. Also in both settings, fatigue was significantly associated with sociodemographic characteristics (being female, not working, and married before) as well as early onset and adult episodes of mood/anxiety disorder. Fatigue prevalence in Ukraine increased with age, but decreased in the U.S. at age 70. Unique risk factors for fatigue in Ukraine included lower socio-economic status, Ukrainian vs Russian ethnicity, and cardiovascular disease. Unique risk factors in the U.S. were parental depression/anxiety, adult episodes of alcohol/drugs, pain conditions, and other health problems. Conclusions The lifetime prevalence of prolonged fatigue in Ukraine was 40% higher than that found in U.S. data. In addition, fatigue prevalence increased sharply with age in Ukraine perhaps due to limited social and medical resources and greater comorbidity. PMID:26807341

  12. Prolonging β-lactam infusion: a review of the rationale and evidence, and guidance for implementation.

    PubMed

    MacVane, Shawn H; Kuti, Joseph L; Nicolau, David P

    2014-02-01

    Given the sparse antibiotic pipeline and the increasing prevalence of resistant organisms, efforts should be made to optimise the pharmacodynamic exposure of currently available agents. Prolonging the infusion duration is a strategy used to increase the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC), the pharmacodynamic efficacy driver for time-dependent antibiotics such as β-lactams. β-Lactams, the most commonly prescribed class of antibiotics owing to their efficacy and safety profile, have been the mainstay of therapy since the discovery of penicillin over 60 years ago. Mounting evidence, including the use of population pharmacokinetic modelling and Monte Carlo simulation, suggests that prolonging the infusion time of β-lactam antibiotics may have advantages over standard infusion techniques, including an enhanced probability of achieving requisite fT>MIC exposures, lower mortality and potentially reductions in infection/antibiotic-related costs. As a result of these favourable attributes, clinical practice guidelines support the use of prolonged-infusion β-lactams in the treatment of many severe infections. This article discusses the rationale and evidence for prolonging the infusion of β-lactam antibiotics and provides guidance for the implementation of a prolonged-infusion programme.

  13. A detailed description and assessment of outcomes of patients with hospital recorded QTc prolongation.

    PubMed

    Laksman, Zachary; Momciu, Bogdan; Seong, You Won; Burrows, Patricia; Conacher, Susan; Manlucu, Jaimie; Leong-Sit, Peter; Gula, Lorne J; Skanes, Allan C; Yee, Raymond; Klein, George J; Krahn, Andrew D

    2015-04-01

    Corrected QT (QTc) interval prolongation has been shown to be an independent predictor of mortality in many clinical settings and is a common finding in hospitalized patients. The causes and outcomes of patients with extreme QTc interval prolongation during a hospital admission are poorly described. The aim of this study was to prospectively identify patients with automated readings of QTc intervals >550 ms at 1 academic tertiary hospital. One hundred seventy-two patients with dramatic QTc interval prolongation (574 ± 53 ms) were identified (mean age 67.6 ± 15.1 years, 48% women). Most patients had underlying heart disease (60%), predominantly ischemic cardiomyopathy (43%). At lease 1 credible and presumed reversible cause associated with QTc interval prolongation was identified in 98% of patients. The most common culprits were QTc interval-prolonging medications, which were deemed most responsible in 48% of patients, with 25% of these patients taking ≥2 offending drugs. Two patients were diagnosed with congenital long-QT syndrome. Patients with electrocardiograms available before and after hospital admission demonstrated significantly lower preadmission and postdischarge QTc intervals compared with the QTc intervals recorded in the hospital. In conclusion, in-hospital mortality was high in the study population (29%), with only 4% of patients experiencing arrhythmic deaths, all of which were attributed to secondary causes.

  14. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate.

    PubMed

    Allam, Ayat; Fetih, Gihan

    2016-01-01

    The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug's bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate.

  15. Mutant models of prolonged life span.

    PubMed

    Mahler, J F

    2001-01-01

    Aging is an important biological process that affects all creatures. For humans, age-related diseases and the question of why we age and die also have tremendous social and philosophical impact. We can therefore expect that models to study mechanisms of the aging process will always attract much interest. Until recently, the mutant model approach to study molecular mechanisms of aging has been limited to lower animals such as yeast, worms, and flies. However, given the current power of genetic technology in mammals, we can expect that phenotypes of prolonged life span will increasingly be seen in mice and subject to evaluation by pathologists. A brief review of current models is presented.

  16. Electrical shock survival after prolonged cardiopulmonary resuscitation.

    PubMed

    Ahmad, Maqsood; Shabbir, Khawar

    2013-07-01

    Electrical shock is typically an untoward exposure of human body to any source of electricity that causes a sufficient current to pass through the skin, muscles or hair causing undesirable effects ranging from simple burns to death. Ventricular fibrillation is believed to be the most common cause of death following electrical shock. The case under discussion is of a young man who survived following electrical shock after prolonged cardiopulmonary resuscitation (CPR), multiple defibrillations and artificial ventilation due to poor respiratory effort. Early start of chest compressions played a vital role in successful CPR.

  17. Survival of soil bacteria during prolonged desiccation.

    NASA Technical Reports Server (NTRS)

    Chen, M.; Alexander, M.

    1973-01-01

    A determination was made of the kinds and numbers of bacteria surviving when two soils were maintained in the laboratory under dry conditions for more than half a year. Certain non-spore-forming bacteria were found to survive in the dry condition for long periods. A higher percentage of drought-tolerant than drought-sensitive bacteria was able to grow at low water activities. When they were grown in media with high salt concentrations, bacteria generally became more tolerant of prolonged drought and they persisted longer. The percent of cells in a bacterial population that remained viable when exposed to drought stress varied with the stage of growth.

  18. Blueberry extract prolongs lifespan of Drosophila melanogaster.

    PubMed

    Peng, Cheng; Zuo, Yuanyuan; Kwan, Kin Ming; Liang, Yintong; Ma, Ka Ying; Chan, Ho Yin Edwin; Huang, Yu; Yu, Hongjian; Chen, Zhen-Yu

    2012-02-01

    Blueberry possesses greater antioxidant capacity than most other fruits and vegetables. The present study investigated the lifespan-prolonging activity of blueberry extracts in fruit flies and explored its underlying mechanism. Results revealed that blueberry extracts at 5mg/ml in diet could significantly extend the mean lifespan of fruit flies by 10%, accompanied by up-regulating gene expression of superoxide dismutase (SOD), catalase (CAT) and Rpn11 and down-regulating Methuselah (MTH) gene. Intensive H(2)O(2) and Paraquat challenge tests showed that lifespan was only extended in Oregon-R wild type flies but not in SOD(n108) or Cat(n1) mutant strains. Chronic Paraquat exposure shortened the maximum survival time from 73 to 35days and decreased the climbing ability by 60% while blueberry extracts at 5mg/ml in diet could significantly increase the survival rate and partially restore the climbing ability with up-regulating SOD, CAT, and Rpn11. Furthermore, gustatory assay demonstrated that those changes were not due to the variation of food intake between the control and the experimental diet containing 5mg/ml blueberry extracts. It was therefore concluded that the lifespan-prolonging activity of blueberry extracts was at least partially associated with its interactions with MTH, Rpn11, and endogenous antioxidant enzymes SOD and CAT.

  19. Review and Outcome of Prolonged Cardiopulmonary Resuscitation

    PubMed Central

    Youness, Houssein; Al Halabi, Tarek; Hussein, Hussein; Awab, Ahmed; Jones, Kellie; Keddissi, Jean

    2016-01-01

    The maximal duration of cardiopulmonary resuscitation (CPR) is unknown. We report a case of prolonged CPR. We have then reviewed all published cases with CPR duration equal to or more than 20 minutes. The objective was to determine the survival rate, the neurological outcome, and the characteristics of the survivors. Measurements and Main Results. The CPR data for 82 patients was reviewed. The median duration of CPR was 75 minutes. Patients mean age was 43 ± 21 years with no significant comorbidities. The main causes of the cardiac arrests were myocardial infarction (29%), hypothermia (21%), and pulmonary emboli (12%). 74% of the arrests were witnessed, with a mean latency to CPR of 2 ± 6 minutes and good quality chest compression provided in 96% of the cases. Adjunct therapy included extracorporeal membrane oxygenation (18%), thrombolysis (15.8%), and rewarming for hypothermia (19.5%). 83% were alive at 1 year, with full neurological recovery reported in 63 patients. Conclusion. Patients undergoing prolonged CPR can survive with good outcome. Young age, myocardial infarction, and potentially reversible causes of cardiac arrest such as hypothermia and pulmonary emboli predict a favorable result, especially when the arrest is witnessed and followed by prompt and good resuscitative efforts. PMID:26885387

  20. [Left ventricular dyssynchrony in prolonged septal stimulation].

    PubMed

    Ferrando-Castagnetto, Federico; Ricca-Mallada, Roberto; Vidal, Alejandro; Martínez, Fabián; Ferrando, Rodolfo

    2016-01-01

    Pacemaker stimulation is associated with unpredictable severe cardiac events. We evaluated left ventricular mechanical dyssynchrony (LVMD) during prolonged septal right ventricular pacing. We performed 99mTc-MIBI gated-SPECT and phase analysis in 6 patients with pacemakers implanted at least one year before scintigraphy due to advanced atrioventricular block. Using V-Sync of Emory Cardiac Toolbox we obtained phase bandwidth (PBW) and standard deviation (PSD) from rest phase histogram. Clinical variables, QRS duration, rate and mode of pacing in septal right ventricle wall, chamber diameters, presence and extension of myocardial scar and ischemia and rest LVEF were recorded. Prolonged septal endocardial pacing is associated with marked LVMD, even when systolic function was preserved. More severe dyssynchrony was found in patients with impaired LVEF, higher left ventricle diameters, extensive infarct or severe ischemia than in patients with preserved LVEF (PBW: 177.3o vs. 88.3o; PSD: 53.1o vs. 33.8o). In the patients with ischemic heart disease and pacemaker, gated-SPECT phase analysis is a valid and potentially useful technique to evaluate LMVD associated with myocardial scar and to decide the upgrading to biventricular pacing mode.

  1. Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma.

    PubMed

    Ramachandran, Ranjith; Junnuthula, Vijayabhaskar Reddy; Gowd, G Siddaramana; Ashokan, Anusha; Thomas, John; Peethambaran, Reshmi; Thomas, Anoop; Unni, Ayalur Kodakara Kochugovindan; Panikar, Dilip; Nair, Shantikumar V; Koyakutty, Manzoor

    2017-03-06

    Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (<100 ng) rendering ~1000 fold differential drug dosage in tumor versus peripheral blood. Most importantly, implant with one month release profile resulted in long-term (>4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence.

  2. Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma

    PubMed Central

    Ramachandran, Ranjith; Junnuthula, Vijayabhaskar Reddy; Gowd, G. Siddaramana; Ashokan, Anusha; Thomas, John; Peethambaran, Reshmi; Thomas, Anoop; Unni, Ayalur Kodakara Kochugovindan; Panikar, Dilip; Nair, Shantikumar V.; Koyakutty, Manzoor

    2017-01-01

    Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (<100 ng) rendering ~1000 fold differential drug dosage in tumor versus peripheral blood. Most importantly, implant with one month release profile resulted in long-term (>4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence. PMID:28262735

  3. Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma

    NASA Astrophysics Data System (ADS)

    Ramachandran, Ranjith; Junnuthula, Vijayabhaskar Reddy; Gowd, G. Siddaramana; Ashokan, Anusha; Thomas, John; Peethambaran, Reshmi; Thomas, Anoop; Unni, Ayalur Kodakara Kochugovindan; Panikar, Dilip; Nair, Shantikumar V.; Koyakutty, Manzoor

    2017-03-01

    Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (<100 ng) rendering ~1000 fold differential drug dosage in tumor versus peripheral blood. Most importantly, implant with one month release profile resulted in long-term (>4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence.

  4. [Use of benzodiazepines in prolonged seizures and status epilepticus in the community].

    PubMed

    Sánchez-Carpintero, R; Camino, R; Smeyers, P; Raspall-Chaure, M; Martínez-Bermejo, A; Ruiz-Falcó, M L; Verdú, A; Sanmarti, F X; Blanco, O; Santos Borbujo, J; Picó, G; Cebollero, M A

    2014-12-01

    Prolonged seizures and status epilepticus are common neurological medical emergencies. Early and appropriate treatment is essential to reduce morbidity and mortality. Most seizures occur in the community, so parents and caregivers must be prepared for their management. Benzodiazepines (BZD) are the first-line drugs used, with rectal diazepam (DZPr) being the most commonly used in pre-hospital treatment in Spain. In September 2011, the European Medicines Agency (EMA) authorized the use of oromucosal midazolam (MDZb) for the treatment of prolonged acute convulsive seizures in patients aged 3 months to <18 years. MDZb has a rapid onset, short duration of effect, and avoids first-pass hepatic metabolism. MDZb has shown to be at least as or more effective than DZPr to stop the seizures. Buccal administration is easier and more socially accepted, especially in adolescents and adults. It is a safe drug with similar effects to other BZD; MDZb improves the overall cost-effectiveness of seizures management.

  5. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate

    PubMed Central

    Allam, Ayat; Fetih, Gihan

    2016-01-01

    The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug’s bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate. PMID:27536063

  6. Prolonged Inner Retinal Photoreception Depends on the Visual Retinoid Cycle

    PubMed Central

    Zhao, Xiwu; Pack, Weston; Khan, Naheed W.

    2016-01-01

    In addition to rods and cones, mammals have inner retinal photoreceptors called intrinsically photosensitive retinal ganglion cells (ipRGCs), which use the photopigment melanopsin and mediate nonimage-forming visual responses, such as pupil reflexes and circadian entrainment. After photic activation, photopigments must be reverted to their dark state to be light-sensitive again. For rods and to some extent cones, photopigment regeneration depends on the retinoid cycle in the adjacent retinal pigment epithelium (RPE). By contrast, ipRGCs are far from the RPE, and previous work suggests that melanopsin is capable of light-dependent self-regeneration. Here, we used in vitro ipRGC recording and in vivo pupillometry to show that the RPE is required for normal melanopsin-based responses to prolonged light, especially at high stimulus intensities. Melanopsin-based photoresponses of rat ipRGCs were remarkably sustained when a functional RPE was attached to the retina, but became far more transient if the RPE was removed, or if the retinoid cycle was inhibited, or when Müller glia were poisoned. Similarly, retinoid cycle inhibition markedly reduced the steady-state amplitude of melanopsin-driven pupil reflexes in both mice and rats. However, melanopsin photoresponses in RPE-separated rat retinas became more sustained in the presence of an 11-cis-retinal analog. In conclusion, during prolonged illumination, melanopsin regeneration depends partly on 11-cis-retinal from the RPE, possibly imported via Müller cells. Implications for RPE-related eye diseases and the acne drug isotretinoin (a retinoid cycle inhibitor) are discussed. SIGNIFICANCE STATEMENT Intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin and drive subconscious physiological responses to light, e.g., pupillary constriction and neuroendocrine regulation. In darkness, each photopigment molecule in ipRGCs, as well as rod/cone photoreceptors, contains 11-cis-retinal (a

  7. Pharmacokinetic Variability of Daptomycin during Prolonged Therapy for Bone and Joint Infections

    PubMed Central

    Roux, Sandrine; Gagnieu, Marie-Claude; Valour, Florent; Lustig, Sébastien; Ader, Florence; Laurent, Frédéric; Chidiac, Christian; Ferry, Tristan

    2016-01-01

    The interindividual and intraindividual variabilities in daptomycin pharmacokinetics were investigated in 23 patients (69 pharmacokinetic profiles) who were treated for several months for bone and joint infections. Population daptomycin clearance was significantly influenced by renal function and was significantly higher in male than in female patients. We observed significant intraindividual changes in daptomycin clearance, which were uncorrelated with changes in renal function, suggesting that therapeutic drug monitoring is important in patients receiving prolonged daptomycin therapy. PMID:26902764

  8. Opioids and designer drugs.

    PubMed

    Ford, M; Hoffman, R S; Goldfrank, L R

    1990-08-01

    Despite the increasing use of other illicit drugs, opioid abuse, overdose, and the ensuing medical complications continue to pose management challenges for the emergency physician. Heroin use is increasing as abusers of cocaine seek a drug to prolong cocaine's effects while blunting the postcocaine depression. Clandestine chemists have created newer, more powerful compounds--designer drugs--whose potencies are many-fold that of the presently available opioids. Aggressive airway support and use of naloxone enable the emergency physician to salvage many of these patients, leaving the many medical complications of parenteral and inhalational use as the greatest management challenge.

  9. Dengue haemorrhagic fever with unusual prolonged thrombocytopaenia.

    PubMed

    Kamil, S M; Mohamad, N H; Narazah, M Y; Khan, F A

    2006-04-01

    We describe a case of dengue haemorrhagic fever with prolonged thrombocytopaenia. A 22-year-old Malay man with no prior illness presented with a history of fever and generalised macular rash of four days duration. Initial work-up suggested the diagnosis of dengue haemorrhagic fever based on thrombocytopaenia and positive dengue serology. Patient recovered from acute illness by day ten, and was discharged from the hospital with improving platelet count. He was then noted to have declining platelet count on follow-up and required another hospital admission on day 19 of his illness because of declining platelet count. The patient remained hospitalised till day 44 of his illness and managed with repeated platelet transfusion and supportive care till he recovered spontaneously.

  10. An elderly female patient with tardive oromandibular dystonia after prolonged use of the histamine analog betahistine.

    PubMed

    De Riu, G; Sanna, M P; De Riu, P L

    2010-10-01

    Tardive oromandibular dystonia (OMD) is iatrogenic in origin and is characterised by orofacial and lingual stereotypes more frequently than the idiopathic form of OMD Tardive OMD is often associated with anti-dopaminergic treatment involving drugs such as anti-psychotics, anti-emetics, and anti-vertigo agents, although the syndrome can also be triggered by anti-epileptic or anti-depressant drugs that do not have anti-dopaminergic properties. We report an elderly female patient with OMD after prolonged, self-administered treatment with betahistine dihydrochloride, a histamine analogue.

  11. Marked QTc Prolongation and Torsades de pointes in Patients with Chronic Inflammatory Arthritis

    PubMed Central

    Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Bertolozzi, Iacopo; Morozzi, Gabriella; Lorenzini, Sauro; Simpatico, Antonella; Selvi, Enrico; Bacarelli, Maria Romana; Acampa, Maurizio; Lazaro, Deana; El-Sherif, Nabil; Boutjdir, Mohamed; Laghi-Pasini, Franco

    2016-01-01

    Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24 h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNFα, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNFα and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other “classical” risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required. PMID:27703966

  12. Respiratory arrest and prolonged respiratory depression after one low, subcutaneous dose of alphaprodine for obstetric analgesia. A case report.

    PubMed

    Fuller, J D; Crombleholme, W R

    1987-02-01

    Alphaprodine hydrochloride is an analgesic used commonly in the obstetric suite. A case of prolonged respiratory depression occurred after the administration of low-dose alphaprodine. Other cases of serious sequelae associated with the use of this drug have been reported on.

  13. Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3

    PubMed Central

    Tsukumo, Yoshinori; Alain, Tommy; Fonseca, Bruno D.; Nadon, Robert; Sonenberg, Nahum

    2016-01-01

    Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1–3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer. PMID:27319316

  14. Calcium Transients Closely Reflect Prolonged Action Potentials in iPSC Models of Inherited Cardiac Arrhythmia

    PubMed Central

    Spencer, C. Ian; Baba, Shiro; Nakamura, Kenta; Hua, Ethan A.; Sears, Marie A.F.; Fu, Chi-cheng; Zhang, Jianhua; Balijepalli, Sadguna; Tomoda, Kiichiro; Hayashi, Yohei; Lizarraga, Paweena; Wojciak, Julianne; Scheinman, Melvin M.; Aalto-Setälä, Katriina; Makielski, Jonathan C.; January, Craig T.; Healy, Kevin E.; Kamp, Timothy J.; Yamanaka, Shinya; Conklin, Bruce R.

    2014-01-01

    Summary Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca2+]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca2+]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca2+. Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca2+]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na+-Ca2+ exchange. These results suggest that LQTS mutations act partly on cytosolic Ca2+ cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site. PMID:25254341

  15. Grace's story: prolonged incestuous abuse from childhood into adulthood.

    PubMed

    Salter, Michael

    2013-02-01

    Some sexually abused women in mental health settings are reporting prolonged incest and yet little is known about the circumstances that enable fathers to sexually abuse their daughters over a period of decades. This article draws from the life history of Grace, a woman who survived prolonged incest, in order to document and analyze the interplay of familial, social, and political factors that entrap girls and women within prolonged incestuous abuse.

  16. Prolonging life and allowing death: infants.

    PubMed

    Campbell, A G; McHaffie, H E

    1995-12-01

    Dilemmas about resuscitation and life-prolonging treatment for severely compromised infants have become increasingly complex as skills in neonatal care have developed. Quality of life and resource issues necessarily influence management. Our Institute of Medical Ethics working party, on whose behalf this paper is written, recognises that the ultimate responsibility for the final decision rests with the doctor in clinical charge of the infant. However, we advocate a team approach to decision-making, emphasising the important role of parents and nurses in the process. Assessing the relative burdens and benefits can be troubling, but doctors and parents need to retain a measure of discretion; legislation which would determine action in all cases is inappropriate. Caution should be exercised in involving committees in decision-making and, where they exist, their remit should remain to advise rather than to decide. Support for families who bear the consequences of their decisions is often inadequate, and facilitating access to such services is part of the wider responsibilities of the intensive care team. The authors believe that allowing death by withholding or withdrawing treatment is legitimate, where those closely involved in the care of the infant together deem the burdens to be unacceptable without compensating benefits for the infant. As part of the process accurate and careful recording is essential.

  17. Pulmonary diffusion limitation after prolonged strenuous exercise.

    PubMed

    Manier, G; Moinard, J; Téchoueyres, P; Varène, N; Guénard, H

    1991-02-01

    To determine the effect of strenuous prolonged exercise on alveolo-capillary membrane diffusing capacity, 11 marathon runners aged 37 +/- 7 years (mean +/- SD) were studied before and during early recovery (28 +/- 14 min) from a marathon race. Lung capillary blood volume (Vc) and the alveolo-capillary diffusing capacity (Dm) were determined in a one-step maneuver by simultaneous measurements of CO and NO lung transfer (DLCO and DLNO, respectively) using the single breath, breath-holding method. After the race, both DLCO and DLNO were significantly decreased in all subjects (-10.9 +/- 4.8%, P less than 10(-4) and -29.0 +/- 11.1%, P less than 10(-4), respectively). The mean value of the derived DmCO decreased by -29.3 +/- 11.1%, whereas Vc had not entirely returned to control resting value. Although these results do not indicate the detailed mechanism involved, interstitial lung fluid was suspected to accumulate, particularly in alveoli, during the race. We concluded that the high overall work load and the extended duration of the exercise both contributed to a transient change in the structure of the alveolo-capillary membrane thereby affecting the diffusing capacity of the alveolo-capillary membrane.

  18. Persistent telomere cohesion triggers a prolonged anaphase.

    PubMed

    Kim, Mi Kyung; Smith, Susan

    2014-01-01

    Telomeres use distinct mechanisms (not used by arms or centromeres) to mediate cohesion between sister chromatids. However, the motivation for a specialized mechanism at telomeres is not well understood. Here we show, using fluorescence in situ hybridization and live-cell imaging, that persistent sister chromatid cohesion at telomeres triggers a prolonged anaphase in normal human cells and cancer cells. Excess cohesion at telomeres can be induced by inhibition of tankyrase 1, a poly(ADP-ribose) polymerase that is required for resolution of telomere cohesion, or by overexpression of proteins required to establish telomere cohesion, the shelterin subunit TIN2 and the cohesin subunit SA1. Regardless of the method of induction, excess cohesion at telomeres in mitosis prevents a robust and efficient anaphase. SA1- or TIN2-induced excess cohesion and anaphase delay can be rescued by overexpression of tankyrase 1. Moreover, we show that primary fibroblasts, which accumulate excess telomere cohesion at mitosis naturally during replicative aging, undergo a similar delay in anaphase progression that can also be rescued by overexpression of tankyrase 1. Our study demonstrates that there are opposing forces that regulate telomere cohesion. The observation that cells respond to unresolved telomere cohesion by delaying (but not completely disrupting) anaphase progression suggests a mechanism for tolerating excess cohesion and maintaining telomere integrity. This attempt to deal with telomere damage may be ultimately futile for aging fibroblasts but useful for cancer cells.

  19. Clinical pharmacists' opportunities to reduce inappropriate prescription of QT-prolonging medications: calls to action.

    PubMed

    Dhanani, Trusha C; Mantovani, Emily H; Turner, J Rick

    2017-04-01

    All biologically active agents carry the potential to lead to adverse reactions in certain individuals, including serious cardiac adverse reactions. Since 2005, there has been an international regulatory landscape governing the investigation of a new drug's propensity to lead to the polymorphic ventricular tachycardia Torsades de Pointes (Torsades), a rare but potentially fatal occurrence. When a regulatory agency considers it appropriate, warning information is placed in a medicine's patient information leaflet (label) concerning drug-induced QT interval prolongation, a phenomenon associated with Torsades. In busy hospital settings, however, prescribers, including cardiologists, make injudicious prescribing decisions that put patients at risk. The science of cardiac safety, including the clinical trials that generate the information about QT prolongation in patient information leaflets, is frequently not part of the curriculum at Schools of Pharmacy. Given that medication-induced cardiotoxicity is extremely serious, we advocate that schools integrate the science of cardiac safety into existing therapeutics/therapeutic medication monitoring courses. Given their expert knowledge of pharmacology, pharmacists working as part of a hospital's clinical team would then be even better placed to review prescribing decisions concerning medications that prolong the QT interval, and alert prescribers in cases where reassessing their decisions seems prudent. National pharmacy societies or other pertinent professional societies could create practice guidelines to support graduates once employed as clinical pharmacists. Clinical pharmacists are well placed to be influential arbiters of safer prescribing decisions. Cardiac safety education during their pharmacy training and practice guideline support from professional societies during their careers can optimize this role.

  20. Clinical assessment of treatments for prolonged bleeding in users of Norplant implants.

    PubMed

    Díaz, S; Croxatto, H B; Pavez, M; Belhadj, H; Stern, J; Sivin, I

    1990-07-01

    The effectiveness of three drugs in controlling prolonged bleeding in the first year of NORPLANT implants use was tested. The drugs were levonorgestrel (L-Ng, 0.03 mg twice a day for 20 days), ethinylestradiol (EE, 0.05 mg per day for 20 days) and ibuprofen (Ib, 800 mg three times a day for 5 days) and were given orally. A control group received a placebo (PL, one pill of lactose for 20 days). Treatment should start each time a woman experienced eight consecutive days of bleeding or spotting. The 183 volunteers were not aware of the drug administered. A daily record of bleeding and spotting and of treatment intake was maintained. One-hundred-forty women completed the study period; 60 never used the prescribed treatment. Women treated with the three test drugs had significantly fewer bleeding and spotting days during the treated month and also throughout the study year than women using the placebo. The mean number of bleeding plus spotting days per actually treated subject in the first year was 77, 94, 101 and 129 days for the EE, Ib, L-Ng and PL groups, respectively. The administration of EE might help in the management of prolonged bleeding during the first year of NORPLANT implants use.

  1. Prolonged remission maintenance in acute myeloid leukaemia.

    PubMed

    Spiers, A S; Goldman, J M; Catovsky, D; Costello, C; Galton, D A; Pitcher, C S

    1977-08-27

    Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia.

  2. Prolonged remission maintenance in acute myeloid leukaemia.

    PubMed Central

    Spiers, A S; Goldman, J M; Catovsky, D; Costello, C; Galton, D A; Pitcher, C S

    1977-01-01

    Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia. PMID:268229

  3. Reactivity of organism in prolonged space flights

    NASA Technical Reports Server (NTRS)

    Vasilyev, P. V.

    1980-01-01

    An analysis of published data are presented as well as the results of experiments which show that the state of weightlessness and hypodynamia result in a reduced orthostatic and vestibular resistance, increased sensitivity to infections, decreased endurance of accelerations and physical exercises, and altered reactivity of the organism to drugs. Various consequences of weightlessness on the human body, especially weightlessness combined with other factors linked to long space flights are also considered.

  4. Cesium-induced QT-interval prolongation in an adolescent.

    PubMed

    O'Brien, Catherine E; Harik, Nada; James, Laura P; Seib, Paul M; Stowe, Cindy D

    2008-08-01

    Alternative medicine is becoming increasingly popular, especially with terminally ill patients. Most alternative remedies have not been adequately studied or proven effective for the diseases for which they are promoted. In the worst cases, these therapies are harmful. We describe a 16-year-old girl with metastatic hepatocellular carcinoma who experienced cesium-induced QT-interval prolongation after the start of a cesium chloride-based alternative treatment regimen. She had received seven courses of chemotherapy, with a cumulative doxorubicin dose of 500 mg/m(2) over 5 months, resulting in minimal tumor regression. Against the advice of her oncologist, she abandoned traditional therapy and started an alternative regimen that included cesium chloride supplements. Two weeks later, the patient went to a local emergency department after experiencing two brief syncopal episodes. An electrocardiogram revealed occasional premature ventricular contractions, a QTc interval of 683 msec (normal range for females 450-460 msec), and R on T phenomenon. She was admitted to the hospital and later experienced monomorphic ventricular tachycardia, which resolved spontaneously. Lidocaine therapy was started, and the patient was transferred to a cardiac intensive care unit at our hospital. Her plasma cesium level was 2400 microg/dl (normal < 1 microg/dl), and her family was told to stop her alternative treatment regimen. On hospital day 5, as no additional arrhythmias had occurred, lidocaine was discontinued. Two days later, the patient's QTc interval had decreased to 546 msec, and she was discharged home. Two months later, at a follow-up visit, her serum cesium level was 1800 microg/dl, and her QTc interval was 494 msec. According to the Naranjo adverse drug reaction probability scale, cesium was the probable cause of the patient's arrhythmia. In animal models, cesium chloride has induced cardiac arrhythmias, including torsade de pointes. It inhibits delayed rectifier potassium

  5. Injectable microparticle-gel system for prolonged and localized lidocaine release. I. In vitro characterization.

    PubMed

    Chen, Pen-Chung; Park, Yoon Jeong; Chang, Li-Chien; Kohane, Daniel S; Bartlett, Robert H; Langer, Robert; Yang, Victor C

    2004-09-01

    Current treatment protocol for postoperative pain is to infuse anesthetic solution around nerves or into the epidural space. This clinical practice is beset by the short duration of the anesthetic effect unless the infusion is continuous. Continuous infusion, however, requires hospitalization of the patients, thereby increasing medical costs. In addition, it also causes systemic accumulation of the drug. We reported herein a novel treatment for the postoperative pain by applying to the surgical site a biodegradable microsphere-gel system for prolonged and localized release of encapsulated anesthetic drugs. This lidocaine-containing biodegradable poly(D,L-lactic acid) (PLA) microsphere system, although being established previously by other investigators, was hindered by a burst release and a followed rapid release of the drug within several hours in vitro. In this article, we demonstrated that by a step-by-step modification of the formulation, prolonged release of lidocaine, up to several days in vitro, could be achieved. Differential scanning calorimetry revealed a lower glass transition temperature for these lidocaine-loaded microspheres comparing to that of lidocaine-free microspheres. This decreased Tg explained for the tendency of the lidocaine-loaded microspheres to physically fuse at higher temperatures. In vitro studies showed that microspheres, when loaded with 35% lidocaine, yielded a threefold increase in the degradation rate. The molecular weight of PLA of the drug-loaded microspheres was reduced by 50% within a period of 1 month. Based on the results (of prolonged lidocaine release and rapid PLA microsphere degradation), this lidocaine-loaded PLA microsphere system could offer a simple solution to the treatment of postoperative pain.

  6. Fatigue associated with prolonged graded running.

    PubMed

    Giandolini, Marlene; Vernillo, Gianluca; Samozino, Pierre; Horvais, Nicolas; Edwards, W Brent; Morin, Jean-Benoît; Millet, Guillaume Y

    2016-10-01

    Scientific experiments on running mainly consider level running. However, the magnitude and etiology of fatigue depend on the exercise under consideration, particularly the predominant type of contraction, which differs between level, uphill, and downhill running. The purpose of this review is to comprehensively summarize the neurophysiological and biomechanical changes due to fatigue in graded running. When comparing prolonged hilly running (i.e., a combination of uphill and downhill running) to level running, it is found that (1) the general shape of the neuromuscular fatigue-exercise duration curve as well as the etiology of fatigue in knee extensor and plantar flexor muscles are similar and (2) the biomechanical consequences are also relatively comparable, suggesting that duration rather than elevation changes affects neuromuscular function and running patterns. However, 'pure' uphill or downhill running has several fatigue-related intrinsic features compared with the level running. Downhill running induces severe lower limb tissue damage, indirectly evidenced by massive increases in plasma creatine kinase/myoglobin concentration or inflammatory markers. In addition, low-frequency fatigue (i.e., excitation-contraction coupling failure) is systematically observed after downhill running, although it has also been found in high-intensity uphill running for different reasons. Indeed, low-frequency fatigue in downhill running is attributed to mechanical stress at the interface sarcoplasmic reticulum/T-tubule, while the inorganic phosphate accumulation probably plays a central role in intense uphill running. Other fatigue-related specificities of graded running such as strategies to minimize the deleterious effects of downhill running on muscle function, the difference of energy cost versus heat storage or muscle activity changes in downhill, level, and uphill running are also discussed.

  7. Exceptionally prolonged tooth formation in elasmosaurid plesiosaurians

    PubMed Central

    Kear, Benjamin P.; Larsson, Dennis; Lindgren, Johan; Kundrát, Martin

    2017-01-01

    Elasmosaurid plesiosaurians were globally prolific marine reptiles that dominated the Mesozoic seas for over 70 million years. Their iconic body-plan incorporated an exceedingly long neck and small skull equipped with prominent intermeshing ‘fangs’. How this bizarre dental apparatus was employed in feeding is uncertain, but fossilized gut contents indicate a diverse diet of small pelagic vertebrates, cephalopods and epifaunal benthos. Here we report the first plesiosaurian tooth formation rates as a mechanism for servicing the functional dentition. Multiple dentine thin sections were taken through isolated elasmosaurid teeth from the Upper Cretaceous of Sweden. These specimens revealed an average of 950 daily incremental lines of von Ebner, and infer a remarkably protracted tooth formation cycle of about 2–3 years–other polyphyodont amniotes normally take ~1–2 years to form their teeth. Such delayed odontogenesis might reflect differences in crown length and function within an originally uneven tooth array. Indeed, slower replacement periodicity has been found to distinguish larger caniniform teeth in macrophagous pliosaurid plesiosaurians. However, the archetypal sauropterygian dental replacement system likely also imposed constraints via segregation of the developing tooth germs within discrete bony crypts; these partly resorbed to allow maturation of the replacement teeth within the primary alveoli after displacement of the functional crowns. Prolonged dental formation has otherwise been linked to tooth robustness and adaption for vigorous food processing. Conversely, elasmosaurids possessed narrow crowns with an elongate profile that denotes structural fragility. Their apparent predilection for easily subdued prey could thus have minimized this potential for damage, and was perhaps coupled with selective feeding strategies that ecologically optimized elasmosaurids towards more delicate middle trophic level aquatic predation. PMID:28241059

  8. Prolonged swimming performance of northern squawfish

    USGS Publications Warehouse

    Mesa, Matthew G.; Olson, Todd M.

    1993-01-01

    We determined the prolonged swimming performance of two size-classes of northern squawfish Ptychocheilus oregonensis at 12 and 18°C. The percentage of fish fatigued was positively related to water velocity and best described by an exponential model. At 12°C, the velocity at which 50% of the fish fatigued (FV50) was estimated to be 2.91 fork lengths per second (FL/s; 100 cm/s) for medium-sized fish (30–39 cm) and 2.45 FL/s (104 cm/s) for large fish (40–49 cm). At 18°C, estimated FV50 was 3.12 FL/s (107 cm/s) for medium fish and 2.65 FL/s (112 cm/s) for large fish. Rate of change in percent fatigue was affected by fish size and water temperature. Large fish fatigued at a higher rate than medium-sized fish; all fish fatigued faster at 12 than at 18°C. The mean times to fatigue at velocities of 102–115 cm/s ranged from 14 to 28 min and were not affected by fish size or water temperature. Our results indicate that water velocities from 100 to 130 cm/s may exclude or reduce predation by northern squawfish around juvenile salmonid bypass outfalls at Columbia River dams, at least during certain times of the year. We recommend that construction or modification of juvenile salmonid bypass facilities place the outfall in an area of high water velocity and distant from eddies, submerged cover, and littoral areas.

  9. [Prolonged epidural analgesia induced by clopheline in combination with lidocaine in obstetric analgesia].

    PubMed

    Semenikhin, A A; En Din Kim; Kurbanov, S D

    1998-01-01

    The study was carried out in 178 women without grave obstetrical or extragenital diseases. In group 1 labor pain was relieved by prolonged epidural anesthesia with 2% lidocaine solution (2-2.5 mg/kg), in group 2 prolonged epidural anesthesia with 1% lidocaine solution (1 mg/kg) and 0.01% clofelin (1 microgram/kg) was administered. Central hemodynamics, heart rhythm, external respiration function, uterine contractility, and fetal intrauterine status were assessed. The findings indicate that none of the methods had a negative impact on the vital parameters of women and newborns at any stage of anesthesia. However, a combination of epidural clofelin (1 microgram/kg) with lidocaine permits an appreciable decrease in the doses of both drugs without decreasing the efficacy of anesthesia. This method has a favorable effect on the course of labor: the mouth of the womb opens sooner at a lower uterine activity and there are no negative effects on the fetus and newborn.

  10. Torsades de pointes induced by concomitant use of chlorpheniramine and propranolol: An unusual presentation with no QT prolongation

    PubMed Central

    Ösken, Altuğ; Yelgeç, Nizamettin Selçuk; Zehir, Regayip; Öz, Tuğba Kemaloğlu; Yaylacı, Selçuk; Akdemir, Ramazan; Gündüz, Hüseyin

    2016-01-01

    Drug-induced torsades de pointes (TdP) is a rare but potentially fatal adverse effect of commonly prescribed medications including cardiac and noncardiac drugs. Importantly, many drugs have been reported to cause the characteristic Brugada syndrome-linked electrocardiography (ECG) abnormalities and/or (fatal) ventricular tachyarrhythmias. Chlorpheniramine and propranolol have the arrhythmogenic effects reported previously. A review of literature revealed a large number of case reports of chlorpheniramine or propranolol use resulting in QTc prolongation, TdP, or both. However, we wish to report the case of a patient who was treated with a combination of chlorpheniramine and propranolol, whose ECG showed no QT prolongation but who suffered from cardiac arrest due to TdP. PMID:27756965

  11. Torsades de pointes induced by concomitant use of chlorpheniramine and propranolol: An unusual presentation with no QT prolongation.

    PubMed

    Ösken, Altuğ; Yelgeç, Nizamettin Selçuk; Zehir, Regayip; Öz, Tuğba Kemaloğlu; Yaylacı, Selçuk; Akdemir, Ramazan; Gündüz, Hüseyin

    2016-01-01

    Drug-induced torsades de pointes (TdP) is a rare but potentially fatal adverse effect of commonly prescribed medications including cardiac and noncardiac drugs. Importantly, many drugs have been reported to cause the characteristic Brugada syndrome-linked electrocardiography (ECG) abnormalities and/or (fatal) ventricular tachyarrhythmias. Chlorpheniramine and propranolol have the arrhythmogenic effects reported previously. A review of literature revealed a large number of case reports of chlorpheniramine or propranolol use resulting in QTc prolongation, TdP, or both. However, we wish to report the case of a patient who was treated with a combination of chlorpheniramine and propranolol, whose ECG showed no QT prolongation but who suffered from cardiac arrest due to TdP.

  12. Drug Development against Viral Diseases

    DTIC Science & Technology

    1987-02-01

    hemorrhagic fever ( CCHF ) virus in infant mice. Most compounds were tested using a single dose of drug administered 45 minutes before virus. Nine...protection from mortality and reproducible prolongation of survival time in primary testing against CCHF virus. These drugs include AVS#1 which is...SUMMARY OF RESULTS OF TESTING IN CCHF MODEL 11 TABLE 2 TEST VARIATION: VIRUS CONTROL (VC)1 4 TABLE 3 TEST VARIATION: POSVE CONTROL (VR+) 1 4 TABLE 4

  13. Mucoadhesive drug delivery systems

    PubMed Central

    Shaikh, Rahamatullah; Raj Singh, Thakur Raghu; Garland, Martin James; Woolfson, A David; Donnelly, Ryan F.

    2011-01-01

    Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal). PMID:21430958

  14. [Efficacy of prolonged therapy of vascular dementia].

    PubMed

    2011-01-01

    This open study was designed to assess efficacy and safety of long-term therapy with cerebrolysin in 48 patients aged 59-77 years with mild and moderately severe vascular dementia. The slowdown in the progress of this condition during the 3-year treatment period was evaluated. The efficacy and safety of the drug was assessed clinically and with the use of standard scales and neuropsychological tests. The long-term therapy with cerebrolysin was shown to be safe and highly efficacious as indicated by the improvement of cognitive and motor functions both at early and late stages of the treatment regardless of the severity of the disease. It is concluded that long-term therapy with cerebrolysin slows down the progress of vascular dementia and prevent deterioration of cognitive abilities.

  15. Development of a reservoir type prolonged release system with felodipine via simplex methodology

    PubMed Central

    IOVANOV, RAREŞ IULIU; TOMUŢĂ, IOAN; LEUCUŢA, SORIN EMILIAN

    2016-01-01

    Background and aims Felodipine is a dihydropyridine calcium antagonist that presents good characteristics to be formulated as prolonged release preparations. The aim of the study was the formulation and in vitro characterization of a reservoir type prolonged release system with felodipine, over a 12 hours period using the Simplex method. Methods The first step of the Simplex method was to study the influence of the granules coating method on the felodipine release. Furthermore the influence of the coating polymer type, the percent of the coating polymer and the percent of pore forming agent in the coating on the felodipine release were studied. Afterwards these two steps of the experimental design the percent of Surelease applied on the felodipine loaded granules and the percent of pore former in the polymeric coating formulation variables were studied. The in vitro dissolution of model drug was performed in phosphate buffer solution (pH 6.5) with 1% sodium lauryl sulfate. The released drug quantification was done using an HPLC method. The release kinetics of felodipine from the final granules was assessed using different mathematical models. Results A 12 hours release was achieved using granules with the size between 315–500 μm coated with 45% Surelease with different pore former ratios in the coating via the top-spray method. Conclusion We have prepared prolonged release coated granules with felodipine using a fluid bed system based on the Simplex method. The API from the studied final formulations was released over a 12 hours period and the release kinetics of the model drug substance from the optimized preparations fitted best the Higuchi and Peppas kinetic models. PMID:27004036

  16. Prolonged neuromuscular block in a preeclamptic patient induced by magnesium sulfate

    PubMed Central

    Berdai, Mohamed Adnane; Labib, Smael; Harandou, Mustapha

    2016-01-01

    Recent large use of magnesium in the obstetric population should incite anesthesiologists to control its side effects and drugs interactions. We report a case of a 30-year-old woman, with severe preeclampsia and HELLP syndrome, receiving sulfate magnesium and nicardipine, who underwent a cesarean section under general anesthesia. She developed a prolonged and deep neuromuscular blockade, which was antagonized three hours later with neostigmine. In case of therapeutic hypermagnesaemia, non-depolarizing relaxants must be used in reduced doses, and at increased time intervals, with appropriate neuromuscular monitoring. PMID:28154698

  17. Follow-up measurements of Nevirapine plasma levels over a prolonged period.

    PubMed

    Sienz, M; Zilly, M; Ebigbo, A; Knipper, A; Winzer, R; Klinker, H; Langmann, Peter

    2004-08-31

    Over a period of more than four years of treatment, 177 Nevirapine plasma levels were taken from 27 patients. The values showed a high inter-patient variability and a lower intra-patient variability. Differences in body weight turned out to be the main reason for inter-patient variability. Treatment over a prolonged period did not result in any change in plasma concentrations. Adjusting dosage by means of therapeutic drug monitoring would appear to be a reasonable way of maximising patient benefit from treatment.

  18. Constrained spheroids for prolonged hepatocyte culture.

    PubMed

    Tong, Wen Hao; Fang, Yu; Yan, Jie; Hong, Xin; Hari Singh, Nisha; Wang, Shu Rui; Nugraha, Bramasta; Xia, Lei; Fong, Eliza Li Shan; Iliescu, Ciprian; Yu, Hanry

    2016-02-01

    Liver-specific functions in primary hepatocytes can be maintained over extended duration in vitro using spheroid culture. However, the undesired loss of cells over time is still a major unaddressed problem, which consequently generates large variations in downstream assays such as drug screening. In static culture, the turbulence generated by medium change can cause spheroids to detach from the culture substrate. Under perfusion, the momentum generated by Stokes force similarly results in spheroid detachment. To overcome this problem, we developed a Constrained Spheroids (CS) culture system that immobilizes spheroids between a glass coverslip and an ultra-thin porous Parylene C membrane, both surface-modified with poly(ethylene glycol) and galactose ligands for optimum spheroid formation and maintenance. In this configuration, cell loss was minimized even when perfusion was introduced. When compared to the standard collagen sandwich model, hepatocytes cultured as CS under perfusion exhibited significantly enhanced hepatocyte functions such as urea secretion, and CYP1A1 and CYP3A2 metabolic activity. We propose the use of the CS culture as an improved culture platform to current hepatocyte spheroid-based culture systems.

  19. Prolonged psychosis after Amanita muscaria ingestion.

    PubMed

    Brvar, Miran; Mozina, Martin; Bunc, Matjaz

    2006-05-01

    Amanita muscaria has a bright red or orange cap covered with small white plaques. It contains the isoxazole derivatives ibotenic acid, muscimol and muscazone and other toxins such as muscarine. The duration of clinical manifestations after A. muscaria ingestion does not usually exceed 24 hours; we report on a 5-day paranoid psychosis after A. muscaria ingestion. A 48-year-old man, with no previous medical history, gathered and ate mushrooms he presumed to be A. caesarea. Half an hour later he started to vomit and fell asleep. He was found comatose having a seizure-like episode. On admission four hours after ingestion he was comatose, but the remaining physical and neurological examinations were unremarkable. Creatine kinase was 8.33 microkat/l. Other laboratory results and brain CT scan were normal. Toxicology analysis did not find any drugs in his blood or urine. The mycologist identified A. muscaria among the remaining mushrooms. The patient was given activated charcoal. Ten hours after ingestion, he awoke and was completely orientated; 18 hours after ingestion his condition deteriorated again and he became confused and uncooperative. Afterwards paranoid psychosis with visual and auditory hallucinations appeared and persisted for five days. On the sixth day all symptoms of psychosis gradually disappeared. One year later he is not undergoing any therapy and has no symptoms of psychiatric disease. We conclude that paranoid psychosis with visual and auditory hallucinations can appear 18 hours after ingestion of A. muscaria and can last for up to five days.

  20. Corticosteroid-responsive prolonged thrombocytopenia following dengue haemorrhagic fever.

    PubMed

    Leong, K W; Srinivas, P

    1993-09-01

    A case of prolonged thrombocytopenia following dengue haemorrhagic fever in a 15 year old boy is reported. The mechanism was presumed to be immunological and he responded dramatically to oral prednisolone.

  1. Prolongation of RBC survival in the hypophysectomized rat.

    NASA Technical Reports Server (NTRS)

    Landaw, S. A.; Bristol, S. K.

    1971-01-01

    Red blood cell (RBC) survival was prolonged in hypophysectomized rats. While the rate of random hemolysis was decreased in some hypophysectomized hosts, in all directly injected and cross-transfused hypophysectomized rat hosts, there was a significant prolongation of the phase of senescent death. In contrast, RBCs from hypophysectomized donors survived normally in normal hosts. These experiments are further evidence of a relationship between RBC aging and metabolic rate, and suggest an intimate involvement with the calorigenic hormones.

  2. Identifying Molecular Targets For PTSD Treatment Using Single Prolonged Stress

    DTIC Science & Technology

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0377 TITLE: Identifying Molecular Targets For PTSD Treatment Using Single ...Targets For PTSD Treatment Using Single Prolonged Stress 5b. GRANT NUMBER W81XWH-13-1-0377 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...on Specific Aims 3 and 4 ahead of schedule. 15. SUBJECT TERMS PTSD, Single Prolonged Stress, Neurobiological Mechanisms 16. SECURITY

  3. Two cases of lichen striatus with prolonged active phase.

    PubMed

    Feely, Meghan A; Silverberg, Nanette B

    2014-01-01

    Lichen striatus is a localized, eczematous disorder distributed along the lines of Blaschko, primarily affecting children. In the literature, lesions have been described as having an active phase of inflamed lesions for 6 to 12 months followed by flattening and persistent pigmentary alteration. We describe two girls who had prolonged active-phase lesions for 2.5 and 3.5 years, respectively. Practitioners should be aware that lesions of lichen striatus may have a prolonged active phase.

  4. Outcome of Induction of Labour in Prolonged Pregnancy.

    PubMed

    Nasrin, S; Islam, S; Shahida, S M; Begum, R A; Haque, N

    2015-10-01

    This was a hospital based prospective clinical study conducted among women having prolonged pregnancy to assess the outcome of induction of labour in prolonged pregnancy cases. One hundred and thirty nine women having uncomplicated prolonged pregnancy were studied. The study was carried out in Sir Salimullah Medical College & Mitford Hospital, Dhaka from 01 July 2010 to 30 March 2011. In this study 66% of the respondents had vaginal delivery on routine induction of labour and in 34% cases induction failed. Ninety three percent (93%) of the multigravida had vaginal delivery and in primigravida their vaginal delivery rate was 47.5%. Regarding cervical condition for delivery, 75% of the respondents having favourable cervix had vaginal delivery and in case of unfavourable cervix respondents, they had 55% cases of vaginal delivery. About the foetal outcome it was evidenced from this study that the perinatal adverse outcome increases with the increasing age of gestation beyond 40 completed weeks of gestation. This study showed that the use of prostaglandins for cervical ripening and by confirming the diagnosis of prolonged pregnancy, the delivery outcome in prolonged pregnancy can be improved. The study also showed that induction of labour is not associated with any major complications and the routine induction of labour in prolonged pregnancy is beneficial for both mother and the baby.

  5. Determinants of prolonged intensive care unit stay in patients after cardiac surgery: a prospective observational study

    PubMed Central

    Kapadohos, Theodore; Angelopoulos, Epameinondas; Vasileiadis, Ioannis; Nanas, Serafeim; Kotanidou, Anastasia; Karabinis, Andreas; Marathias, Katerina

    2017-01-01

    Background Prolonged intensive care unit (ICU) stay of patients after cardiac surgery has a major impact on overall cost and resource utilization. The aim of this study was to identify perioperative factors which prolong stay in ICU. Methods All adult patients from a single, specialized cardiac center who were admitted to the ICU after cardiac surgery during a 2-month period were included. Demographic and clinical characteristics, comorbidities, preoperative use of drugs, intraoperative variables, and postoperative course were recorded. Hemodynamic and blood gas measurements were recorded at four time intervals during the first 24 postoperative hours. Routine hematologic and biochemical laboratory results were recorded preoperatively and in the first postoperative hours. Results During the study period 145 adult patients underwent cardiac surgery: 65 (45%) underwent coronary artery bypass graft surgery, 38 (26%) valve surgery, 26 (18%) combined surgery and 16 (11%) other types of cardiac operation. Seventy nine (54%) patients had an ICU stay of less than 24 hours. Random forests analysis identified four variables that had a major impact on the length of stay (LOS) in ICU; these variables were subsequently entered in a logistic regression model: preoperative hemoglobin [odds ratio (OR) =0.68], duration of aortic clamping (OR =1.01) and ratio of arterial oxygen partial pressure to inspired oxygen fraction (PaO2/FiO2) (OR =0.99) and blood glucose during the first four postoperative hours (OR =1.02). ROC curve analysis showed an AUC =0.79, P<0.001, 95% CI: 0.71–0.86. Conclusions Low preoperative hemoglobin, prolonged aortic clamping time and low PaO2/FiO2 ratio and blood glucose measured within the first postoperative hours, were strongly related with prolonged LOS in ICU. PMID:28203408

  6. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

    PubMed Central

    Calver, Leonie; Isbister, Geoffrey K

    2014-01-01

    Aims To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings. Methods This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist's discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QTcF (Fridericia's HR correction) was calculated and >500 ms was defined as abnormal. Results Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QTcF >500 ms but only in one taking methadone was the timing of QTcF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias. Conclusion QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs. PMID:24168079

  7. [New drugs for colorectal cancer].

    PubMed

    Pestalozzi, B C; Jäger, D; Knuth, A

    2004-09-01

    Drug treatment of colorectal cancer has made impressive progress during the past 10 years. In addition to fluorouracil new anticancer drugs like irinotecan and oxaliplatin have become available. The activity of fluorouracil was optimized by using schedules of prolonged infusion. Capecitabine is an oral pro-drug of fluorouracil. When colorectal metastases are limited to the liver they should be resected if possible. Sometimes they can be reduced in size by primary chemotherapy (downstaging) and resected later. Very new and exciting are reports with the monoclonal antibody bevacizumab in combination with chemotherapy. Bevacizumab blocks angiogenesis. So far it is available only in the USA.

  8. Prolonged cardiac arrest complicating a massive ST-segment elevation myocardial infarction associated with marijuana consumption

    PubMed Central

    Orsini, Jose; Blaak, Christa; Rajayer, Salil; Gurung, Vikash; Tam, Eric; Morante, Joaquin; Shamian, Ben; Malik, Ryan

    2016-01-01

    Recreational substance use and misuse constitute a major public health issue. The annual rate of recreational drug overdose-related deaths is increasing exponentially, making unintentional overdose as the leading cause of injury-related deaths in the United States. Marijuana is the most widely used recreational illicit drug, with approximately 200 million users worldwide. Although it is generally regarded as having low acute toxicity, heavy marijuana usage has been associated with life-threatening consequences. Marijuana is increasingly becoming legal in the United States for both medical and recreational use. Although the most commonly seen adverse effects resulting from its consumption are typically associated with neurobehavioral and gastrointestinal symptoms, cases of severe toxicity involving the cardiovascular system have been reported. In this report, the authors describe a case of cannabis-associated ST-segment elevation myocardial infarction leading to a prolonged cardiac arrest. PMID:27609717

  9. Severe prolonged gastroparesis after cytoreductive surgery in an advanced ovarian cancer patient.

    PubMed

    Caprino, P; Fagotti, A; Missere, M; Fanfani, F; Scambia, G

    2006-01-01

    Number and type of complications after ovarian cancer surgery can vary greatly according to both the patient's characteristics, and the extension and type of surgery. Current literature lacks in mentioning specific gastrointestinal side effects, which could be evidenced during the early postoperative course of patients submitted to major gynecological oncologic surgery. A severe gastroparesis prolonged for 2 months after cytoreductive surgery in an advanced ovarian cancer patient was successfully treated with conservative multidrug therapy. Gastroparesis has to be enumerated as a rare but possible event after major gynecological oncologic surgery. A conservative management involving decompressive nasogastric tube, nutritional support, antiemetic drugs, prokinetic drugs is suggested, while surgical therapy is only recommended in a very small subset of unmanageable patients.

  10. Prolonged cardiac arrest complicating a massive ST-segment elevation myocardial infarction associated with marijuana consumption.

    PubMed

    Orsini, Jose; Blaak, Christa; Rajayer, Salil; Gurung, Vikash; Tam, Eric; Morante, Joaquin; Shamian, Ben; Malik, Ryan

    2016-01-01

    Recreational substance use and misuse constitute a major public health issue. The annual rate of recreational drug overdose-related deaths is increasing exponentially, making unintentional overdose as the leading cause of injury-related deaths in the United States. Marijuana is the most widely used recreational illicit drug, with approximately 200 million users worldwide. Although it is generally regarded as having low acute toxicity, heavy marijuana usage has been associated with life-threatening consequences. Marijuana is increasingly becoming legal in the United States for both medical and recreational use. Although the most commonly seen adverse effects resulting from its consumption are typically associated with neurobehavioral and gastrointestinal symptoms, cases of severe toxicity involving the cardiovascular system have been reported. In this report, the authors describe a case of cannabis-associated ST-segment elevation myocardial infarction leading to a prolonged cardiac arrest.

  11. Transmural dispersion of repolarization as a preclinical marker of drug-induced proarrhythmia.

    PubMed

    Said, Tamer H; Wilson, Lance D; Jeyaraj, Darwin; Fossa, Anthony A; Rosenbaum, David S

    2012-08-01

    Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.

  12. Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

    PubMed Central

    Anand, Kanwaljeet J. S.; Willson, Douglas F.; Berger, John; Harrison, Rick; Meert, Kathleen L.; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J. L.; Prodhan, Parthak; Dean, J. Michael; Nicholson, Carol

    2012-01-01

    OBJECTIVE After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal. PMID:20403936

  13. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

  14. Dissociated grey matter changes with prolonged addiction and extended abstinence in cocaine users.

    PubMed

    Connolly, Colm G; Bell, Ryan P; Foxe, John J; Garavan, Hugh

    2013-01-01

    Extensive evidence indicates that current and recently abstinent cocaine abusers compared to drug-naïve controls have decreased grey matter in regions such as the anterior cingulate, lateral prefrontal and insular cortex. Relatively little is known, however, about the persistence of these deficits in long-term abstinence despite the implications this has for recovery and relapse. Optimized voxel based morphometry was used to assess how local grey matter volume varies with years of drug use and length of abstinence in a cross-sectional study of cocaine users with various durations of abstinence (1-102 weeks) and years of use (0.3-24 years). Lower grey matter volume associated with years of use was observed for several regions including anterior cingulate, inferior frontal gyrus and insular cortex. Conversely, higher grey matter volumes associated with abstinence duration were seen in non-overlapping regions that included the anterior and posterior cingulate, insular, right ventral and left dorsal prefrontal cortex. Grey matter volumes in cocaine dependent individuals crossed those of drug-naïve controls after 35 weeks of abstinence, with greater than normal volumes in users with longer abstinence. The brains of abstinent users are characterized by regional grey matter volumes, which on average, exceed drug-naïve volumes in those users who have maintained abstinence for more than 35 weeks. The asymmetry between the regions showing alterations with extended years of use and prolonged abstinence suggest that recovery involves distinct neurobiological processes rather than being a reversal of disease-related changes. Specifically, the results suggest that regions critical to behavioral control may be important to prolonged, successful, abstinence.

  15. Prolonged Cortisol Reactivity to Stress and White Matter in Schizophrenia

    PubMed Central

    Nugent, Katie L.; Chiappelli, Joshua; Sampath, Hemalatha; Rowland, Laura M.; Thangavelu, Kavita; Davis, Beshaun; Du, Xiaoming; Muellerklein, Florian; Daughters, Stacey; Kochunov, Peter; Hong, L. Elliot

    2015-01-01

    Objective While acute hypothalamic-pituitary-adrenal axis response to stress is often adaptive, prolonged responses may have detrimental effects. Many components of white matter structures are sensitive to prolonged cortisol exposure. We aimed to identify a behavioral laboratory assay for which cortisol response related to brain pathophysiology in schizophrenia. We hypothesized that an abnormally prolonged cortisol response to stress may be linked to abnormal white matter integrity in patients with schizophrenia. Methods Acute and prolonged salivary cortisol response was measured outside the scanner at pre-test and then at 0, 20, and 40 minutes after a psychological stress task in patients with schizophrenia (n=45) and controls (n=53). Tract-averaged white matter was measured by 64-direction diffusion tensor imaging in a subset of patients (n=30) and controls (n=33). Results Patients who did not tolerate and quit the psychological stress task had greater acute (t=2.52, p=0.016; t=3.51, p=0.001 at zero and 20 minutes) and prolonged (t=3.62, p=0.001 at 40 minutes) cortisol reactivity compared with patients who finished the task. Abnormally prolonged cortisol reactivity in patients was significantly associated with reduced white matter integrity (r=−0.468, p=0.009). Regardless of task completion status, acute cortisol response was not related to the white matter measures in patients or controls. Conclusions This paradigm was successful at identifying a subset of patients whose cortisol response was associated with brain pathophysiology. Abnormal cortisol response may adversely affect white matter integrity, partly explaining this pathology observed in schizophrenia. Prolonged stress responses may be targeted for intervention to test for protective effects against white matter damages. PMID:26186431

  16. From prolonging life to prolonging working life: Tackling unemployment among liver-transplant recipients

    PubMed Central

    Åberg, Fredrik

    2016-01-01

    Return to active and productive life is a key goal of modern liver transplantation (LT). Despite marked improvements in quality of life and functional status, a substantial proportion of LT recipients are unable to resume gainful employment. Unemployment forms a threat to physical and psychosocial health, and impairs LT cost-utility through lost productivity. In studies published after year 2000, the average post-LT employment rate is 37%, ranging from 22% to 55% by study. Significant heterogeneity exists among studies. Nonetheless, these employment rates are lower than in the general population and kidney-transplant population. Most consistent employment predictors include pre-LT employment status, male gender, functional/health status, and subjective work ability. Work ability is impaired by physical fatigue and depression, but affected also by working conditions and society. Promotion of post-LT employment is hampered by a lack of interventional studies. Prevention of pre-LT disability by effective treatment of (minimal) hepatic encephalopathy, maintaining mobility, and planning work adjustments early in the course of chronic liver disease, as well as timely post-LT physical rehabilitation, continuous encouragement, self-efficacy improvements, and depression management are key elements of successful employment-promoting strategies. Prolonging LT recipients’ working life would further strengthen the success of transplantation, and this is likely best achieved through multidisciplinary efforts ideally starting even before LT candidacy. PMID:27076755

  17. No Evidence for Prolonged Visible Persistence in Patients with Schizophrenia

    PubMed Central

    Grimsen, Cathleen; Brand, Andreas; Fahle, Manfred

    2013-01-01

    Background Temporal visual processing is strongly deteriorated in patients with schizophrenia. For example, the interval required between a visual stimulus and a subsequent mask has to be much longer in schizophrenic patients than in healthy controls. We investigated whether this deficit in temporal resolution is accompanied by prolonged visual persistence and/or deficient temporal precision (temporal asynchrony perception). Methodology/Principal Findings We investigated visual persistence in three experiments. In the first, measuring temporal processing by so-called backward masking, prolonged visible persistence is supposed to decrease performance. In the second experiment, requiring temporal integration, prolonged persistence is supposed to improve performance. In the third experiment, we investigated asynchrony detection, as another measure of temporal resolution. Eighteen patients with schizophrenia and 15 healthy controls participated. Asynchrony detection was intact in the patients. However, patients' performance was inferior compared to healthy controls in the first two experiments. Hence, temporal processing in schizophrenic patients is indeed significantly impaired but this impairment is not caused by prolonged temporal integration. Conclusions/Significance Our results argue against a generally prolonged visual persistence in patients with schizophrenia. Together with the preserved ability of patients, to detect temporal asynchronies in permanently presented stimuli, the results indicate a more specific deficit in temporal processing of schizophrenic patients. PMID:23536838

  18. Integration of asynchronously released quanta prolongs the postsynaptic spike window.

    PubMed

    Iremonger, Karl J; Bains, Jaideep S

    2007-06-20

    Classically, the release of glutamate in response to a presynaptic action potential causes a brief increase in postsynaptic excitability. Previous reports indicate that at some central synapses, a single action potential can elicit multiple, asynchronous release events. This raises the possibility that the temporal dynamics of neurotransmitter release may determine the duration of altered postsynaptic excitability. In response to physiological challenges, the magnocellular neurosecretory cells (MNCs) in the paraventricular nucleus of the hypothalamus (PVN) exhibit robust and prolonged increases in neuronal activity. Although the postsynaptic conductances that may facilitate this form of activity have been investigated thoroughly, the role of presynaptic release has been largely overlooked. Because the specific patterns of activity generated by MNCs require the activation of excitatory synaptic inputs, we sought to characterize the release dynamics at these synapses and determine whether they contribute to prolonged excitability in these cells. We obtained whole-cell recordings from MNCs in brain slices of postnatal day 21-44 rats. Stimulation of glutamatergic inputs elicited large and prolonged postsynaptic events that resulted from the summation of multiple, asynchronously released quanta. Asynchronous release was selectively inhibited by the slow calcium buffer EGTA-AM and potentiated by brief high-frequency stimulus trains. These trains caused a prolonged increase in postsynaptic spike activity that could also be eliminated by EGTA-AM. Our results demonstrate that glutamatergic terminals in PVN exhibit asynchronous release, which is important in generating large postsynaptic depolarizations and prolonged spiking in response to brief, high-frequency bursts of presynaptic activity.

  19. Drug allergies

    MedlinePlus

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  20. [Cardiovascular monitoring of psychotropic drugs].

    PubMed

    Momomura, Shin-ichi

    2014-01-01

    It has been reported that a variety of cardiovascular side effects are induced by drugs, including psychotropic drugs. Among them, myocarditis/cardiomyopathy and long QT syndrome are addressed in this article. Myocarditis is due to inflammation of the myocardium, and the pericardium is also often involved. In that case, it is called myopericarditis. Myocarditis is caused by a variety of etiologies, including viruses, bacteria, inflammatory diseases, and drugs. Psychotropic drugs such as clozapine have been reported to induce myocarditis. In critical cases, the hemodynamics deteriorate due to cardiac insufficiency, which can be fatal. The principal of treatment of drug-induced myocarditis is, of course, cessation of the causative drug. Cardio-circulatory support including inotropes and, in severe cases, mechanical support, are also necessary. Cardiomyopathy can also be induced by drugs. Drug-induced cardiomyopathy usually presents as dilated cardiomyopathy, characterized by left ventricular dilatation and reduced contraction. Anthracyclin is well-known as a cause of drug-induced cardiomyopathy. The treatment of drug-induced cardiomyopathy is in accordance with chronic heart failure. Long QT syndrome (LQTS) is also a relatively common manifestation of the cardiovascular side effects of drugs. Especially, many psychotropic drugs can induce LQTS. LQTS does not simply mean prolongation of the QT interval in electrocardiography, but it includes life-threatening ventricular arrhythmia derived from QT prolongation. Torsade de Pointes is a common ventricular arrhythmia accompanying LQTS. To avoid or detect the occurrence of these serious cardiovascular side effects in time, careful monitoring based on ECG, symptoms, and blood tests is recommended when a drug reported to induce such side effects must be used. ECG must be routinely taken before the drug is initiated. In 2 to 4 weeks after initiation, ECG may be taken regardless of the cardiovascular symptoms. If any ECG

  1. Poly(DL:lactic acid-castor oil) 3:7-bupivacaine formulation: reducing burst effect prolongs efficacy in vivo.

    PubMed

    Sokolsky-Papkov, Marina; Golovanevski, Ludmila; Domb, Abraham J; Weiniger, Carolyn F

    2010-06-01

    Prolonged analgesia may be achieved using a single injection of slow-release local anesthetic formulation. The study objective was to improve the efficacy of a previously reported formulation comprising 10% bupivacaine in poly(DL:lactic acid co castor oil) 3:7. The polymer was loaded with 15% bupivacaine and injected through a 22G needle close to the sciatic nerve of ICR mice. Sensory and motor nerve blockade were measured. The efficacy and toxicity of the polymer-drug combination were determined. Sixty percent of the incorporated bupivacaine was released during 1 week in vitro. During in vitro release no burst effect was seen, suggesting low toxicity of the formulation. Single injection of 0.1 mL of 15% polymer-bupivacaine formulation caused motor block that lasted 64 h and sensory block that lasted 96 h. The MTD of the polymer-drug formulation was established as 0.175 mL. Microscopic examination of the injection sites revealed reversible nerve inflammation and normal internal organs. The polymer poly(DL:lactic acid co castor oil) 3:7 is a safe carrier for prolonged activity of bupivacaine up to 96 h. The increase of drug load in the formulation reduces the drug release rates due to stronger polymer-drug interactions and higher overall hydrophobicity of the formulation.

  2. Prolonged Eyelid Closure Episodes during Sleep Deprivation in Professional Drivers

    PubMed Central

    Alvaro, Pasquale K.; Jackson, Melinda L.; Berlowitz, David J.; Swann, Philip; Howard, Mark E.

    2016-01-01

    Study Objectives: Real life ocular measures of drowsiness use average blink duration, amplitude and velocity of eyelid movements to reflect drowsiness in drivers. However, averaged data may conceal the variability in duration of eyelid closure episodes, and more prolonged episodes that indicate higher levels of drowsiness. The current study aimed to describe the frequency and duration of prolonged eyelid closure episodes during acute sleep deprivation. Methods: Twenty male professional drivers (mean age ± standard deviation = 41.9 ± 8.3 years) were recruited from the Transport Workers Union newsletter and newspaper advertisements in Melbourne, Australia. Each participant underwent 24 hours of sleep deprivation and completed a simulated driving task (AusEd), the Psychomotor Vigilance Task, and the Karolinska Sleepiness Scale. Eyelid closure episodes during the driving task were recorded and analyzed manually from digital video recordings. Results: Eyelid closure episodes increased in frequency and duration with a median of zero s/h of eyelid closure after 3 h increasing to 34 s/h after 23 h awake. Eyelid closure episodes were short and infrequent from 3 to 14 h of wakefulness. After 17 h of sleep deprivation, longer and more frequent eyelid closure episodes began to occur. Episodes lasting from 7 seconds up to 18 seconds developed after 20 h of wakefulness. Length of eyelid closure episodes was moderately to highly correlated with the standard deviation of lateral lane position, braking reaction time, crashes, impaired vigilance, and subjective sleepiness. Conclusions: The frequency and duration of episodes of prolonged eyelid closure increases during acute sleep deprivation, with very prolonged episodes after 17 hours awake. Automated devices that assess drowsiness using averaged measures of eyelid closure episodes need to be able to detect prolonged eyelid closure episodes that occur during more severe sleep deprivation. Citation: Alvaro PK, Jackson ML

  3. Cell-Mediated Drugs Delivery

    PubMed Central

    Batrakova, Elena V.; Gendelman, Howard E.; Kabanov, Alexander V.

    2011-01-01

    INTRODUCTION Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils, and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus immune cells can be exploited as trojan horses for drug delivery. AREAS COVERED IN THIS REVIEW This paper reviews how immunocytes laden with drugs can cross the blood brain or blood tumor barriers, to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points. EXPERT OPINION Using cells as delivery vehicles enables targeted drug transport, and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a novel disease combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms into drug delivery may open new perspectives for the active delivery of drugs. PMID:21348773

  4. Bartonella henselae Infective Endocarditis Detected by a Prolonged Blood Culture.

    PubMed

    Mito, Tsutomu; Hirota, Yusuke; Suzuki, Shingo; Noda, Kazutaka; Uehara, Takanori; Ohira, Yoshiyuki; Ikusaka, Masatomi

    A 65-year-old Japanese man was admitted with a 4-month history of fatigue and exertional dyspnea. Transthoracic echocardiography revealed a vegetation on the aortic valve and severe aortic regurgitation. Accordingly, infective endocarditis and heart failure were diagnosed. Although a blood culture was negative on day 7 after admission, a prolonged blood culture with subculture was performed according to the patient's history of contact with cats. Consequently, Bartonella henselae was isolated. Bartonella species are fastidious bacteria that cause blood culture-negative infective endocarditis. This case demonstrates that B. henselae may be detected by prolonged incubation of blood cultures.

  5. Bartonella henselae Infective Endocarditis Detected by a Prolonged Blood Culture

    PubMed Central

    Mito, Tsutomu; Hirota, Yusuke; Suzuki, Shingo; Noda, Kazutaka; Uehara, Takanori; Ohira, Yoshiyuki; Ikusaka, Masatomi

    2016-01-01

    A 65-year-old Japanese man was admitted with a 4-month history of fatigue and exertional dyspnea. Transthoracic echocardiography revealed a vegetation on the aortic valve and severe aortic regurgitation. Accordingly, infective endocarditis and heart failure were diagnosed. Although a blood culture was negative on day 7 after admission, a prolonged blood culture with subculture was performed according to the patient's history of contact with cats. Consequently, Bartonella henselae was isolated. Bartonella species are fastidious bacteria that cause blood culture-negative infective endocarditis. This case demonstrates that B. henselae may be detected by prolonged incubation of blood cultures. PMID:27746451

  6. Changes in the human blood coagulating system during prolonged hypokinesia

    NASA Technical Reports Server (NTRS)

    Filatova, L. M.; Anashkin, O. D.

    1978-01-01

    Changes in the coagulating system of the blood were studied in six subjects during prolonged hypokinesia. Thrombogenic properties of the blood rose in all cases on the 8th day. These changes are explained by stress reaction due to unusual conditions for a healthy person. Changes in the blood coagulating system in the group subjected to physical exercise and without it ran a practically parallel course. Apparently physical exercise is insufficient to prevent such changes that appear in the coagulating system of the blood during prolonged hypokinesia.

  7. Sponsored parachute jumps--can they cause prolonged pain?

    PubMed

    Straiton, N; Sterland, J

    1986-06-01

    A survey of parachute injuries sustained in 1984 at a local parachute club was made using hospital notes and a questionnaire. The overall injury rate was 0.2%. The injury rate in first time jumpers was 1.1%. The injuries often resulted in a prolonged hospital stay, time off work and residual pain and disability. Injury rates may be reduced by more prolonged and intensive training preceding the first jumps. Those people not interested in parachuting as a regular sport and who jump once only in order to raise money for charity are at risk of serious injury and perhaps should consider less dangerous alternatives.

  8. Drug Safety

    MedlinePlus

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  9. Screening for Older Emergency Department Inpatients at Risk of Prolonged Hospital Stay: The Brief Geriatric Assessment Tool

    PubMed Central

    Launay, Cyrille P.; de Decker, Laure; Kabeshova, Anastasiia; Annweiler, Cédric; Beauchet, Olivier

    2014-01-01

    Background The aims of this study were 1) to confirm that combinations of brief geriatric assessment (BGA) items were significant risk factors for prolonged LHS among geriatric patients hospitalized in acute care medical units after their admission to the emergency department (ED); and 2) to determine whether these combinations of BGA items could be used as a prognostic tool of prolonged LHS. Methods Based on a prospective observational cohort design, 1254 inpatients (mean age ± standard deviation, 84.9±5.9 years; 59.3% female) recruited upon their admission to ED and discharged in acute care medical units of Angers University Hospital, France, were selected in this study. At baseline assessment, a BGA was performed and included the following 6 items: age ≥85years, male gender, polypharmacy (i.e., ≥5 drugs per day), use of home-help services, history of falls in previous 6 months and temporal disorientation (i.e., inability to give the month and/or year). The LHS in acute care medical units was prospectively calculated in number of days using the hospital registry. Results Area under receiver operating characteristic (ROC) curves of prolonged LHS of different combinations of BGA items ranged from 0.50 to 0.57. Cox regression models revealed that combinations defining a high risk of prolonged LHS, identified from ROC curves, were significant risk factors for prolonged LHS (hazard ratio >1.16 with P>0.010). Kaplan-Meier distributions of discharge showed that inpatients classified in high-risk group of prolonged LHS were discharged later than those in low-risk group (P<0.003). Prognostic value for prolonged LHS of all combinations was poor with sensitivity under 77%, a high variation of specificity (from 26.6 to 97.4) and a low likelihood ratio of positive test under 5.6. Conclusion Combinations of 6-item BGA tool were significant risk factors for prolonged LHS but their prognostic value was poor in the studied sample of older inpatients. PMID:25333271

  10. Persistent cue-evoked activity of accumbens neurons after prolonged abstinence from self-administered cocaine.

    PubMed

    Ghitza, Udi E; Fabbricatore, Anthony T; Prokopenko, Volodymyr; Pawlak, Anthony P; West, Mark O

    2003-08-13

    Persistent neural processing of information regarding drug-predictive environmental stimuli may be involved in motivating drug abusers to engage in drug seeking after abstinence. The addictive effects of various drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens. We used single-unit recording in rats to test whether accumbens neurons exhibit responses to a discriminative stimulus (SD) tone previously paired with cocaine availability during cocaine self-administration. Presentation of the tone after 3-4 weeks of abstinence resulted in a cue-induced relapse of drug seeking under extinction conditions. Accumbens neurons did not exhibit tone-evoked activity before cocaine self-administration training but exhibited significant SD tone-evoked activity during extinction. Under extinction conditions, shell neurons exhibited significantly greater activity evoked by the SD tone than that evoked by a neutral tone (i.e., never paired with reinforcement). In contrast, core neurons responded indiscriminately to presentations of the SD tone or the neutral tone. Accumbens shell neurons exhibited significantly greater SD tone-evoked activity than did accumbens core neurons. Although the onset of SD tone-evoked activity occurred well before the earliest movements commenced (150 msec), this activity often persisted beyond the onset of tone-evoked movements. These results indicate that accumbens shell neurons exhibit persistent processing of information regarding reward-related stimuli after prolonged drug abstinence. Moreover, the accumbens shell appears to be involved in discriminating the motivational value of reward-related associative stimuli, whereas the accumbens core does not.

  11. Fitness benefits of prolonged post-reproductive lifespan in women.

    PubMed

    Lahdenperä, Mirkka; Lummaa, Virpi; Helle, Samuli; Tremblay, Marc; Russell, Andrew F

    2004-03-11

    Most animals reproduce until they die, but in humans, females can survive long after ceasing reproduction. In theory, a prolonged post-reproductive lifespan will evolve when females can gain greater fitness by increasing the success of their offspring than by continuing to breed themselves. Although reproductive success is known to decline in old age, it is unknown whether women gain fitness by prolonging lifespan post-reproduction. Using complete multi-generational demographic records, we show that women with a prolonged post-reproductive lifespan have more grandchildren, and hence greater fitness, in pre-modern populations of both Finns and Canadians. This fitness benefit arises because post-reproductive mothers enhance the lifetime reproductive success of their offspring by allowing them to breed earlier, more frequently and more successfully. Finally, the fitness benefits of prolonged lifespan diminish as the reproductive output of offspring declines. This suggests that in female humans, selection for deferred ageing should wane when one's own offspring become post-reproductive and, correspondingly, we show that rates of female mortality accelerate as their offspring terminate reproduction.

  12. Diet-consumer nitrogen isotope fractionation for prolonged fasting arthropods.

    PubMed

    Mizota, Chitoshi; Yamanaka, Toshiro

    2011-12-01

    Nitrogen acquisition for cellular metabolism during diapause is a primary concern for herbivorous arthropods. Analyses of naturally occurring stable isotopes of nitrogen help elucidate the mechanism. Relevant articles have cited (58 times up to mid-June 2011) anomalously elevated δ(15)N (per mil deviation of (15)N/(14)N, relative to atmospheric nitrogen=0 ‰) values (diet-consumer nitrogen isotope fractionation; up to 12 ‰) for a prolonged fasting raspberry beetle (Byturus tomentosus Degeer (Coleoptera: Byturidae)), which feeds on red raspberries (Rubus idaeus: δ(15)N= ~ +2 ‰). Biologists have hypothesised that extensive recycling of amino acid nitrogen is responsible for the prolonged fasting. Since this hypothesis was proposed in 1995, scientists have integrated biochemical and molecular knowledge to support the mechanism of prolonged diapausing of animals. To test the validity of the recycling hypothesis, we analysed tissue nitrogen isotope ratios for four Japanese arthropods: the shield bug Parastrachia japonensis Scott (Hemiptera: Cydnidae), the burrower bug Canthophorus niveimarginatus Scott (Hemiptera: Cydnidae), leaf beetle Gastrophysa atrocyanea Motschulsky (Coleoptera: Chrysomelidae) and the Japanese oak silkworm Antheraea yamamai (Lepidoptera: Saturniidae), all of which fast for more than 6 months as part of their life-history strategy. Resulting diet-consumer nitrogen isotope discrimination during fasting ranged from 0 to 7‰, as in many commonly known terrestrial arthropods. We conclude that prolonged fasting of arthropods does not always result in anomalous diet-consumer nitrogen isotope fractionation, since the recycling process is closed or nearly closed with respect to nitrogen isotopes.

  13. Economic viability of beef cattle grazing systems under prolonged drought

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prolonged drought in the Southern Great Plains of the USA in recent years has raised concerns about vulnerability of beef cattle grazing systems under adverse climate change. To help address the economic viability of beef grazing operations in the Southern Great Plains, this paper provides an econom...

  14. Long term cognitive development in children with prolonged crying

    PubMed Central

    Rao, M; Brenner, R; Schisterman, E; Vik, T; Mills, J

    2004-01-01

    Background: Long term studies of cognitive development and colic have not differentiated between typical colic and prolonged crying. Objective: To evaluate whether colic and excessive crying that persists beyond 3 months is associated with adverse cognitive development. Design: Prospective cohort study. A sample of 561 women was enrolled in the second trimester of pregnancy. Colic and prolonged crying were based on crying behaviour assessed at 6 and 13 weeks. Children's intelligence, motor abilities, and behaviour were measured at 5 years (n = 327). Known risk factors for cognitive impairment were ascertained prenatally, after birth, at 6 and 13 weeks, at 6, 9, and 13 months, and at 5 years of age. Results: Children with prolonged crying (but not those with colic only) had an adjusted mean IQ that was 9 points lower than the control group. Their performance and verbal IQ scores were 9.2 and 6.7 points lower than the control group, respectively. The prolonged crying group also had significantly poorer fine motor abilities compared with the control group. Colic had no effect on cognitive development. Conclusions: Excessive, uncontrolled crying that persists beyond 3 months of age in infants without other signs of neurological damage may be a marker for cognitive deficits during childhood. Such infants need to be examined and followed up more intensively. PMID:15499048

  15. Delirium in Prolonged Hospitalized Patients in the Intensive Care Unit

    PubMed Central

    Vahedian Azimi, Amir; Ebadi, Abbas; Ahmadi, Fazlollah; Saadat, Soheil

    2015-01-01

    Background: Prolonged hospitalization in the intensive care unit (ICU) can impose long-term psychological effects on patients. One of the most significant psychological effects from prolonged hospitalization is delirium. Objectives: The aim of this study was to assess the effect of prolonged hospitalization of patients and subsequent delirium in the intensive care unit. Patients and Methods: This conventional content analysis study was conducted in the General Intensive Care Unit of the Shariati Hospital of Tehran University of Medical Sciences, from the beginning of 2013 to 2014. All prolonged hospitalized patients and their families were eligible participants. From the 34 eligible patients and 63 family members, the final numbers of actual patients and family members were 9 and 16, respectively. Several semi-structured interviews were conducted face-to-face with patients and their families in a private room and data were gathered. Results: Two main themes from two different perspectives emerged, 'patients' perspectives' (experiences during ICU hospitalization) and 'family members' perspectives' (supportive-communicational experiences). The main results of this study focused on delirium, Patients' findings were described as pleasant and unpleasant, factual and delusional experiences. Conclusions: Family members are valuable components in the therapeutic process of delirium. Effective use of family members in the delirium caring process can be considered to be one of the key non-medical nursing components in the therapeutic process. PMID:26290854

  16. Metabolic and Cardiovascular Responses of Children during Prolonged Physical Activity.

    ERIC Educational Resources Information Center

    Chausow, Sharon A.; And Others

    1984-01-01

    Metabolic and cardiovascular responses during 45 minutes of continuous moderate intensity exercise were investigated in 11 children, 8-11 years of age. Results indicate that children exhibit metabolic and cardiovascular adjustments similar to those noted in adults during prolonged exercise. (Author/JMK)

  17. Preferences for Prolonging Life: A Prospect Theory Approach

    ERIC Educational Resources Information Center

    Winter, Laraine; Lawton, M. Powell; Ruckdeschel, Katy

    2003-01-01

    Kahneman and Tversky's (1979) Prospect theory was tested as a model of preferences for prolonging life under various hypothetical health statuses. A sample of 384 elderly people living in congregate housing (263 healthy, 131 frail) indicated how long (if at all) they would want to live under each of nine hypothetical health conditions (e.g.,…

  18. Family presence during cardiopulmonary resuscitation: grief therapy or prolonged futility?

    PubMed

    Sherman, David A

    2008-01-01

    Nursing leaders are responsible in part for implementing procedures supporting family presence during cardiopulmonary resuscitation. Family presence has received broad support in nursing literature and from professional organizations. A case study suggests that, when a patient's spokesperson is struggling with the question of whether to set limits to treatments, allowing family presence may inappropriately prolong futile care.

  19. Effect of prolonged bed rest on the anterior hip muscles.

    PubMed

    Dilani Mendis, M; Hides, Julie A; Wilson, Stephen J; Grimaldi, Alison; Belavý, Daniel L; Stanton, Warren; Felsenberg, Dieter; Rittweger, Joern; Richardson, Carolyn

    2009-11-01

    Prolonged bed rest and inactivity is known to cause muscular atrophy with previous research indicating that muscles involved in joint stabilisation are more susceptible. The anterior hip muscles are important for hip joint function and stability but little is known about the effects of prolonged inactivity on their function. This study investigated the effect of prolonged bed rest on the size of the anterior hip muscles and their pattern of recovery. The effect of resistive vibration exercise (RVE) as a countermeasure to muscle atrophy was also investigated. 12 male participants, randomly assigned to either a control or an exercise group, underwent 8 weeks of bed rest with 6 months follow-up. Changes in muscle cross-sectional area (CSA) of the iliacus, psoas, iliopsoas, sartorius and rectus femoris muscles were measured by magnetic resonance imaging at regular intervals during bed rest and recovery phases. CSAs of iliopsoas and sartorius decreased at the hip joint (p<0.05) during bed rest but iliacus, psoas, and rectus femoris CSAs were unchanged (p>0.05). No significant difference was found between the two groups for all muscles (all p>0.1), suggesting inefficacy of the countermeasure in this sample. These findings suggest that prolonged bed rest can result in the atrophy of specific muscles across the hip joint which may affect its stability and function.

  20. Prolonged idiopathic gastric dilatation following revascularization for chronic mesenteric ischemia.

    PubMed

    Gauci, Julia L; Stoven, Samantha; Szarka, Lawrence; Papadakis, Konstantinos A

    2014-01-01

    A 71-year-old female presented with nausea, emesis, early satiety, and abdominal distension following revascularization for chronic mesenteric ischemia. Computed tomography angiogram showed gastric dilatation. Esophagogastroduodenoscopy, small bowel follow through, and paraneoplastic panel were negative. Gastric emptying was delayed. Despite conservative management, she required a percutaneous endoscopic jejunostomy. The development of a prolonged gastroparetic state has not been previously described.

  1. Recognition Memory Is Impaired in Children after Prolonged Febrile Seizures

    ERIC Educational Resources Information Center

    Martinos, Marina M.; Yoong, Michael; Patil, Shekhar; Chin, Richard F. M.; Neville, Brian G.; Scott, Rod C.; de Haan, Michelle

    2012-01-01

    Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal…

  2. Single Prolonged Stress Disrupts Retention of Extinguished Fear in Rats

    ERIC Educational Resources Information Center

    Knox, Dayan; George, Sophie A.; Fitzpatrick, Christopher J.; Rabinak, Christine A.; Maren, Stephen; Liberzon, Israel

    2012-01-01

    Clinical research has linked post-traumatic stress disorder (PTSD) with deficits in fear extinction. However, it is not clear whether these deficits result from stress-related changes in the acquisition or retention of extinction or in the regulation of extinction memories by context, for example. In this study, we used the single prolonged stress…

  3. Intrinsic motivation and amotivation in first episode and prolonged psychosis.

    PubMed

    Luther, Lauren; Lysaker, Paul H; Firmin, Ruth L; Breier, Alan; Vohs, Jenifer L

    2015-12-01

    The deleterious functional implications of motivation deficits in psychosis have generated interest in examining dimensions of the construct. However, there remains a paucity of data regarding whether dimensions of motivation differ over the course of psychosis. Therefore, this study examined two motivation dimensions, trait-like intrinsic motivation, and the negative symptom of amotivation, and tested the impact of illness phase on the 1) levels of these dimensions and 2) relationship between these dimensions. Participants with first episode psychosis (FEP; n=40) and prolonged psychosis (n=66) completed clinician-rated measures of intrinsic motivation and amotivation. Analyses revealed that when controlling for group differences in gender and education, the FEP group had significantly more intrinsic motivation and lower amotivation than the prolonged psychosis group. Moreover, intrinsic motivation was negatively correlated with amotivation in both FEP and prolonged psychosis, but the magnitude of the relationship did not statistically differ between groups. These findings suggest that motivation deficits are more severe later in the course of psychosis and that low intrinsic motivation may be partially independent of amotivation in both first episode and prolonged psychosis. Clinically, these results highlight the importance of targeting motivation in early intervention services.

  4. Prolonged unassisted survival in an infant with anencephaly.

    PubMed

    Dickman, Holly; Fletke, Kyle; Redfern, Roberta E

    2016-10-31

    Anencephaly is one of the most lethal congenital defects. This case report is of an anencephalic infant who lived to 28 months of life and defies current literature. She is the longest surviving anencephalic infant who did not require life-sustaining interventions. This case presents the obstacles that arose from this infant's prolonged life and recommendations based on these findings.

  5. Competing for Consciousness: Prolonged Mask Exposure Reduces Object Substitution Masking

    ERIC Educational Resources Information Center

    Goodhew, Stephanie C.; Visser, Troy A. W.; Lipp, Ottmar V.; Dux, Paul E.

    2011-01-01

    In object substitution masking (OSM) a sparse, temporally trailing 4-dot mask impairs target identification, even though it has different contours from, and does not spatially overlap with the target. Here, we demonstrate a previously unknown characteristic of OSM: Observers show reduced masking at prolonged (e.g., 640 ms) relative to intermediate…

  6. Efficacy of an Emotion-Focused Treatment for Prolonged Fatigue

    ERIC Educational Resources Information Center

    Schutte, Nicola S.; Malouff, John M.; Brown, Rhonda F.

    2008-01-01

    Previous research findings have suggested a relationship between less adaptive emotional functioning and fatigue. The present study used a research design involving multiple baselines across participants to evaluate the efficacy of a new emotion-focused treatment for prolonged fatigue delivered in a cognitive behavioral therapy framework. The 13…

  7. Technologies for Prolonging Cardiac Implantable Electronic Device Longevity.

    PubMed

    Lau, Ernest W

    2017-01-01

    Prolonged longevity of cardiac implantable electronic devices (CIEDs) is needed not only as a passive response to match the prolonging life expectancy of patient recipients, but will also actively prolong their life expectancy by avoiding/deferring the risks (and costs) associated with device replacement. CIEDs are still exclusively powered by nonrechargeable primary batteries, and energy exhaustion is the dominant and an inevitable cause of device replacement. The longevity of a CIED is thus determined by the attrition rate of its finite energy reserve. The energy available from a battery depends on its capacity (total amount of electric charge), chemistry (anode, cathode, and electrolyte), and internal architecture (stacked plate, folded plate, and spiral wound). The energy uses of a CIED vary and include a background current for running electronic circuitry, periodic radiofrequency telemetry, high-voltage capacitor reformation, constant ventricular pacing, and sporadic shocks for the cardiac resynchronization therapy defibrillators. The energy use by a CIED is primarily determined by the patient recipient's clinical needs, but the energy stored in the device battery is entirely under the manufacturer's control. A larger battery capacity generally results in a longer-lasting device, but improved battery chemistry and architecture may allow more space-efficient designs. Armed with the necessary technical knowledge, healthcare professionals and purchasers will be empowered to make judicious selection on device models and maximize the utilization of all their energy-saving features, to prolong device longevity for the benefits of their patients and healthcare systems.

  8. Hemodynamic effects of eating and prolonged supine position in healthy subjects studied under clinical-pharmacological test conditions.

    PubMed

    Sziegoleit, W; Lautenschläger, C; Walther, C; Presek, P

    2010-10-01

    The influences of both being in a supine position for a prolonged period and food intake on cardiovascular variables were studied under clinical-pharmacological test conditions. In a randomized crossover design study without drug or placebo administration, 6 healthy male volunteers received a light standard meal before and during test A and fasted in test B. In both tests, while they were continuously supine for more than 8 h, a synchronous recording of cardiovascular variables was done at 24, 26 and 28 min after starting the supine position (first recordings) and 25 times from 2 to 480 min after the first recordings. Using a multifactorial statistical analysis, each parameter was evaluated regarding the factors eating and time of supine recording. Eating led to a significant decrease in diastolic and mean blood pressure, PQ time and QS₂ time, a downward trend in systemic vascular resistance and an upward trend in systolic blood pressure and cardiac output. When the subjects remained in a supine position for prolonged periods, significant increases in systolic, diastolic, mean blood pressure and systemic vascular resistance were noted as well as significant decreases in cardiac output and QS₂ time. Thus, eating and remaining in a supine position for prolonged periods should be considered as sources of bias in clinical-pharmacological studies on cardiovascular drug effects and accompanying placebo controls.

  9. A swine model of acute thrombocytopenia with prolonged bleeding time produced by busulfan

    PubMed Central

    Abe, Tomoyuki; Kono, Shota; Ohnuki, Takahiro; Hishikawa, Shuji; Kunita, Satoshi; Hanazono, Yutaka

    2016-01-01

    Animal models of thrombocytopenia are indispensable for evaluating the in vivo efficacy of hemostatic agents, cryopreserved platelets, and artificial platelets, but no large animal models are available. In this study, we generated a swine model of acute thrombocytopenia with prolonged bleeding times by administering the chemotherapeutic drug busulfan. First, we tested multiple doses of busulfan (4, 6, and 8 mg/kg) in pigs, and found that 6 mg/kg of busulfan is an optimal dose for producing a safe and moderate thrombocytopenia, with a platelet count of less than 30,000/µl. The pigs administered 6 mg/kg of busulfan (n=8) reached half their initial counts at day 7, counts below 30,000/µl at day 12, and their nadirs at day 15 (on average). The minimal platelet count was 14,000/µl. With this dose of busulfan (6 mg/kg), bleeding times were significantly prolonged in addition to the decrease in platelet counts (r=−0.63, P<0.01), while there were no cases of apparent hemorrhage. White blood cell counts were maintained at over 5,000/µl, and there were no infections or other adverse events including anemia or appetite or body weight loss. All pigs were sacrificed on day 16, with subsequent examination showing a significant reduction in cellularity and colony-forming units in the bone marrow, indicating that thrombocytopenia was the result of myelosuppression. In summary, administration with 6 mg/kg of busulfan induces safe and moderate thrombocytopenia with a prolonged bleeding time in swine. PMID:27333841

  10. Effect of prolonged hydroxytamoxifen treatment of MCF-7 cells on mitogen activated kinase cascade.

    PubMed

    Rabenoelina, Fanjaniriana; Semlali, Abdelhabib; Duchesne, Marie-Josèphe; Freiss, Gilles; Pons, Michel; Badia, Eric

    2002-04-10

    Resistance to the antiestrogen tamoxifen is the main stumbling block for the success of breast cancer therapy. We focused our study on cellular alterations induced by a prolonged treatment with the active tamoxifen metabolite hydroxytamoxifen (OHT). We show that a prolonged OHT treatment (for up to 7 days) led to a progressive increase in the level of phosphorylated p44/42 mitogen activated kinase (MAP kinase) induced by 10(-7) M TPA stimulation, without any significant change in the protein level. This effect was also observed in MCF-7 cells grown first in medium containing dextran-coated charcoal-treated FCS (DCC medium) for 20 days prior to OHT treatment, indicating a specific effect of the antiestrogen and not an effect of estrogen deprivation. It was prevented by cotreatment with estradiol and not observed in the estrogen receptor negative HeLa cell line, suggesting that it was mediated by the estrogen receptor. TPA induced phosphorylation of MEK1/2 was also raised by OHT treatment, without any change in their protein level or Raf-1 and H-Ras levels. When the MCF-7R OHT resistant cell line was grown in antiestrogen containing medium, the level of phosphorylated p44/42 MAP kinase was also high but reversed when the antiestrogen was removed. The 2 other MAP kinase, JNK and P38 pathways were not affected in the same way by OHT treatment. In conclusion, our data reveal that a prolonged OHT treatment, by increasing p44/42 MAPK activity, affects a key step in the growth control of MCF-7 cells, although not sufficiently to overcome the growth inhibitory effect of the drug.

  11. False Prolongation of Prothrombin Time in the Presence of a High Blood Concentration of Daptomycin.

    PubMed

    Yamada, Tomoyuki; Kato, Ryuji; Oda, Kazutaka; Tanaka, Hidema; Suzuki, Kaoru; Ijiri, Yoshio; Ikemoto, Toshiyuki; Nishihara, Masami; Hayashi, Tetsuya; Tanaka, Kazuhiko; Tamai, Hiroshi; Ukimura, Akira; Katsumata, Takahiro

    2016-10-01

    Prothrombin time (PT) can reportedly be falsely prolonged by the antimicrobial drug daptomycin (DAP), and concomitant use of phosphatidylglycerol (PG). Although high doses of DAP (>6 mg/kg/day) are recommended for severe infection and result in a high blood concentration, the extent to which high blood concentrations of DAP interfere with PT, in the presence or absence of PG, has yet to be determined when using the HemosIL RecombiPlasTin 2G (Werfen Japan, Tokyo, Japan). We examined the effects of high doses of DAP on PT using this reagent. DAP (0-500 mg/L) was added to normal plasma and plasma with an already prolonged PT in the presence or absence of liposomal amphotericin B (L-AMB, 5-50 mg/L) or COATSOME EL-01 empty cationic liposomes (CS, 25-250 mg/L). Furthermore, we undertook a Monte Carlo simulation to calculate the probability of achieving DAP concentrations >100, >200 and >500 mg/L 0-48 hr after administering 6-12 mg/kg of DAP. Apparent PT increased with increasing DAP concentration, but neither L-AMB nor CS appeared to further elevate PT when co-administered with DAP. The probability of achieving DAP concentrations >100 and >200 mg/L increased with DAP dose. Higher doses of DAP than the approved dose caused false prolongation of PT. PT should be monitored carefully in patients taking high doses of DAP; ideally, PT should be measured at the trough blood concentration of DAP. Concomitant use of L-AMB and CS did not generally further elevate PT when co-administered with DAP.

  12. LONG-TERM BEHAVIORAL EFFECTS IN A RAT MODEL OF PROLONGED POSTNATAL MORPHINE EXPOSURE

    PubMed Central

    Craig, Michael M.; Bajic, Dusica

    2015-01-01

    Prolonged morphine treatment in neonatal pediatric populations is associated with a high incidence of opioid tolerance and dependence. Despite the clinical relevance of this problem, our knowledge of the long-term consequences is sparse. The main objective of this study was to investigate whether prolonged morphine administration in a neonatal rat is associated with long-term behavioral changes in adulthood. Newborn animals received either morphine (10mg/kg) or equal volume of saline subcutaneously twice daily for the first 2 weeks of life. Morphine treated animals underwent 10 days of morphine weaning to reduce the potential for observable physical signs of withdrawal. Animals were subjected to non-stressful testing (locomotor activity recording and a Novel-Object Recognition test) at a young age (PD27-31) or later in adulthood (PD55-56), as well as stressful testing (calibrated forceps test, Hot Plate test, and Forced Swim test) only in adulthood. Analysis revealed that prolonged neonatal morphine exposure resulted in decreased thermal, but not mechanical threshold. Importantly, no differences were found for total locomotor activity (proxy of drug reward/reinforcement behavior), individual Forced Swim test behaviors (proxy of affective processing), or Novel-Object Recognition test. Performance on the Novel-Object Recognition test was compromised in the morphine treated group at the young age, however the effect disappeared in adulthood. These novel results provide insight into the long-term consequences of opioid treatment during an early developmental period and suggest long-term neuroplastic differences in sensory processing related to thermal stimuli. PMID:26214209

  13. Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS

    PubMed Central

    Schuster, J. E.; Fu, R.; Siddique, T.

    2012-01-01

    Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 μM riluzole for 4–9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1G93A motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1G93A motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2–3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 μM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective. PMID:22013234

  14. Prolonged patient emergence time among clinical anesthesia resident trainees

    PubMed Central

    House, L. McLean; Calloway, Nathan H.; Sandberg, Warren S.; Ehrenfeld, Jesse M.

    2016-01-01

    Background and Aims: Emergence time, or the duration between incision closure and extubation, is costly nonoperative time. Efforts to improve operating room efficiency and identify trainee progress make such time intervals of interest. We sought to calculate the incidence of prolonged emergence (i.e., >15 min) for patients under the care of clinical anesthesia (CA) residents. We also sought to identify factors from resident training, medical history, anesthetic use, and anesthesia staffing, which affect emergence. Material and Methods: In this single-center, historical cohort study, perioperative information management systems provided data for surgical cases under resident care at a tertiary care center in the United States from 2006 to 2008. Using multiple logistic regression, the effects of variables on emergence was analyzed. Results: Of 7687 cases under the care of 27 residents, the incidence of prolonged emergence was 13.9%. Emergence prolongation decreased by month in training for 1st-year (CA-1) residents (r2 = 0.7, P < 0.001), but not for CA-2 and CA-3 residents. Mean patient emergence time differed among 27 residents (P < 0.01 for 58.4% or 205/351 paired comparisons). In a model restricted to 1st-year residents, patient male gender, American Society of Anesthesiologists (ASA) physical status >II, emergency surgical case, operative duration ≥2 h, and paralytic agent use were associated with higher frequency of prolonged emergence, while sevoflurane or desflurane use was associated with lower frequency. Attending anesthesiologist handoff was not associated with longer emergence. Conclusion: Incidence of prolonged emergence from general anesthesia differed significantly among trainees, by resident training duration, and for patients with ASA >II. PMID:28096573

  15. Relationship between brief and prolonged repeated sprint ability.

    PubMed

    Oliver, Jonathan L; Armstrong, Neil; Williams, Craig A

    2009-01-01

    Repeated sprint ability (RSA) is often assessed over a brief time period with limited recovery between sprints; however, it is not known how performance in such tests is related to the ability to perform repeated sprints over a more prolonged duration. Eighteen boys aged 15.3+/-0.5 years completed both a brief and prolonged RSA test on a non-motorised treadmill. The brief RSA test consisted of seven 5s sprints with 20s of recovery between sprints and the prolonged RSA test lasted for 42min and included a 5s sprint every 2min. There was a moderate but significant relationship between the mean speed in both tests (r=0.51, p<0.05). The maximal speed achieved in a single sprint provided strong relationships with both brief RSA speed (r> or =0.72, p<0.001) and prolonged RSA speed (r> or =0.77, p<0.001). Total work done during the brief protocol was significantly correlated to both total work (r=0.81, p<0.001) and total sprint distance (r=0.79, p<0.001) during the prolonged test. There were no significant relationships between percentage decrement scores across the two protocols (r< or =0.33, p>0.05). Maximal speed in a single sprint and total work done during repeated sprints represent general qualities related to RSA that are independent of the test protocol. The mean speed and decrements in performance represent specific RSA qualities, which are dependent on the frequency of sprints and duration of the test protocol.

  16. Drugs, drugs--who has the drugs?

    PubMed

    Blair, James

    2012-01-01

    Drug diversion, although on the increase, is not the only problem involving drugs that hospital security officials should be concerned with. Growing drug shortages, offshore production, counterfeiting, and weaknesses in the drug supply chain in case of a world-wide pandemic, are even greater causes for concern, the author claims.

  17. [Drug therapy for cough].

    PubMed

    Koskela, Heikki; Naaranlahti, Toivo

    2016-01-01

    An efficient therapy for cough usually requires identification and treatment of the underlying disease, like asthma. However an underlying disease in cough is not found in all cases and conventional treatment of the underlying disease is ineffective against cough. Drug therapy options are available also for these situations. Honey or menthol can be tried for cough associated with respitatory infections, antihistamines for cough associated with allergic rhinitis, blockers of the leukotriene receptor or muscarinic receptor for asthma-associated cough and morphine for cough associated with a malignant disease. Menthol, blockers of the muscarinic receptor, or dextrometorphan can be tried for prolonged idiopathic cough. Codeine is not necessary in the treatment of cough. Refraining from drug treatment should always be considered.

  18. Correlations between edema and the immediate and prolonged painful consequences of inflammation: therapeutic implications?

    SciTech Connect

    Chesler, Elissa J; Lariviere, William R; Zhen, Li; Shang, G; Chen, Ya; Yu, Yao; Lu, Zhuo; Chang, Ying; Luo, Ceng; Li, KaiCheng; Chen, Jun

    2005-06-01

    The precise relationship between the degree of pan and the degree of inflammation in the individual remains debated. A quantitative analysis simultaneously applied to the immediate and prolonged painful consequences of inflammation has not yet been done. Thus, the correlations between edema, nociception and hypersensitivity following an inflammatory insult were assessed in rodents. To better understand the therapeutic value of modifying specific aspects of inflammation, the effects of anti-inflammatory drug were compared to the results. Inbred strains of mice and outbred rats received an intraplantar injection of honeybee venom and the between group and within-group correlations were calculated for spontaneous nociceptive measures, thermal and mechanical hypersensitivity, and edema and temperature. The effect of indomethacin on the pain and the inflammation measures was examined. Edema correlated with spontaneous flinching, licking and lifting of the inject paw, and not with thermal or mechanical hypersensitivity. Indomethacin affected edema and spontaneous nociception dose-dependently, and affected hypersensitivity only at the highest dose test (P <0.005). These results suggest that edema may contribute only to immediate spontaneous nociceptive responses to an inflammatory insult, and not to the more clinically relevant prolonged hypersensitivity. This analysis represents a method for determine which inflammatory processes are the most promising therapeutic targets against the multiple painful consequences of inflammation.

  19. Diffuse alveolar damage in a patient with rheumatoid arthritis under prolonged leflunomide treatment

    PubMed Central

    Keng, Li-Ta; Lin, Mong-Wei; Huang, Hsien-Neng; Chung, Kuei-Pin

    2016-01-01

    Abstract Patients with rheumatoid arthritis (RA) often have pulmonary involvement, and interstitial lung disease (ILD) is the primary manifestation, in which diffuse alveolar damage (DAD) is a rare histopathologic pattern. Leflunomide (LEF) is a frequently prescribed disease-modifying antirheumatic drug for treating RA. LEF-related ILD in the form of DAD has been reported in patients with RA, with the duration of LEF treatment before symptom onset ranging from 6 to 1204 days. We present a case of elderly woman with RA under prolonged LEF treatment for >9 years (3291 days), who had acute respiratory failure with the initial presentation of exertional dyspnea, fever, chills, and productive cough for 2 days. The histopathologic result of surgical lung biopsy was compatible with DAD. She was diagnosed as having LEF-related ILD, based on correlated clinical history, compatible histopathologic examination and excluding possible infection after extensive survey. Although the causative role of LEF cannot be confirmed, this case still hints that LEF-related DAD may occur even if LEF has been prescribed for a prolonged period. PMID:27368035

  20. Neoteny, Prolongation of Youth: From Naked Mole Rats to "Naked Apes" (Humans).

    PubMed

    Skulachev, Vladimir P; Holtze, Susanne; Vyssokikh, Mikhail Y; Bakeeva, Lora E; Skulachev, Maxim V; Markov, Alexander V; Hildebrandt, Thomas B; Sadovnichii, Viktor A

    2017-04-01

    It has been suggested that highly social mammals, such as naked mole rats and humans, are long-lived due to neoteny (the prolongation of youth). In both species, aging cannot operate as a mechanism facilitating natural selection because the pressure of this selection is strongly reduced due to 1) a specific social structure where only the "queen" and her "husband(s)" are involved in reproduction (naked mole rats) or 2) substituting fast technological progress for slow biological evolution (humans). Lists of numerous traits of youth that do not disappear with age in naked mole rats and humans are presented and discussed. A high resistance of naked mole rats to cancer, diabetes, cardiovascular and brain diseases, and many infections explains why their mortality rate is very low and almost age-independent and why their lifespan is more than 30 years, versus 3 years in mice. In young humans, curves of mortality versus age start at extremely low values. However, in the elderly, human mortality strongly increases. High mortality rates in other primates are observed at much younger ages than in humans. The inhibition of the aging process in humans by specific drugs seems to be a promising approach to prolong our healthspan. This might be a way to retard aging, which is already partially accomplished via the natural physiological phenomenon neoteny.

  1. Development and Optimization of a Novel Prolonged Release Formulation to Resist Alcohol-Induced Dose Dumping.

    PubMed

    Gujjar, Chaitanya Yogananda; Rallabandi, Balaramesha Chary; Gannu, Ramesh; Deulkar, Vallabh Subashrao

    2016-04-01

    Alcohol-induced dose dumping is a serious concern for the orally administered prolonged release dosage forms. The study was designed to optimize the independent variables, propylene glycol alginate (PGA), Eudragit RS PO (ERS) and coating in mucoadhesive quetiapine prolonged release tablets 200 mg required for preventing the alcohol-induced dose dumping. Optimal design based on response surface methodology was employed for the optimization of the composition. The formulations are evaluated for in vitro drug release in hydrochloric acid alone and with 40% v/v ethanol. The responses, dissolution at 120 min without alcohol (R1) and dissolution at 120 min with alcohol (R2), were statistically evaluated and regression equations are generated. PGA as a hydrophilic polymeric matrix was dumping the dose when dissolutions are carried in 0.1 N hydrochloric acid containing 40% v/v ethanol. ERS addition was giving structural support to the swelling and gelling property of PGA, and thus, was reducing the PGA erosion in dissolution media containing ethanol. Among the formulations, four formulations with diverse composition were meeting the target dissolution (30-40%) in both the conditions. The statistical validity of the mathematical equations was established, and the optimum concentration of the factors was established. Validation of the study with six confirmatory runs indicated high degree of prognostic ability of response surface methodology. Further coating with ReadiLycoat was providing an additional resistance to the alcohol-induced dose dumping. Optimized compositions showed resistance to dose dumping in the presence of alcohol.

  2. Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells.

    PubMed

    Nakamura, T; Nakao, T; Yoshimura, N; Ashihara, E

    2015-09-01

    Mammalian target of rapamycin (mTOR) inhibitors are the main immunosuppressive drugs for organ transplant recipients. Nevertheless, the mechanisms by which mTOR inhibitors induce immunosuppression is not fully understood. Myeloid-derived suppressor cells (MDSCs) maintain host immunity; however, the relationship between mTOR inhibitors and MDSCs is unclear. Here, the results from a murine cardiac transplantation model revealed that rapamycin treatment (3 mg/kg, intraperitoneally on postoperative days 0, 2, 4, and 6) led to the recruitment of MDSCs and increased their expression of inducible nitric oxide synthase (iNOS). Immunohistochemical analysis revealed that rapamycin induced the migration of iNOS-expressing MDSCs into the subintimal space within the allograft vessels, resulting in a significant prolongation of graft survival compared with that in the untreated group (67 days vs. 7 days, respectively). These effects were counterbalanced by the administration of an anti-Gr-1, which reduced allograft survival to 21 days. Moreover, adoptive transcoronary arterial transfer of MDSCs from rapamycin-treated recipients prolonged allograft survival; this increase was reversed by the anti-Gr-1 antibody. Finally, co-administration of rapamycin and a mitogen-activated protein kinase kinase (MEK) inhibitor trametinib reversed rapamycin-mediated MDSC recruitment. Thus, the mTOR and Raf/MEK/extracellular signal regulated kinase (ERK) signaling pathways appear to play an important role in MDSC expansion.

  3. Development of QTc prolongation model incorporating circadian rhythm using harmonic model.

    PubMed

    Back, Hyun-moon; Lee, Jong-Hwa; Yun, Hwi-yeol; Kwon, Kwang-il

    2015-05-01

    1. QT prolongation is one of the major safety tests used in the development of a new drug. The ICH guidelines for the evaluation of QT prolongation recommend the use of the in vitro hERG assay and the in vivo telemetry test. However, QT intervals change under normal conditions due to circadian rhythm and can affect the results of the tests. In this study, we developed a PK/PD model to describe the QT interval after the administration of astemizole allowing for the normal changes by circadian rhythm. 2. The typical PK parameters of absorption rate constant (ka), volume of distribution (Vc and Vm), metabolism (km), and elimination rate constant (kel and kel-m) were 0.49 h(-1), 4950 L, 20 L, 0.0127 h(-1), 0.0095 h(-1), and 0.95 h(-1), respectively. The final PK/PD model was the biophase model with the modified harmonic model. The typical PK/PD parameters, base QTc interval (QT0), amplitude (T1, T3), period of QTc interval changing (T2, T4), and EC50 were 233 ms, 3.31, 1.5, -9.24 h, 1.85 h, and 0.81 ng/ml, respectively. 3. The PK/PD model to explain the changes of the QT interval that allows normal changes in the circadian rhythm after the administration of astemizole was developed successfully. This final model can be applied to the development of a human model.

  4. Phentolamine mesylate: It's role as a reversal agent for unwarranted prolonged local analgesia.

    PubMed

    Grover, Harpreet Singh; Gupta, Anil; Saksena, Neha; Saini, Neha

    2015-01-01

    Administration of local anesthesia is an integral procedure prior to dental treatments to minimize the associated pain. It is learned that its effect stays more than the time required for the dental procedure to be completed. This prolonged soft tissue anesthesia (STA) can be detrimental, inconvenient, and unnecessary. Phentolamine mesylate, a Food and Drug Administration-approved drug essentially serves the purpose of faster recovery from numbness at the site of local anesthesia. This article reviews the development of the drug phentolamine mesylate and its indication as a local anesthetic reversal agent. A literature search for phentolamine mesylate as a STA reversal agent was conducted in PubMed using the terms "dental local anesthesia reversal, phentolamine mesylate" up to March 2014. The search was limited to articles published in English. The search revealed 13 PubMed indexed articles stating the development and application of phentolamine mesylate. Phentolamine mesylate is an important step in the progress of developing patient care as well as an aid to the dental clinician.

  5. A novel oromucosal prolonged release mucoadhesive suspension by one step spray coagulation method.

    PubMed

    Cilurzo, Francesco; Gennari, Chiara G M; Selmin, Francesca; Musazzi, Umberto M; Rumio, Cristiano; Minghetti, Paola

    2013-06-01

    An oromucosal mucoadhesive suspension (OMS) able to combine the peculiarities of prolonged release mucoadhesive microparticles with those of an immediate release oromucosal solution is described. Microparticles were obtained by ionotropic gelation of alginate blended with another mucoadhesive material in a one step process where the cross-linking bath constituted the suspension vehicle. The effects of formulation and processing conditions on OMS performances were measured in-vitro determining the enhancement of drug penetration in buccal porcine mucosa and inhibition of tooth plaque formation using flurbiprofen and delmopinol as model drugs, respectively. Well-formed and spherical microparticles were obtained combining alginate with carbomer; linear dependence of particle size from the feed composition, viscosity and atomization pressure was found. As demonstrated by using FITC-labelled microparticles, the system remained onto the buccal mucosa at least for a six hour period. As a consequence, 0.1% flurbiprofen OMS guaranteed a concentration of flurbiprofen into buccal porcine mucosa over 6 hours comparable to 0.25% flurbiprofen reference solution, allowing a potential reduction of the 60% administered dose. The use of in-house made artificial mouth revealed that the once-a-day administration of 0.1% delmopinol OMS was as effective in plaque inhibition as the 0.2% delmopinol reference solution product given twice-a-day. These results suggested that the development of bioadhesive oromucosal suspensions, localizing the drug into buccal cavity, can reduce regimen and administrated dose.

  6. Escitalopram prolonged fear induced by simulated public speaking and released hypothalamic-pituitary-adrenal axis activation.

    PubMed

    Garcia-Leal, C; Del-Ben, C M; Leal, F M; Graeff, F G; Guimarães, F S

    2010-05-01

    Simulated public speaking (SPS) test is sensitive to drugs that interfere with serotonin-mediated neurotransmission and is supposed to recruit neural systems involved in panic disorder. The study was aimed at evaluating the effects of escitalopram, the most selective serotonin-selective reuptake inhibitor available, in SPS. Healthy males received, in a double-blind, randomized design, placebo (n = 12), 10 (n = 17) or 20 (n = 14) mg of escitalopram 2 hours before the test. Behavioural, autonomic and neuroendocrine measures were assessed. Both doses of escitalopram did not produce any effect before or during the speech but prolonged the fear induced by SPS. The test itself did not significantly change cortisol and prolactin levels but under the higher dose of escitalopram, cortisol and prolactin increased immediately after SPS. This fear-enhancing effect of escitalopram agrees with previously reported results with less selective serotonin reuptake inhibitors and the receptor antagonist ritanserin, indicating that serotonin inhibits the fear of speaking in public.

  7. Lethal or protective effects of prolonged treatment with hypoxic cell sensitizers

    SciTech Connect

    Edgren, M.R.

    1995-12-31

    AK-2123 [N-(2-methoxyethyl)-2-(3-nitro-1-triazolyl)acetamide] is a hypoxic cell radiosensitizer which is currently being tested in several oncology clinics and which has a lower toxicity than misonidazole (MISO) in vivo. The positive experiences reported recently certainly warrant further clinical evaluations. The experimental observations reported so far need further experimental studies to clarify the sensitization mechanism, especially as recent intratumoral strategies used in the clinical administration of the sensitizers can result in a large local concentration of the drug that may persist for a prolonged period of time between and after radiation exposures. Model experiments in vitro using V79 cells were performed with AK-2123 under these conditions. Misonidazole (MISO) and metronidazole (METRO), well known hypoxic cell radiosensitizers, were used for comparison of the effects. Clonogenic survival and induction and repair of DNA damage were used as end-points.

  8. Liposomes prolong the therapeutic effect of anti-asthmatic medication via pulmonary delivery

    PubMed Central

    Chen, Xiaoyu; Huang, Wenhua; Wong, Blenda Chi; Yin, Linlin; Wong, Yuen Fan; Xu, Min; Yang, Zhijun

    2012-01-01

    Purpose The main objective of this study was to develop a novel aerosolized liposome formulation for pulmonary delivery of anti-asthmatic medication and to explore the relationship between the bioavailability and anti-asthmatic efficacy of such a formulation. Asthma treatment usually requires frequent administration of medication for sustained bronchodilating response. Liposomes are known for their capability for sustained drug release and thus would be a suitable delivery system for anti-asthmatic medication for prolonged therapeutic effect. Salbutamol sulfate (SBS) was chosen as the model drug in this study because of its high water solubility and fast absorption after administration. Methods SBS was efficiently encapsulated into liposomes by the vesicular phospholipid gel technique. SBS permeability across the pulmonary membrane of an Asian toad was determined by in vitro study. Intratracheal administration of liposomes labeled with the fluorescent dye 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) in a rat model was assessed by a small animal imaging system and pharmacokinetic analysis. Pharmacodynamic analysis was performed in guinea pigs using the Konzett–Rössler method. Results SBS was efficiently encapsulated into liposomes with encapsulation efficiency as high as 70%. The particle size of the SBS liposome suspension was approximately 57 ± 21 nm. In the in vitro study of permeability across the pulmonary membrane of Asian toads, SBS from liposomes demonstrated a slower transport rate compared to free SBS solution. Pulmonary delivery of liposomes in a rat model showed that the liposomes were effectively distributed in the respiratory tract and lungs, and that the release of SBS from liposomes was sustained for at least 48 hours. Pharmacodynamic analysis in a guinea pig model showed that the anti-asthmatic effect of SBS liposomes persisted for up to 18 hours, whereas that of free SBS solution was less than 8 hours. Conclusion The overall

  9. Diagnostic and clinical considerations in prolonged grief disorder

    PubMed Central

    Maercker, Andreas; Lalor, John

    2012-01-01

    This review focuses on the similarities and differences between prolonged grief disorder (PGD) and post-traumatic stress disorder (PTSD). It highlights how a PTSD-related understanding aids the investigation and clinical management of PGD. Grief has long been understood as a natural response to bereavement, as serious psychological and physiological stress has been regarded as a potential outcome of extreme or traumatic stress. PTSD was first included in DSM-III in 1980. In the mid-1980s, the first systematic investigation began into whether there is an extreme or pathological form of mourning. Meanwhile, there is much research literature on complicated, traumatic, or prolonged grief This literature is reviewed in this article, with the following questions: Is it possible to distinguish normal from non-normal grief? Which clinical presentation does PGD have—and how does this compare with PTSD? Finally, diagnostic, preventive, and therapeutic approaches and existing tools are presented. PMID:22754289

  10. Prolonged Remission in Neuromyelitis Optica Following Cessation of Rituximab Treatment.

    PubMed

    Weinfurtner, Kelley; Graves, Jennifer; Ness, Jayne; Krupp, Lauren; Milazzo, Maria; Waubant, Emmanuelle

    2015-09-01

    Neuromyelitis optica is an autoimmune disease characterized by acute episodes of transverse myelitis and optic neuritis. Several small, open-label studies suggest rituximab, a monoclonal antibody against CD20, prevents relapses in neuromyelitis optica; however, there is little consensus on timing or duration of treatment. Here we report four patients with severe relapsing neuromyelitis optica who were stabilized on rituximab and, after discontinuing treatment, continued to experience prolonged remission of their disease. Remission ranged from 4.5 to 10.5 years total, including 3 to 9 years off all therapies. The patients had sustained clinical responses despite normal B-lymphocyte levels and, in at least 2 patients, continued seropositivity for aquaporin-4 antibodies. These cases suggest that rituximab may induce prolonged remission in certain neuromyelitis optica patients, and they highlight the need for further elucidation of rituximab's mechanism in neuromyelitis optica.

  11. Is prolonged and excessive cooling of a scalded wound effective?

    PubMed

    Sawada, Y; Urushidate, S; Yotsuyanagi, T; Ishita, K

    1997-02-01

    An experimental study was carried out using rats to evaluate the effectiveness of prolonged and excessive cooling on the burned wound just immediately after injury. The wound was produced by applying a lint immersed in boiled water at 99 degrees C. The wound produced by applying a lint for 3 s, and then immediately soaking with tap water for 1 min, resulted in little damage. However, the wound produced by applying a lint for 10 s, and immediately after an ice cube applied for 10 min, resulted in the most severe damage. The wound produced by applying a lint for 10 s, and no treatment applied thereafter, and the wound produced by applying a lint for 10 s and immediately after soaked with tap water for 1 min, resulted in moderate damage. From this experiment, it is suggested excessive and prolonged cooling of the burn wound, such as using an ice cube immediately after injury, is harmful in some instances.

  12. Deep, prolonged torpor by pregnant, free-ranging bats

    NASA Astrophysics Data System (ADS)

    Willis, Craig K. R.; Brigham, R. Mark; Geiser, Fritz

    2006-02-01

    Many mammals save energy during food shortage or harsh weather using controlled reductions in body temperature and metabolism called torpor. However, torpor slows offspring growth, and reproductive individuals are thought to avoid using it because of reduced fitness resulting from delayed offspring development. We tested this hypothesis by investigating torpor during reproduction in hoary bats ( Lasiurus cinereus, Vespertilionidae) in southern Canada. We recorded deep, prolonged torpor bouts, which meet the definition for hibernation, by pregnant females. Prolonged torpor occurred during spring storms. When conditions improved females aroused and gave birth within several days. Our observations imply a fitness advantage of torpor in addition to energy conservation because reduced foetal growth rate could delay parturition until conditions are more favourable for lactation and neonatal survival.

  13. Infection prevention and control during prolonged human space travel.

    PubMed

    Mermel, Leonard A

    2013-01-01

    Prolonged human spaceflight to another planet or an asteroid will introduce unique challenges of mitigating the risk of infection. During space travel, exposure to microgravity, radiation, and stress alter human immunoregulatory responses, which can in turn impact an astronaut's ability to prevent acquisition of infectious agents or reactivation of latent infection. In addition, microgravity affects virulence, growth kinetics, and biofilm formation of potential microbial pathogens. These interactions occur in a confined space in microgravity, providing ample opportunity for heavy microbial contamination of the environment. In addition, there is the persistence of aerosolized, microbe-containing particles. Any mission involving prolonged human spaceflight must be carefully planned to minimize vulnerabilities and maximize the likelihood of success.

  14. DRUG THERAPY IN KNEE OSTEOARTHROSIS

    PubMed Central

    de Rezende, Márcia Uchôa; Gobbi, Riccardo Gomes

    2015-01-01

    Clinical treatment for osteoarthritis (OA) is very important and is based on patient’s self care and guided by the physician. Drug therapy is additional to losing weight, improving muscular strength, proprioception, flexibility and range of motion. Between the available drugs for osteoarthritis’ treatment, some are basically analgesics and do not interfere on disease’s progression; some are anti-inflammatory with good analgesic power but with side effects that compromise their prolonged usage; and the structure modifying drugs that slow down the progression of OA. The medications are presented in topic, oral, intra-muscular, intra-venous and intra-articular forms. The hyaluronic acid has various presentations with good analgesic effect and some evidence of structure modifying property. There is IA evidence level for the use of diacerhein and of glucosamine to slow down the disease. Still, more technology for diagnosis and therapy control of OA is necessary to define the efficacy of other drugs. PMID:26998447

  15. Drug discovery: lessons from evolution

    PubMed Central

    Warren, John

    2011-01-01

    A common view within the pharmaceutical industry is that there is a problem with drug discovery and we should do something about it. There is much sympathy for this from academics, regulators and politicians. In this article I propose that lessons learnt from evolution help identify those factors that favour successful drug discovery. This personal view is influenced by a decade spent reviewing drug development programmes submitted for European regulatory approval. During the prolonged gestation of a new medicine few candidate molecules survive. This process of elimination of many variants and the survival of so few has much in common with evolution, an analogy that encourages discussion of the forces that favour, and those that hinder, successful drug discovery. Imagining a world without vaccines, anaesthetics, contraception and anti-infectives reveals how medicines revolutionized humanity. How to manipulate conditions that favour such discoveries is worth consideration. PMID:21395642

  16. Hormone supply of the organism in prolonged emotional stress

    NASA Technical Reports Server (NTRS)

    Amiragova, M. G.; Stulnikov, B. V.; Svirskaya, R. I.

    1980-01-01

    The effect of prolonged emotional stress of varying genesis on the hormonal function of the pancreas, thyroid gland, and adrenal cortex was studied. The amount of the hormonal secretion was found to depend on the type of adaptation activity and its duration. High secretion of the hormones observed outside the adaptation activity was examined as an index of the phase transition of defense reactions to the phase of overstress.

  17. Tetrodotoxin-bupivacaine-epinephrine combinations for prolonged local anesthesia.

    PubMed

    Berde, Charles B; Athiraman, Umeshkumar; Yahalom, Barak; Zurakowski, David; Corfas, Gabriel; Bognet, Christina

    2011-12-01

    Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.

  18. Prolonged Soil Frost Affects Hydraulics and Phenology of Apple Trees

    PubMed Central

    Beikircher, Barbara; Mittmann, Claudia; Mayr, Stefan

    2016-01-01

    Restoration of an adequate water supply in spring is a prerequisite for survival of angiosperm trees in temperate regions. Trees must re-establish access to soil water and recover xylem functionality. We thus hypothesized that prolonged soil frost impairs recovery and affects hydraulics and phenology of Malus domestica var. ‘Golden Delicious.’ To test this hypothesis, over two consecutive winters the soil around some trees was insulated to prolong soil frosting, From mid-winter to early summer, the level of native embolism, the water and starch contents of wood, bark and buds were quantified at regular intervals and findings correlated with various phenological parameters, xylogenesis and fine root growth. The findings confirm that prolonged soil frost affects tree hydraulics and phenology but the severity of the effect depends on the climatic conditions. In both study years, percentage loss of hydraulic conductivity (PLC) decreased from about 70% at the end of winter to about 10% in May. Thereby, xylem refilling strongly coincided with a decrease of starch in wood and bark. Also treated trees were able to restore their hydraulic system by May but, in the warm spring of 2012, xylem refilling, the increases in water content and starch depolymerization were delayed. In contrast, in the cold spring of 2013 only small differences between control and treated trees were observed. Prolongation of soil frost also led to a delay in phenology, xylogenesis, and fine root growth. We conclude that reduced water uptake from frozen or cold soils impairs refilling and thus negatively impacts tree hydraulics and growth of apple trees in spring. Under unfavorable circumstances, this may cause severe winter damage or even dieback. PMID:27379146

  19. Prolonged Soil Frost Affects Hydraulics and Phenology of Apple Trees.

    PubMed

    Beikircher, Barbara; Mittmann, Claudia; Mayr, Stefan

    2016-01-01

    Restoration of an adequate water supply in spring is a prerequisite for survival of angiosperm trees in temperate regions. Trees must re-establish access to soil water and recover xylem functionality. We thus hypothesized that prolonged soil frost impairs recovery and affects hydraulics and phenology of Malus domestica var. 'Golden Delicious.' To test this hypothesis, over two consecutive winters the soil around some trees was insulated to prolong soil frosting, From mid-winter to early summer, the level of native embolism, the water and starch contents of wood, bark and buds were quantified at regular intervals and findings correlated with various phenological parameters, xylogenesis and fine root growth. The findings confirm that prolonged soil frost affects tree hydraulics and phenology but the severity of the effect depends on the climatic conditions. In both study years, percentage loss of hydraulic conductivity (PLC) decreased from about 70% at the end of winter to about 10% in May. Thereby, xylem refilling strongly coincided with a decrease of starch in wood and bark. Also treated trees were able to restore their hydraulic system by May but, in the warm spring of 2012, xylem refilling, the increases in water content and starch depolymerization were delayed. In contrast, in the cold spring of 2013 only small differences between control and treated trees were observed. Prolongation of soil frost also led to a delay in phenology, xylogenesis, and fine root growth. We conclude that reduced water uptake from frozen or cold soils impairs refilling and thus negatively impacts tree hydraulics and growth of apple trees in spring. Under unfavorable circumstances, this may cause severe winter damage or even dieback.

  20. A Case of QT Prolongation Associated with Panhypopituitarism

    PubMed Central

    Garip, Tayfun; Tamer, Ali

    2013-01-01

    We describe a 37-year-old patient with panhypopituitarism who experienced symptoms and signs of hormonal insufficiency and QT prolongation on electrocardiogram without electrolyte disturbances. After hormonal (steroidal and thyroid) replacement therapy electrocardiographic findings were normalized. Hormonal disorders should be considered as a cause of long QT intervals which may lead to torsade de pointes, even if plasma electrolyte levels are normal, because life-threatening arrhythmia is treatable by supplementation of the hormone that is lacking. PMID:23762665

  1. Drug Resistance

    MedlinePlus

    HIV Treatment Drug Resistance (Last updated 3/2/2017; last reviewed 3/2/2017) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  2. Slow recovery in desert perennial vegetation following prolonged human disturbance

    USGS Publications Warehouse

    Guo, Q.

    2004-01-01

    Questions: How long may it take for desert perennial vegetation to recover from prolonged human disturbance and how do different plant community variables (i.e. diversity, density and cover) change during the recovery process? Location: Sonoran Desert, Arizona, USA. Methods: Since protection from grazing from 1907 onwards, plant diversity, density and cover of perennial species were monitored intermittently on ten 10 m x 10 m permanent plots on Tumamoc Hill, Tucson, Arizona, USA. Results: The study shows an exceptionally slow recovery of perennial vegetation from prolonged heavy grazing and other human impacts. Since protection, overall species richness and habitat heterogeneity at the study site continued to increase until the 1960s when diversity, density and cover had been stabilized. During the same period, overall plant density and cover also increased. Species turnover increased gradually with time but no significant relation between any of the three community variables and precipitation or Palmer Drought Severity Index (PDSI) was detected. Conclusions: It took more than 50 yr for the perennial vegetation to recover from prolonged human disturbance. The increases in plant species richness, density, and cover of the perennial vegetation were mostly due to the increase of herbaceous species, especially palatable species. The lack of a clear relationship between environment (e.g. precipitation) and community variables suggests that site history and plant life history must be taken into account in examining the nature of vegetation recovery processes after disturbance.

  3. Prosthodontic Approach in Management of Prolonged Neonatal Intubation

    PubMed Central

    Shah, Shital K; Rathod, Vishnu B; Ambadkar, Priyanka S; Patil, Charudutt N

    2016-01-01

    Intubation is a routine intervention in the Neonatal Intensive Care Unit (NICU) for preterm neonates with respiratory distress, inadequate gag reflex, poor sucking and swallowing. Prolonged intubation in neonates can be done by nasal or oral route. Although naso-tracheal intubation may reduce movement of the tube, it may contribute to airway obstruction, possible hypoxia, and occlusion of the nasal aperture during a crucial period of development further contributing to laboured breathing. Being obligate nasal breathers, oro-tracheal route is the preferred method of intubation in premature infants as oral mucosa is less susceptible to damage than nasal mucosa. Ineffective stabilization of the tubes is a frequent problem often resulting in accidental extubation and displacement of orotracheal and orogastric tube. Hence, these tubes must be stabilized against displacement from tongue and jaw movements to prevent discomfort and subsequent tissue trauma. Complications of prolonged endotracheal intubation include palatal groove formation by pressure against the hard palate, infection, accidental extubation, malposition, laryngeal or tracheal edema and ulceration, tracheal stenosis, vocal cord injury. Various oral appliances are used for infants to stabilize the tubes and prevent complications associated with long term intubation. This case report describes a prosthodontic approach in management of prolonged neonatal intubation. PMID:28050517

  4. Prosthodontic Approach in Management of Prolonged Neonatal Intubation.

    PubMed

    Kamble, Vikas B; Shah, Shital K; Rathod, Vishnu B; Ambadkar, Priyanka S; Patil, Charudutt N

    2016-11-01

    Intubation is a routine intervention in the Neonatal Intensive Care Unit (NICU) for preterm neonates with respiratory distress, inadequate gag reflex, poor sucking and swallowing. Prolonged intubation in neonates can be done by nasal or oral route. Although naso-tracheal intubation may reduce movement of the tube, it may contribute to airway obstruction, possible hypoxia, and occlusion of the nasal aperture during a crucial period of development further contributing to laboured breathing. Being obligate nasal breathers, oro-tracheal route is the preferred method of intubation in premature infants as oral mucosa is less susceptible to damage than nasal mucosa. Ineffective stabilization of the tubes is a frequent problem often resulting in accidental extubation and displacement of orotracheal and orogastric tube. Hence, these tubes must be stabilized against displacement from tongue and jaw movements to prevent discomfort and subsequent tissue trauma. Complications of prolonged endotracheal intubation include palatal groove formation by pressure against the hard palate, infection, accidental extubation, malposition, laryngeal or tracheal edema and ulceration, tracheal stenosis, vocal cord injury. Various oral appliances are used for infants to stabilize the tubes and prevent complications associated with long term intubation. This case report describes a prosthodontic approach in management of prolonged neonatal intubation.

  5. Kaolin-correctable prolongation of the activated partial thromboplastin time.

    PubMed

    Briselli, M F; Ellman, L

    1980-11-01

    Seven patients who had normal prothrombin times but prolonged activated partial thromboplastin times (aPTT) are described. The prolonged aPTT, obtained with micronized silica as the contact activating agent in a semi-automated optical end-point system, a nonautomated optical end-point system, and a conductivity end-point system, corrected to normal when kaolin was used as the contact activating agent. Abnormal results were also obtained with celite and ellagic acid as contact activating agents. The activities of various clotting factors were within normal limits in all cases where they were assayed. The thromboplastin dilution test was uniformly negative, and mixtures of one patient's plasma with that of another patient failed to correct the abnormal aPTT. No patients had a personal or family history of bleeding, and all underwent surgery without bleeding difficulties. This pattern of a prolonged aPTT that corrects to normal when kaolin is used as the contact activator appears to represent a previously unrecognized laboratory phenomenon.

  6. Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

    PubMed Central

    Ayub, Ahmar; Poulose, Ninu; Raju, Raghavan

    2015-01-01

    Resveratrol has been shown to potentiate mitochondrial function and extend longevity; however, there is no evidence to support whether resveratrol can improve survival or prolong life following hemorrhagic shock. We sought to determine whether (a) resveratrol can improve survival following hemorrhage and resuscitation and (b) prolong life in the absence of resuscitation. Using a hemorrhagic injury (HI) model in the rat, we describe for the first time that the naturally occurring small molecule, resveratrol, may be an effective adjunct to resuscitation fluid. In a series of three sets of experiments we show that resveratrol administration during resuscitation improves survival following HI (p < 0.05), resveratrol and its synthetic mimic SRT1720 can significantly prolong life in the absence of resuscitation fluid (<30 min versus up to 4 h; p < 0.05), and resveratrol as well as SRT1720 restores left ventricular function following HI. We also found significant changes in the expression level of mitochondria-related transcription factors Ppar-α and Tfam, as well as Pgc-1α in the left ventricular tissues of rats subjected to HI and treated with resveratrol. The results indicate that resveratrol is a strong candidate adjunct to resuscitation following severe hemorrhage. PMID:25879628

  7. Prolonged weaning: from the intensive care unit to home.

    PubMed

    Navalesi, P; Frigerio, P; Patzlaff, A; Häußermann, S; Henseke, P; Kubitschek, M

    2014-01-01

    Weaning is the process of withdrawing mechanical ventilation which starts with the first spontaneous breathing trial (SBT). Based on the degree of difficulty and duration, weaning is classified as simple, difficult and prolonged. Prolonged weaning, which includes patients who fail 3 SBTs or are still on mechanical ventilation 7 days after the first SBT, affects a relatively small fraction of mechanically ventilated ICU patients but these, however, requires disproportionate resources. There are several potential causes which can lead to prolonged weaning. It is nonetheless important to understand the problem from the point of view of each individual patient in order to adopt appropriate treatment and define precise prognosis. An otherwise stable patient who remains on mechanical ventilation will be considered for transfer to a specialized weaning unit (SWU). Though there is not a precise definition, SWU can be considered as highly specialized and protected environments for patients requiring mechanical ventilation despite resolution of the acute disorder. Proper staffing, well defined short-term and long-term goals, attention to psychological and social problems represent key determinants of SWU success. Some patients cannot be weaned, either partly or entirely, and may require long-term home mechanical ventilation. In these cases the logistics relating to caregivers and the equipment must be carefully considered and addressed.

  8. Designing carbohydrate nanoparticles for prolonged efficacy of antimicrobial peptide.

    PubMed

    Bi, Lin; Yang, Lei; Narsimhan, Ganesan; Bhunia, Arun K; Yao, Yuan

    2011-03-10

    In this work, carbohydrate nanoparticles were created to prolong the efficacy of antimicrobial peptide against pathogens. Nisin and Listeria monocytogenes were used as the peptide and pathogen models, respectively, and phytoglycogen (PG)-based nanoparticles were developed as carriers of nisin. PG from su1 mutant maize was subjected to β-amylolysis as well as subsequent succinate or octenyl succinate substitutions. The goal was to minimize the loss of peptide during storage and meanwhile realize an effective release in the presence of bacteria. The capabilities of PG derivatives as carriers of nisin were evaluated using centrifugal ultrafiltration, zeta-potential, and the initial availability of nisin against L. monocytogenes. All methods indicated that nisin loading was favored by a high degree of substitution (DS), presence of hydrophobic octenyl moiety, and β-amylolysis of PG nanoparticles. To evaluate the prolonged nisin efficacy, preparations containing nisin and PG derivatives were loaded into a BHI-agar deep-well model (mimicking nisin depletion at the nutrient-containing surface). The residual inhibitory activities of preparations against L. monocytogenes were monitored during 21 days of storage at 4 °C. The results showed that all PG derivatives led to the prolonged retention of nisin activity and the longest retention was associated with high DS, β-amylolysis, and octenyl succinate. Evidently, both electrostatic and hydrophobic interactions are the driving forces of nisin adsorption, and the glucan structure at the nanoparticle surface also affects nisin loading and retention during storage.

  9. Characterization of new stable ghrelin analogs with prolonged orexigenic potency.

    PubMed

    Maletínská, Lenka; Pýchová, Miroslava; Holubová, Martina; Blechová, Miroslava; Demianová, Zuzana; Elbert, Tomáš; Železná, Blanka

    2012-03-01

    Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.

  10. Effect of sleep deprivation on tolerance of prolonged exercise.

    PubMed

    Martin, B J

    1981-01-01

    Acute loss of sleep produces few apparent physiological effects at rest. Nevertheless, many anecdotes suggest that adequate sleep is essential for optimum endurance athletic performance. To investigate this question, heavy exercise performance after 36 h without sleep was compared with that after normal sleep in eight subjects. During prolonged treadmill walking at about 80% of the VO2 max, sleep loss reduced work time to exhaustion by an average of 11% (p = 0.05). This decrease occurred despite doubling monetary incentives for subjects during work after sleeplessness. Subjects appeared to fall into "resistant" and "susceptible" categories: four showed less than a 5% change in performance after sleep loss, while four others showed decrements in exercise tolerance ranging from 15 to 40%. During the walk, sleep loss resulted in significantly greater perceived exertion (p less than 0.05), even though exercise heart rate and metabolic rate (VO2 and VCO2) were unchanged. Minute ventilation was significantly elevated during exercise after sleep loss ( p less than 0.05). Sleep loss failed to alter the continuous slow rises in VE and heart rate that occurred as work was prolonged. These findings suggest that the psychological effects of acute sleep loss may contribute to decreased tolerance of prolonged heavy exercise.

  11. Hydrogels for ocular drug delivery and tissue engineering

    PubMed Central

    Fathi, Marzieh; Barar, Jaleh; Aghanejad, Ayuob; Omidi, Yadollah

    2015-01-01

    Hydrogels, as crosslinked polymeric three dimensional networks, possess unique structure and behavior in response to the internal and/or external stimuli. As a result, they offer great prospective applications in drug delivery, cell therapy and human tissue engineering. Here, we highlight the potential of hydrogels in prolonged intraocular drug delivery and ocular surface therapy using stem cells incorporated hydrogels. PMID:26929918

  12. A study of microemulsions as prolonged-release injectables through in-situ phase transition.

    PubMed

    Wu, Zimei; Alany, Raid G; Tawfeek, Noor; Falconer, James; Zhang, Wenli; Hassan, Ibrahim M; Rutland, Michael; Svirskis, Darren

    2014-01-28

    Microemulsions (MEs) have been studied extensively as colloidal carriers for the delivery of both water-soluble and lipid-soluble drugs. Our previous study showed that addition of water to ME formulations resulted in phase transition to either liquid crystal (LC) or coarse emulsion (CE). The aim of this study was to investigate whether these MEs could be used as drug delivery vehicles for prolonged release through in-situ phase transition following extravascular injection. Three ME formulations from the same pseudo-ternary phase diagram were investigated with respect to their phase transition behavior, and in-vivo drug release; a coarse emulsion-forming ME (CE-ME), an oil rich LC-forming ME (LC-ME1), and an oil poor LC-forming ME (LC-ME2). CE-ME was a W/O ME and both LC-MEs were O/W type. The release profiles of (99m)Tc labeled MEs following subcutaneous (SC) injection in rabbits were investigated with gamma-scintigraphy. The CE-ME dispersed readily in water, forming a CE, whereas the LC-forming MEs formed 'depots' in water. Polarized microscopy revealed a LC boundary spontaneously formed at the water/ME interface for the LC-MEs with the LC-ME2 forming a substantially thicker LC layer. The CE resulting from the water-induced transition of the CE-forming ME had a higher viscosity than the MEs, but lower than the LCs resulted from LC-MEs. Compared to LC-ME1, LC-ME2 underwent more rapid phase transition and the resultant LC had significant higher viscosity. The LCs formed from both ME formulations exhibited pseudoplastic properties; increasing the shear rate decreased the apparent viscosity exponentially. Following SC injection into the animal thigh, the LC-MEs had more prolonged release of (99m)Tc in a first-order manner, than CE-ME. The oil poor LC-ME2 had the slowest release with a t1/2 of 77min, 2.3 times longer than the oil rich LC-ME1; consistent with the thickness of LC layer formation observed in-vitro and their relative viscosities. In conclusion, the present

  13. Drug-mineral interactions

    SciTech Connect

    Kramer, L.

    1986-03-01

    The effect of drugs such as glucocorticoids and thyroid extract on calcium metabolism is unknown. However, several other medications affect the excretion and intestinal absorption of calcium. A controlled study was carried out to investigate these aspects. Urinary calcium was determined for 3 months during the long-term intake of the antituberculous drug isoniazid (INH) and of the antibiotic tetracycline. The effect of the diuretics furosemide and hydrochlorothiazide, of several aluminum-containing antacids, of thyroid extract and of corticosteroids was also studied. Metabolic balances of calcium, phosphorus, magnesium and zinc were determined, as well as the intestinal absorption of calcium using Ca 47. Plasma levels, urinary and fecal excretions of Ca 47 were determined. All drugs tested increased urinary calcium except for the diuretic hydrochlorothiazide. Regarding the effect of corticosteroids: the intestinal absorption of calcium was unchanged after the short-term use and was very high after long-term use. The studies have shown that several commonly used drugs induce an increase in urinary calcium excretion which may contribute to calcium loss, if this increase persists for prolonged periods of time. Urinary excretions of phosphorus, magnesium and zinc increased in some of the studies.

  14. Fabrication of drug eluting implants: study of drug release mechanism from titanium dioxide nanotubes

    NASA Astrophysics Data System (ADS)

    Hamlekhan, Azhang; Sinha-Ray, Suman; Takoudis, Christos; Mathew, Mathew T.; Sukotjo, Cortino; Yarin, Alexander L.; Shokuhfar, Tolou

    2015-06-01

    Formation of titanium dioxide nanotubes (TNTs) on a titanium surface holds great potential for promoting desirable cellular response. However, prolongation of drug release from these nano-reservoirs remains to be a challenge. In our previous work TNTs were successfully loaded with a drug. In this study the effect of TNTs dimensions on prolongation of drug release is quantified aiming at the introduction of a simple novel technique which overcomes complications of previously introduced methods. Different groups of TNTs with different lengths and diameters are fabricated. Samples are loaded with a model drug and rate of drug release over time is monitored. The relation of the drug release rate to the TNT dimensions (diameter, length, aspect ratio and volume) is established. The results show that an increase in any of these parameters increases the duration of the release process. However, the strongest parameter affecting the drug release is the aspect ratio. In fact, TNTs with higher aspect ratios release drug slower. It is revealed that drug release from TNT is a diffusion-limited process. Assuming that diffusion of drug in (Phosphate-Buffered Saline) PBS follows one-dimensional Fick’s law, the theoretical predictions for drug release profile is compatible with our experimental data for release from a single TNT.

  15. An update on drug-induced arthritis.

    PubMed

    Adwan, Marwan H

    2016-08-01

    A large and heterogeneous group of drugs can cause drug-induced arthritis. No single pathogenetic mechanism or drug class unifies these diverse culprits. Recognizing that joint symptoms may, in fact, be drug-related not only saves time and unnecessary investigations but can also prevent needless suffering and morbidity due to late recognition of a drug-induced arthritic condition. The extent of drug-induced arthritis is variable and ranges from minor short-lived and reversible arthralgia to a prolonged and occasionally destructive arthritis. The onset of arthritis due to various medications in relation to the timing of drug initiation is also variable and may range from a few days to several months.

  16. A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity

    PubMed Central

    Pang, Hong-Bo; Braun, Gary B.; She, Zhi-Gang; Kotamraju, Venkata R.; Sugahara, Kazuki N.; Teesalu, Tambet; Ruoslahti, Erkki

    2014-01-01

    The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors. PMID:24345789

  17. Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of I(Ca,L).

    PubMed

    Christ, Torsten; Wettwer, Erich; Ravens, Ursula

    2005-05-01

    The neuroleptic risperidone is an effective blocker of the rapidly activating component of the delayed rectifier current (I(Kr)) and hence is expected to prolong cardiac action potential duration (APD). However, unlike with other typical I(Kr) blockers we failed to demonstrate a marked prolongation of late repolarization with risperidone. It is hypothesized that the APD-prolonging effect of risperidone is masked by the high repolarization reserve due to the prominent delayed rectifier currents I(Kr) and I(Ks) in guinea pig papillary muscle. Action potentials and force of contraction were recorded in isolated guinea pig papillary muscles. L-type calcium current I(Ca,L) and I(Kr) were measured using the standard patch clamp technique in single ventricular cardiomyocytes. Reduction of the repolarization reserve by the blocking of I(Ks) with chromanol 239B augmented the effect of the selective I(Kr) blocker E-4031, but not of risperidone, although both drugs completely blocked I(Kr). In contrast to E-4031 risperidone markedly reduced the force of contraction due to the partial blocking of I(Ca,L) in the same concentration range as required for block of I(Kr). Reduction of the repolarization reserve by the blocking of I(Ks) cannot exacerbate the APD-prolonging effect of risperidone. However, even incomplete concomitant blocking of I(Ca,L) attenuates the APD-prolonging effect of the complete blocking of I(Kr). This behaviour may explain the small APD-prolonging effect of risperidone despite the drug's robust blocking of I(Kr).

  18. New approaches in the management of insomnia: weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists

    PubMed Central

    Hardeland, Rüdiger

    2009-01-01

    Hypnotic effects of melatonin and melatoninergic drugs are mediated via MT1 and MT2 receptors, especially those in the circadian pacemaker, the suprachiasmatic nucleus, which acts on the hypothalamic sleep switch. Therefore, they differ fundamentally from GABAergic hypnotics. Melatoninergic agonists primarily favor sleep initiation and reset the circadian clock to phases allowing persistent sleep, as required in circadian rhythm sleep disorders. A major obstacle for the use of melatonin to support sleep maintenance in primary insomnia results from its short half-life in the circulation. Solutions to this problem have been sought by developing prolonged-release formulations of the natural hormone, or melatoninergic drugs of longer half-life, such as ramelteon, tasimelteon and agomelatine. With all these drugs, improvements of sleep are statistically demonstrable, but remain limited, especially in primary chronic insomnia, so that GABAergic drugs may be indicated. Melatoninergic agonists do not cause next-day hangover and withdrawal effects, or dependence. They do not induce behavioral changes, as sometimes observed with z-drugs. Despite otherwise good tolerability, the use of melatoninergic drugs in children, adolescents, and during pregnancy has been a matter of concern, and should be avoided in autoimmune diseases and Parkinsonism. Problems and limits of melatoninergic hypnotics are compared. PMID:19557144

  19. Generic Drugs

    MedlinePlus

    Generic Drugs: The Same Medicine for Less Money What is a generic drug? A generic is a copy of a brand-name drug. A brand- name drug has a patent. When ... benefit to your health, and you will save money. 7KH IHGHUDO )RRG DQG 'UXJ $GPLQLVWUDWLRQ )'$ UHJXODWHV ERWK ...

  20. Drug hypersensitivity.

    PubMed

    Yawalkar, N

    2009-01-01

    Drug hypersensitivity represents an immune-mediated reaction to a drug. Although several drug hypersensitivity reactions are confined to the skin and rather mild, some may be life threatening and also involve further organs such as liver, kidney and bone marrow. The exact pathogenesis of many drug hypersensitivity reactions is still obscure. In this review the concepts on how small molecular drugs can activate the immune system are discussed and the hapten, prohapten and p-i concept are explained. Furthermore, the classification of drug hypersensitivity reactions and some common and severe clinical manifestations of drug-induced T cell mediated reactions are presented.

  1. Effect of prolonged status epilepticus as a result of intoxication on epileptogenesis in a UK canine population.

    PubMed

    Jull, P; Risio, L D; Horton, C; Volk, H A

    2011-10-01

    The aim of the present study was to investigate if prolonged status epilepticus (SE), secondary to a chemoconvulsant, can induce spontaneous recurrent seizures in dogs. Clinical records at two UK referral hospitals were searched for dogs that presented in SE secondary to intoxication. Dogs were only included in the study if there was clear historical evidence of intoxication and a prolonged SE. Clinical and follow-up information was retrieved and verified by using a combination of clinical records from the two hospitals and the referring veterinarian and by contacting the owners using a telephone questionnaire. Twenty dogs met the inclusion criteria: 17 presented for metaldehyde toxicity, one for moxidectin toxicity, one for theobromine toxicity and one for mycotoxin toxicity. Of these 20 dogs, three dogs had an SE duration between 0.5 and one hour, four dogs between one and 12 hours, 10 dogs between 12 and 24 hours and three dogs greater then 24 hours. Median follow-up time for the 20 dogs was 757 days (range 66 to 1663 days). No dog had any further seizures after its SE. The present study supports the view that dogs with a prolonged SE following intoxication with the aforementioned toxins might not need long-term treatment with antiepileptic drugs after the SE has been controlled.

  2. Depressive Disorders during Weaning from Prolonged Mechanical Ventilation

    PubMed Central

    Jubran, Amal; Lawm, Gerald; Kelly, Joanne; Duffner, Lisa A.; Gungor, Gokay; Collins, Eileen G.; Lanuza, Dorothy M.; Hoffman, Leslie A.; Tobin, Martin J.

    2010-01-01

    Purpose Patients who require mechanical ventilation are at risk of emotional stress because of total dependence on a machine for breathing. The stress may negatively impact ventilator weaning and survival. The purpose of this study was to determine whether depressive disorders in patients being weaned from prolonged mechanical ventilation are linked to weaning failure and decreased survival. Methods A prospective study of 478 consecutive patients transferred to a long-term acute care hospital for weaning from prolonged ventilation was undertaken. A clinical psychologist conducted a psychiatric interview to assess for the presence of depressive disorders. Results Of the 478 patients, 142 had persistent coma or delirium and were unable to be evaluated for depressive disorders. Of the remaining 336 patients, 142 (42%) were diagnosed with depressive disorders. In multivariate analysis, co-morbidity score (odds ratio [OR], 1.23, p=0.007), functional dependence before the acute illness (OR, 1.70, p=0.03), and history of psychiatric disorders (OR, 3.04, p=0.0001) were independent predictors of depressive disorders. The rate of weaning failure was higher in patients with depressive disorders than in those without such disorders (61% versus 33%, p=0.0001), as was mortality (24% versus 10%, p=0.0008). The presence of depressive disorders was independently associated with mortality (OR, 4.3; p=0.0002); age (OR, 1.06; p=0.001) and co-morbidity score (OR, 1.24; p=0.02) also predicted mortality. Conclusion Depressive disorders were diagnosed in 42% of patients who are being weaned from prolonged ventilation. Patients with depressive disorders were more likely to experience weaning failure and death. PMID:20232042

  3. Neural compensation within the human triceps surae during prolonged walking.

    PubMed

    Cronin, Neil J; Peltonen, Jussi; Sinkjaer, Thomas; Avela, Janne

    2011-02-01

    During human walking, muscle activation strategies are approximately constant across consecutive steps over a short time, but it is unknown whether they are maintained over a longer duration. Prolonged walking may increase tendinous tissue (TT) compliance, which can influence neural activation, but the neural responses of individual muscles have not been investigated. This study investigated the hypothesis that muscle activity is up- or down-regulated in individual triceps surae muscles during prolonged walking. Thirteen healthy subjects walked on a treadmill for 60 min at 4.5 km/h, while triceps surae muscle activity, maximal muscle compound action potentials, and kinematics were recorded every 5 min, and fascicle lengths were estimated at the beginning and end of the protocol using ultrasound. After 1 h of walking, soleus activity increased by 9.3 ± 0.2% (P < 0.05) and medial gastrocnemius activity decreased by 9.3 ± 0.3% (P < 0.01). Gastrocnemius fascicle length at ground contact shortened by 4.45 ± 0.99% (P < 0.001), whereas soleus fascicle length was unchanged (P = 0.988). Throughout the stance phase, medial gastrocnemius fascicle lengthening decreased by 44 ± 13% (P < 0.001), whereas soleus fascicle lengthening amplitude was unchanged (P = 0.650). The data suggest that a compensatory neural strategy exists between triceps surae muscles and that changes in muscle activation are generally mirrored by changes in muscle fascicle length. These findings also support the notion of muscle-specific changes in TT compliance after prolonged walking and highlight the ability of the CNS to maintain relatively constant movement patterns in spite of neuromechanical changes in individual muscles.

  4. Fetal brain hypometabolism during prolonged hypoxaemia in the llama.

    PubMed

    Ebensperger, Germán; Ebensperger, Renato; Herrera, Emilio A; Riquelme, Raquel A; Sanhueza, Emilia M; Lesage, Florian; Marengo, Juan J; Tejo, Rodrigo I; Llanos, Aníbal J; Reyes, Roberto V

    2005-09-15

    In this study we looked for additional evidence to support the hypothesis that fetal llama reacts to hypoxaemia with adaptive brain hypometabolism. We determined fetal llama brain temperature, Na(+) and K(+) channel density and Na(+)-K(+)-ATPase activity. Additionally, we looked to see whether there were signs of cell death in the brain cortex of llama fetuses submitted to prolonged hypoxaemia. Ten fetal llamas were instrumented under general anaesthesia to measure pH, arterial blood gases, mean arterial pressure, heart rate, and brain and core temperatures. Measurements were made 1 h before and every hour during 24 h of hypoxaemia (n = 5), which was imposed by reducing maternal inspired oxygen fraction to reach a fetal arterial partial pressure of oxygen (P(a,O(2))) of about 12 mmHg. A normoxaemic group was the control (n = 5). After 24 h of hypoxaemia, we determined brain cortex Na(+)-K(+)-ATPase activity, ouabain binding, and the expression of NaV1.1, NaV1.2, NaV1.3, NaV1.6, TREK1, TRAAK and K(ATP) channels. The lack of brain cortex damage was assessed as poly ADP-ribose polymerase (PARP) proteolysis. We found a mean decrease of 0.56 degrees C in brain cortex temperature during prolonged hypoxaemia, which was accompanied by a 51% decrease in brain cortex Na(+)-K(+)-ATPase activity, and by a 44% decrease in protein content of NaV1.1, a voltage-gated Na(+) channel. These changes occurred in absence of changes in PARP protein degradation, suggesting that the cell death of the brain was not enhanced in the fetal llama during hypoxaemia. Taken together, these results provide further evidence to support the hypothesis that the fetal llama responds to prolonged hypoxaemia with adaptive brain hypometabolism, partly mediated by decreases in Na(+)-K(+)-ATPase activity and expression of NaV channels.

  5. Adaptive prolonged postreproductive life span in killer whales.

    PubMed

    Foster, Emma A; Franks, Daniel W; Mazzi, Sonia; Darden, Safi K; Balcomb, Ken C; Ford, John K B; Croft, Darren P

    2012-09-14

    Prolonged life after reproduction is difficult to explain evolutionarily unless it arises as a physiological side effect of increased longevity or it benefits related individuals (i.e., increases inclusive fitness). There is little evidence that postreproductive life spans are adaptive in nonhuman animals. By using multigenerational records for two killer whale (Orcinus orca) populations in which females can live for decades after their final parturition, we show that postreproductive mothers increase the survival of offspring, particularly their older male offspring. This finding may explain why female killer whales have evolved the longest postreproductive life span of all nonhuman animals.

  6. Prolonged ictal monoparesis with parietal Periodic Lateralised Epileptiform Discharges (PLEDs).

    PubMed

    Murahara, Takashi; Kinoshita, Masako; Usami, Kiyohide; Matsui, Masashi; Yamashita, Kouhei; Takahashi, Ryosuke; Ikeda, Akio

    2013-06-01

    We report a patient with prolonged monoparesis and parietal periodic lateralised epileptiform discharges (PLEDs). The patient was a 73-year-old man with chronic myelomonocytic leukaemia who developed persisting monoparesis of the right arm, sensory aphasia, and finger agnosia, initially associated with focal clonic seizures. These neurological deficits remained for seven days without subsequent focal clonic seizures. The EEG showed left-sided PLEDs, maximal in the left occipito-parietal area. Ten days later, following phenytoin treatment, these symptoms suddenly improved and parietal PLEDs disappeared. Sustained PLEDs in the left parietal region may have been causally associated with ictal paresis in this patient.

  7. How long would SDH/SONET be prolonged?

    NASA Astrophysics Data System (ADS)

    Tao, Zhiyong; Mao, Qian

    2004-04-01

    As we all know, the increasing speed of data traffic is exceeding gradually from voice in today"s communication network. The main reason is the explosive of Internet. The controversy with IP over ATM/SDH/Optical becomes hotter and hotter, Many people in the telecommunication field are doubt: HOW LONG WOULD SDH/SONET BE PROLONGED? WHAT KIND OF SDH EQUIPMENTS COULD BE USED IN THE NETWORK? With the analysis from several aspects: services in the network, new development with SDH technology, market in transport equipment, This paper is considered that the SDH with some new features would be predominant transport technology in the recent years.

  8. Hemiplegic Migraine Presenting with Prolonged Somnolence: A Case Report

    PubMed Central

    Saleh, Christian; Pierquin, Geneviève; Beyenburg, Stefan

    2016-01-01

    Hemiplegic migraine is a rare and complex disease, characterized by migraine with a reversible motor aura. Hemiplegic migraine can be easily misdiagnosed at its first presentation with an atypical severe form of migraine, a stroke, multiple sclerosis, metabolic disorders, conversion disorder or an epilepsy. We present the case of a young 24-year-old male patient, who since the age of 4 years had been having multiple episodes of migraine associated with hemiparesis, paraesthesia, prolonged somnolence, aphasia and confusion. We review the literature and discuss important diagnostic findings in hemiplegic migraine to help establishing a prompt diagnosis. PMID:27790126

  9. Extracorporeal Free Flap Perfusion in Case of Prolonged Ischemia Time.

    PubMed

    Taeger, C D; Präbst, K; Beier, J P; Meyer, A; Horch, R E

    2016-04-01

    In free flap surgery, a clinically established concept still has to be found for the reduction of ischemia-related cell damage in the case of prolonged ischemia. Although promising results using extracorporeal free flap perfusion in the laboratory have been published in the past, until now this concept has not yet paved its way into clinical routine. This might be due to the complexity of perfusion systems and a lack of standardized tools. Here, we want to present the results of the first extracorporeal free flap perfusion in a clinical setting using a simple approach without the application of a complex perfusion machinery.

  10. In Situ Loading of Basic Fibroblast Growth Factor Within Porous Silica Nanoparticles for a Prolonged Release

    NASA Astrophysics Data System (ADS)

    Zhang, Jin; Postovit, Lynne-Marie; Wang, Dashan; Gardiner, Richard B.; Harris, Richard; Abdul, Mumin Md; Thomas, Anu Alice

    2009-11-01

    Basic fibroblast growth factor (bFGF), a protein, plays a key role in wound healing and blood vessel regeneration. However, bFGF is easily degraded in biologic systems. Mesoporous silica nanoparticles (MSNs) with well-tailored porous structure have been used for hosting guest molecules for drug delivery. Here, we report an in situ route to load bFGF in MSNs for a prolonged release. The average diameter ( d) of bFGF-loaded MSNs is 57 ± 8 nm produced by a water-in-oil microemulsion method. The in vitro releasing profile of bFGF from MSNs in phosphate buffer saline has been monitored for 20 days through a colorimetric enzyme linked immunosorbent assay. The loading efficiency of bFGF in MSNs is estimated at 72.5 ± 3%. In addition, the cytotoxicity test indicates that the MSNs are not toxic, even at a concentration of 50 μg/mL. It is expected that the in situ loading method makes the MSNs a new delivery system to deliver protein drugs, e.g. growth factors, to help blood vessel regeneration and potentiate greater angiogenesis.

  11. Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats.

    PubMed

    Erbas, Oytun; Yilmaz, Mustafa

    2015-12-01

    Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p < 0.0005 and p < 0.0001, respectively). The study demonstrated the effectiveness of metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone.

  12. Ocular Dorzolamide Nanoliposomes for Prolonged IOP Reduction: in-vitroand in-vivo Evaluation in Rabbits

    PubMed Central

    Kouchak, Maryam; Bahmandar, Reza; Bavarsad, Neda; Farrahi, Fereydoun

    2016-01-01

    Dorzolamide ophthalmic drop is one of the most common glaucoma medications but it has a short residence time in the eye. The aim of this study is to develop ocular dorzolamide HCl nanoliposomes (DRZ – nanoliposomes) and to evaluate their potential use for the treatment of ocular hypertension. Nanoliposomes were prepared using Reverse-phase evaporation vesicle (REV) and thin layer hydration (TLH) method with 7:3 and 7:4 molar ratios of phosphatidylcholine:cholesterol. The physicochemical properties of the formulations were investigated. Formulations with 7:4 lipid ratios were evaluated in terms of drug release, physical stability and ex-vivo permeation through the excised albino rabbit cornea. The rabbits in groups of 6 were treated with selected DRZ – nanoliposomes or dorzolamide solution or marketed dorzolamid preparation (Biosopt®) and intraocular pressure (IOP) was monitored. Formulations with 7:4 molar ratio entrapped greater amount of drug compared to those with 7:3 lipid components ratio. DRZ – nanoliposomes with 7:4 lipid ratio showed more transcorneal permeation than Dorzolamide solution (p<0.05); and the formulation prepared by TLH method exhibited higher permeability than that prepared by REV method (p<0.05). The selected DRZ – nanoliposomes showed greater IOP lowering activity and a more prolonged effect compared to dorzolamide solution and Biosopt®. DRZ – nanoliposomes prepared by TLH method with 7:4 ratios showed promising results as a candidate for the treatment of ocular hypertension. PMID:27610160

  13. pH-dependent inhibition of K₂P3.1 prolongs atrial refractoriness in whole hearts.

    PubMed

    Skarsfeldt, Mark A; Jepps, Thomas A; Bomholtz, Sofia H; Abildgaard, Lea; Sørensen, Ulrik S; Gregers, Emilie; Svendsen, Jesper H; Diness, Jonas G; Grunnet, Morten; Schmitt, Nicole; Olesen, Søren-Peter; Bentzen, Bo H

    2016-04-01

    In isolated human atrial cardiomyocytes, inhibition of K2P3.1 K(+) channels results in action potential (action potential duration (APD)) prolongation. It has therefore been postulated that K2P3.1 (KCNK3), together with K2P9.1 (KCNK9), could represent novel drug targets for the treatment of atrial fibrillation (AF). However, it is unknown whether these findings in isolated cells translate to the whole heart. The purposes of this study were to investigate the expression levels of KCNK3 and KCNK9 in human hearts and two relevant rodent models and determine the antiarrhythmic potential of K2P3.1 inhibition in isolated whole-heart preparations. By quantitative PCR, we found that KCNK3 is predominantly expressed in human atria whereas KCNK9 was not detectable in heart human tissue. No differences were found between patients in AF or sinus rhythm. The expression in guinea pig heart resembled humans whereas rats displayed a more uniform expression of KCNK3 between atria and ventricle. In voltage-clamp experiments, ML365 and A293 were found to be potent and selective inhibitors of K2P3.1, but at pH 7.4, they failed to prolong atrial APD and refractory period (effective refractory period (ERP)) in isolated perfused rat and guinea pig hearts. At pH 7.8, which augments K2P3.1 currents, pharmacological channel inhibition produced a significant prolongation of atrial ERP (11.6 %, p = 0.004) without prolonging ventricular APD but did not display a significant antiarrhythmic effect in our guinea pig AF model (3/8 hearts converted on A293 vs 0/7 hearts in time-matched controls). These results suggest that when K2P3.1 current is augmented, K2P3.1 inhibition leads to atrial-specific prolongation of ERP; however, this ERP prolongation did not translate into significant antiarrhythmic effects in our AF model.

  14. Helping Affluent Families Help Their Acting-Out, Alienated Drug Abusing Adolescent

    ERIC Educational Resources Information Center

    Bratter, Thomas Edward

    1974-01-01

    Suggests that the psychotherapist working with families of adolescent drug abuser must work for parental involvement, strengthening of the family group, and increased adolescent responsibility and independence from parents who unwittingly encourage a prolonged symbiotic relationship. (Author/CJ)

  15. Influence of a Prolonged Tennis Match Play on Serve Biomechanics

    PubMed Central

    Martin, Caroline; Bideau, Benoit; Delamarche, Paul; Kulpa, Richard

    2016-01-01

    The aim of this study was to quantify kinematic, kinetic and performance changes that occur in the serve throughout a prolonged tennis match play. Serves of eight male advanced tennis players were recorded with a motion capture system before, at mid-match, and after a 3-hour tennis match. Before and after each match, electromyographic data of 8 upper limb muscles obtained during isometric maximal voluntary contraction were compared to determine the presence of muscular fatigue. Vertical ground reaction forces, rating of perceived exertion, ball speed, and ball impact height were measured. Kinematic and upper limb kinetic variables were computed. The results show decrease in mean power frequency values for several upper limb muscles that is an indicator of local muscular fatigue. Decreases in serve ball speed, ball impact height, maximal angular velocities and an increase in rating of perceived exertion were also observed between the beginning and the end of the match. With fatigue, the majority of the upper limb joint kinetics decreases at the end of the match. No change in timing of maximal angular velocities was observed between the beginning and the end of the match. A prolonged tennis match play may induce fatigue in upper limb muscles, which decrease performance and cause changes in serve maximal angular velocities and joint kinetics. The consistency in timing of maximal angular velocities suggests that advanced tennis players are able to maintain the temporal pattern of their serve technique, in spite of the muscular fatigue development. PMID:27532421

  16. Caffeine ingestion, affect and perceived exertion during prolonged cycling.

    PubMed

    Backhouse, Susan H; Biddle, Stuart J H; Bishop, Nicolette C; Williams, Clyde

    2011-08-01

    Caffeine's metabolic and performance effects have been widely reported. However, caffeine's effects on affective states during prolonged exercise are unknown. Therefore, this was examined in the present study. Following an overnight fast and in a randomised, double-blind, counterbalanced design, twelve endurance trained male cyclists performed 90 min of exercise at 70% VO(₂ max) 1h after ingesting 6 mg kg⁻¹ BM of caffeine (CAF) or placebo (PLA). Dimensions of affect and perceived exertion were assessed at regular intervals. During exercise, pleasure ratings were better maintained (F(₃,₃₈)=4.99, P < 0.05) in the CAF trial compared to the PLA trial with significantly higher ratings at 15, 30 and 75 min (all P < 0.05). Perceived exertion increased (F(₃,₃₈) = 19.86, P < 0.01) throughout exercise and values, overall, were significantly lower (F(₁,₁₁) = 9.26, P < 0.05) in the CAF trial compared to the PLA trial. Perceived arousal was elevated during exercise but did not differ between trials. Overall, the results suggest that a moderate dose of CAF ingested 1h prior to exercise maintains a more positive subjective experience during prolonged cycling. This observation may partially explain caffeine's ergogenic effects.

  17. High efficiency holographic Bragg grating with optically prolonged memory

    PubMed Central

    Khoo, Iam Choon; Chen, Chun-Wei; Ho, Tsung-Jui

    2016-01-01

    In this paper, we show that photosensitive azo-dye doped Blue-phase liquid crystals (BPLC) formed by natural molecular self-assembly are capable of high diffraction efficiency holographic recording with memory that can be prolonged from few seconds to several minutes by uniform illumination with the reference beam. Operating in the Bragg regime, we have observed 50 times improvement in the grating diffraction efficiency and shorter recording time compared to previous investigations. The enabling mechanism is BPLC’s lattice distortion and index modulation caused by the action of light on the azo-dopant; upon photo-excitation, the azo-molecules undergo transformation from the oblong-shaped Trans-state to the bent-shaped Cis-state, imparting disorder and also cause the surrounding BPLC molecules to undergo coupled flow & reorientation leading to lattice distortion and index modulation. We also showed that the same mechanism at work here that facilitates lattice distortion can be used to frustrate free relaxation of the lattice distortion, thereby prolonging the lifetime of the written grating, provided the reference beam is kept on after recording. Due to the ease in BPLC fabrication and the availability of azo-dopants with photosensitivity throughout the entire visible spectrum, one can optimize the controlling material and optical parameters to obtain even better performance. PMID:27782197

  18. High efficiency holographic Bragg grating with optically prolonged memory

    NASA Astrophysics Data System (ADS)

    Khoo, Iam Choon; Chen, Chun-Wei; Ho, Tsung-Jui

    2016-10-01

    In this paper, we show that photosensitive azo-dye doped Blue-phase liquid crystals (BPLC) formed by natural molecular self-assembly are capable of high diffraction efficiency holographic recording with memory that can be prolonged from few seconds to several minutes by uniform illumination with the reference beam. Operating in the Bragg regime, we have observed 50 times improvement in the grating diffraction efficiency and shorter recording time compared to previous investigations. The enabling mechanism is BPLC’s lattice distortion and index modulation caused by the action of light on the azo-dopant; upon photo-excitation, the azo-molecules undergo transformation from the oblong-shaped Trans-state to the bent-shaped Cis-state, imparting disorder and also cause the surrounding BPLC molecules to undergo coupled flow & reorientation leading to lattice distortion and index modulation. We also showed that the same mechanism at work here that facilitates lattice distortion can be used to frustrate free relaxation of the lattice distortion, thereby prolonging the lifetime of the written grating, provided the reference beam is kept on after recording. Due to the ease in BPLC fabrication and the availability of azo-dopants with photosensitivity throughout the entire visible spectrum, one can optimize the controlling material and optical parameters to obtain even better performance.

  19. Prolonged fasting impairs neural reactivity to visual stimulation.

    PubMed

    Kohn, N; Wassenberg, A; Toygar, T; Kellermann, T; Weidenfeld, C; Berthold-Losleben, M; Chechko, N; Orfanos, S; Vocke, S; Laoutidis, Z G; Schneider, F; Karges, W; Habel, U

    2016-01-01

    Previous literature has shown that hypoglycemia influences the intensity of the BOLD signal. A similar but smaller effect may also be elicited by low normal blood glucose levels in healthy individuals. This may not only confound the BOLD signal measured in fMRI, but also more generally interact with cognitive processing, and thus indirectly influence fMRI results. Here we show in a placebo-controlled, crossover, double-blind study on 40 healthy subjects, that overnight fasting and low normal levels of glucose contrasted to an activated, elevated glucose condition have an impact on brain activation during basal visual stimulation. Additionally, functional connectivity of the visual cortex shows a strengthened association with higher-order attention-related brain areas in an elevated blood glucose condition compared to the fasting condition. In a fasting state visual brain areas show stronger coupling to the inferior temporal gyrus. Results demonstrate that prolonged overnight fasting leads to a diminished BOLD signal in higher-order occipital processing areas when compared to an elevated blood glucose condition. Additionally, functional connectivity patterns underscore the modulatory influence of fasting on visual brain networks. Patterns of brain activation and functional connectivity associated with a broad range of attentional processes are affected by maturation and aging and associated with psychiatric disease and intoxication. Thus, we conclude that prolonged fasting may decrease fMRI design sensitivity in any task involving attentional processes when fasting status or blood glucose is not controlled.

  20. Effect of Multiparity and Prolonged Lactation on Bone Mineral Density

    PubMed Central

    Natung, Tanie; Barooah, Rituparna; Ahanthem, Santa Singh

    2016-01-01

    Objectives This study was done to determine the effect of multiparity and prolonged lactation on bone mineral density (BMD). Methods This cross-sectional study included 196 perimenopausal and postmenopausal women aged 40 to 60 years old. Age, body mass index (BMI), menopausal status, duration of menopause, parity and total duration of lactation, nutritional history were recorded. Lumbar spine (LS; L2-L4) and femur neck (FN) BMD were measured using dual energy X-ray absorptiometry. Correlation of parity and lactation with BMD were investigated using multiple regression analysis. Results Parity was inversely correlated to BMD for LS (β = −0.266, P = 0.001) and FN (β = −0.380, P = 0.000). This relation remained significant even after adjusting for age, BMI and duration of menopause. Duration of lactation was inversely correlated with BMD for LS (β = −0.271, P = 0.001) but no for FN (β = −0.124, P = 0.130). Conclusions Multiparity and prolonged lactation have negative impact on BMD especially with in a socioeconomic group whose nutritional intake is borderline. Our data support that parity and duration of lactation can be associated with future osteoporosis. PMID:28119896

  1. Simplified methods for the prolonged treatment of fish diseases

    USGS Publications Warehouse

    Fish, F.F.

    1939-01-01

    The prevention or control of epidemics of fish diseases by applying a disinfecting solution in a uniform concentration directly to the water supply of a fish pond or trough for a definite period of time has been exceedingly slow in development. In so far as can be determined, the original idea should be credited to. Marsh and Robinson (1910). In their work on the control of algae in fish ponds by the continuous application of dilute copper sulphate solution, administered to the inflowing water supply by means of a floating syphon, they suggested this method as a possibility in the treatment of fish diseases. Following their work, this commendable idea seems to have remained quite dormant and apparently forgotten until Hess (1930) revived it twenty or more years later. This worker found that a prolonged immersion in a dilute disinfecting bath was more efficacious in remowng fluke parasites from goldfish than was the customary short "hand dip" method. Kingsbury and Embody (1932) later adapted the idea of a prolonged treatment to running water by the use of a float valve for maintaining a constant level in a reservoir, resulting in a constant flow to the pond or trough to be treated. Shortly thereafter, Fish (1933) modified the floating syphon of Marsh and Robinson, as it was a simpler apparatus than that of Kingsbury and Embody.

  2. Influence of a Prolonged Tennis Match Play on Serve Biomechanics.

    PubMed

    Martin, Caroline; Bideau, Benoit; Delamarche, Paul; Kulpa, Richard

    2016-01-01

    The aim of this study was to quantify kinematic, kinetic and performance changes that occur in the serve throughout a prolonged tennis match play. Serves of eight male advanced tennis players were recorded with a motion capture system before, at mid-match, and after a 3-hour tennis match. Before and after each match, electromyographic data of 8 upper limb muscles obtained during isometric maximal voluntary contraction were compared to determine the presence of muscular fatigue. Vertical ground reaction forces, rating of perceived exertion, ball speed, and ball impact height were measured. Kinematic and upper limb kinetic variables were computed. The results show decrease in mean power frequency values for several upper limb muscles that is an indicator of local muscular fatigue. Decreases in serve ball speed, ball impact height, maximal angular velocities and an increase in rating of perceived exertion were also observed between the beginning and the end of the match. With fatigue, the majority of the upper limb joint kinetics decreases at the end of the match. No change in timing of maximal angular velocities was observed between the beginning and the end of the match. A prolonged tennis match play may induce fatigue in upper limb muscles, which decrease performance and cause changes in serve maximal angular velocities and joint kinetics. The consistency in timing of maximal angular velocities suggests that advanced tennis players are able to maintain the temporal pattern of their serve technique, in spite of the muscular fatigue development.

  3. Survival without sequelae after prolonged cardiopulmonary resuscitation after electric shock.

    PubMed

    Motawea, Mohamad; Al-Kenany, Al-Sayed; Hosny, Mostafa; Aglan, Omar; Samy, Mohamad; Al-Abd, Mohamed

    2016-03-01

    "Electrical shock is the physiological reaction or injury caused by electric current passing through the human body. It occurs upon contact of a human body part with any source of electricity that causes a sufficient current through the skin, muscles, or hair causing undesirable effects ranging from simple burns to death." Ventricular fibrillation is believed to be the most common cause of death after electrical shock. "The ideal duration of cardiac resuscitation is unknown. Typically prolonged cardiopulmonary resuscitation is associated with poor neurologic outcomes and reduced long term survival. No consensus statement has been made and traditionally efforts are usually terminated after 15-30 minutes." The case under discussion seems worthy of the somewhat detailed description given. It is for a young man who survived after 65 minutes after electrical shock (ES) after prolonged high-quality cardiopulmonary resuscitation (CPR), multiple defibrillations, and artificial ventilation without any sequelae. Early start of adequate chest compressions and close adherence to advanced cardiac life support protocols played a vital role in successful CPR.

  4. Prolonged preconditioning with natural honey against myocardial infarction injuries.

    PubMed

    Eteraf-Oskouei, Tahereh; Shaseb, Elnaz; Ghaffary, Saba; Najafi, Moslem

    2013-07-01

    Potential protective effects of prolonged preconditioning with natural honey against myocardial infarction were investigated. Male Wistar rats were pre-treated with honey (1%, 2% and 4%) for 45 days then their hearts were isolated and mounted on a Langendorff apparatus and perfused with a modified Krebs-Henseleit solution during 30 min regional ischemia fallowed by 120 min reperfusion. Two important indexes of ischemia-induced damage (infarction size and arrhythmias) were determined by computerized planimetry and ECG analysis, respectively. Honey (1% and 2%) reduced infarct size from 23±3.1% (control) to 9.7±2.4 and 9.5±2.3%, respectively (P<0.001). At the ischemia, honey (1%) significantly reduced (P<0.05) the number and duration of ventricular tachycardia (VT). Honey (1% and 2%) also significantly decreased number of ventricular ectopic beats (VEBs). In addition, incidence and duration of reversible ventricular fibrillation (Rev VF) were lowered by honey 2% (P<0.05). During reperfusion, honey produced significant reduction in the incidences of VT, total and Rev VF, duration and number of VT. The results showed cardioprotective effects of prolonged pre-treatment of rats with honey following myocardial infarction. Maybe, the existence of antioxidants and energy sources (glucose and fructose) in honey composition and improvement of hemodynamic functions may involve in those protective effects.

  5. Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

    PubMed

    Sonabend, Adam M; Stuart, R Morgan; Yun, Jonathan; Yanagihara, Ted; Mohajed, Hamed; Dashnaw, Steven; Bruce, Samuel S; Brown, Truman; Romanov, Alex; Sebastian, Manu; Arias-Mendoza, Fernando; Bagiella, Emilia; Canoll, Peter; Bruce, Jeffrey N

    2011-08-01

    Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.

  6. Prolonged stays in hospital acute geriatric care units: identification and analysis of causes.

    PubMed

    Parent, Vivien; Ludwig-Béal, Stéphanie; Sordet-Guépet, Hélène; Popitéan, Laura; Camus, Agnès; Da Silva, Sofia; Lubrano, Anne; Laissus, Frederick; Vaillard, Laurence; Manckoundia, Patrick

    2016-06-01

    In France, the population of very old frail patients, who require appropriate high-quality care, is increasing. Given the current economic climate, the mean duration of hospitalization (MDH) needs to be optimized. This prospective study analyzed the causes of prolonged hospitalization in an acute geriatric care unit. Over 6 months, all patients admitted to the target acute geriatric care unit were included and distributed into two groups according to a threshold stay of 14 days: long MDH group (LMDHG) and short MDH group (SMDHG). These two groups were compared. 757 patients were included. The LMDHG comprised 442 with a mean age of 86.7 years, of whom 67.65% were women and the SMDHG comprised 315 with a mean age of 86.6 years, of whom 63.2% were women. The two groups were statistically similar for age, sex, living conditions at home (alone or not, help), medical history and number of drugs. Patients in the LMDHG were more dependent (p=0.005), and were more likely to be hospitalized for social reasons (p=0.024) and to have come from their homes (p=0.011) than those in the SMDHG. The reasons for the prolonged stay, more frequent in the LMDHG than the SMDHG (p<0.05), were principally: waiting for imaging examinations, medical complications, and waiting for discharge solutions, assistance from social workers and/or specialist consultations. In order to reduce the MDH in acute geriatric care unit, it is necessary to consider the particularities of the patients who are admitted, their medico-socio-psychological management, access to technical facilities/consultations and post-discharge accommodation.

  7. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.

    PubMed

    Grace, Peter M; Strand, Keith A; Galer, Erika L; Urban, Daniel J; Wang, Xiaohui; Baratta, Michael V; Fabisiak, Timothy J; Anderson, Nathan D; Cheng, Kejun; Greene, Lisa I; Berkelhammer, Debra; Zhang, Yingning; Ellis, Amanda L; Yin, Hang Hubert; Campeau, Serge; Rice, Kenner C; Roth, Bryan L; Maier, Steven F; Watkins, Linda R

    2016-06-14

    Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.

  8. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

    PubMed Central

    Strand, Keith A.; Galer, Erika L.; Urban, Daniel J.; Wang, Xiaohui; Baratta, Michael V.; Fabisiak, Timothy J.; Anderson, Nathan D.; Cheng, Kejun; Greene, Lisa I.; Berkelhammer, Debra; Zhang, Yingning; Ellis, Amanda L.; Yin, Hang Hubert; Campeau, Serge; Rice, Kenner C.; Roth, Bryan L.; Maier, Steven F.; Watkins, Linda R.

    2016-01-01

    Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain—namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent “two-hit hypothesis” of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain. PMID:27247388

  9. FTY720 treatment prolongs skin graft survival in a completely incompatible strain combination.

    PubMed

    Lima, R S M; Nogueira-Martins, M F; Silva, H T; Pestana, J O M; Bueno, V

    2004-05-01

    FTY720 has shown potent immunomodulatory activity in a variety of animal organ transplant models. However, the in vivo immunosuppressive mechanism of FTY720 is still not fully understood. It has been suggested that the marked decrease in the number of peripheral blood lymphocytes during FTY720 administration could be responsible for its immunosuppressive effects. Our aims were: (1) to study the effects of FTY720 treatment on skin graft survival using a fully mismatched strain combination and (2) to evaluate lymphocyte numbers in different sites at 5 days after skin transplant. C57BL/6 mice and BALB/c mice were the donors and recipients respectively. BALB/c mice received FTY720 (1 mg/kg/d) orally for 4 consecutive days. Drug administration started 1 day before skin transplants. A small segment of tail skin was affixed on the right dorsal side of the mouse via sutures. The administration of FTY720 (4 mg/kg) prolonged skin graft survival from 12.6 +/- 2.2 days (no treatment) to 16.6 +/- 4.2 days. The histologic findings of rejection were similar for all groups. Five days after transplant, lymphocyte numbers were significantly increased in lymph nodes compared with nontransplanted or isogenic graft mice. FTY720 decreased lymphocyte numbers only in the spleen. In conclusion, FTY720 prolonged skin graft survival in a fully mismatched strain combination when administered for 4 days (day -1 to day +2) at a dose of 1 mg/kg/d. The decreased number of lymphocytes in the spleen suggests that the spleen may be a target of FTY720 activity, during the early posttransplant period.

  10. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias.

    PubMed

    Cubeddu, Luigi X

    2016-01-01

    Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended.

  11. A Case of Atypical Delayed and Prolonged Hematologic Toxicity With Azacitidine in Chronic Myelomonocytic Leukemia (CMML) and Review of Literature

    PubMed Central

    Elli, Elena; Cecchetti, Caterina; Belotti, Angelo; Borin, Lorenza; Pogliani, Enrico Maria

    2012-01-01

    Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10–29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting. PMID:22550562

  12. Drug-induced long QT syndrome increases the risk of drowning.

    PubMed

    Vincenzi, Frank F

    2016-02-01

    There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation.

  13. Drug Allergy

    MedlinePlus

    ... of other allergies, such as food allergy or hay fever Allergic reaction to another drug A family history ... so, what drug was it? Do you have hay fever, food allergy or other allergies? Is there a ...

  14. Drugged Driving

    MedlinePlus

    ... Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Prescription Drugs & Cold ... in the past year. Middle Figure: Driving after marijuana use is more common than driving after alcohol ...

  15. Drugs (image)

    MedlinePlus

    ... Drugs for fever, cough, stuffy nose, runny nose, diarrhea, and allergies are common drugs which are especially helpful during times of illness. All medications should be kept out of the reach of children.

  16. Drug Abuse

    MedlinePlus

    ... abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a ...

  17. Drug Control

    ERIC Educational Resources Information Center

    Leviton, Harvey S.

    1975-01-01

    This article attempts to assemble pertinent information about the drug problem, particularily marihuana. It also focuses on the need for an educational program for drug control with the public schools as the main arena. (Author/HMV)

  18. Drug Debacle.

    PubMed

    Sorrel, Amy Lynn

    2016-07-01

    Medicaid's Vendor Drug Program is under examination by the Texas Legislature. TMA's Physicians Medicaid Congress is seizing the opportunity to call for an administrative overhaul of a drug benefit physicians describe as unnecessarily complicated and confusing.

  19. Fetal brain hypometabolism during prolonged hypoxaemia in the llama

    PubMed Central

    Ebensperger, Germán; Ebensperger, Renato; Herrera, Emilio A; Riquelme, Raquel A; Sanhueza, Emilia M; Lesage, Florian; Marengo, Juan J; Tejo, Rodrigo I; Llanos, Aníbal J; Reyes, Roberto V

    2005-01-01

    In this study we looked for additional evidence to support the hypothesis that fetal llama reacts to hypoxaemia with adaptive brain hypometabolism. We determined fetal llama brain temperature, Na+ and K+ channel density and Na+–K+-ATPase activity. Additionally, we looked to see whether there were signs of cell death in the brain cortex of llama fetuses submitted to prolonged hypoxaemia. Ten fetal llamas were instrumented under general anaesthesia to measure pH, arterial blood gases, mean arterial pressure, heart rate, and brain and core temperatures. Measurements were made 1 h before and every hour during 24 h of hypoxaemia (n = 5), which was imposed by reducing maternal inspired oxygen fraction to reach a fetal arterial partial pressure of oxygen (Pa,O2) of about 12 mmHg. A normoxaemic group was the control (n = 5). After 24 h of hypoxaemia, we determined brain cortex Na+–K+-ATPase activity, ouabain binding, and the expression of NaV1.1, NaV1.2, NaV1.3, NaV1.6, TREK1, TRAAK and KATP channels. The lack of brain cortex damage was assessed as poly ADP-ribose polymerase (PARP) proteolysis. We found a mean decrease of 0.56°C in brain cortex temperature during prolonged hypoxaemia, which was accompanied by a 51% decrease in brain cortex Na+–K+-ATPase activity, and by a 44% decrease in protein content of NaV1.1, a voltage-gated Na+ channel. These changes occurred in absence of changes in PARP protein degradation, suggesting that the cell death of the brain was not enhanced in the fetal llama during hypoxaemia. Taken together, these results provide further evidence to support the hypothesis that the fetal llama responds to prolonged hypoxaemia with adaptive brain hypometabolism, partly mediated by decreases in Na+–K+-ATPase activity and expression of NaV channels. PMID:16037083

  20. Prolonging the postcomplex spike pause speeds eyeblink conditioning.

    PubMed

    Maiz, Jaione; Karakossian, Movses H; Pakaprot, Narawut; Robleto, Karla; Thompson, Richard F; Otis, Thomas S

    2012-10-09

    Climbing fiber input to the cerebellum is believed to serve as a teaching signal during associative, cerebellum-dependent forms of motor learning. However, it is not understood how this neural pathway coordinates changes in cerebellar circuitry during learning. Here, we use pharmacological manipulations to prolong the postcomplex spike pause, a component of the climbing fiber signal in Purkinje neurons, and show that these manipulations enhance the rate of learning in classical eyelid conditioning. Our findings elucidate an unappreciated aspect of the climbing fiber teaching signal, and are consistent with a model in which convergent postcomplex spike pauses drive learning-related plasticity in the deep cerebellar nucleus. They also suggest a physiological mechanism that could modulate motor learning rates.

  1. Carnitine prolongs the half-life of ethanol in broilers.

    PubMed

    Smith, M O; Cha, Y S; Sachan, D S

    1994-09-01

    The object was to determine if carnitine attenuated ethanol metabolism in broilers similar to that reported in the rats. Two groups (n = 5) of 5-week-old broilers were given for 10 days the feed with or without 0.5% L-carnitine supplement. A single oral dose of ethanol on day 8 was followed by serial blood samples which were analysed for ethanol. Another dose of ethanol was given on day 10 and 2 hr later, plasma and liver were collected and analysed for ethanol, total lipid, triglycerides and carnitine. The carnitine supplemented diet prolonged the half-life of ethanol due to attenuation of ethanol metabolism which is similar to that reported earlier in rodents. The increases in plasma and hepatic acylcarnitines indicate that supplementary carnitine lessens the load of free acyl groups in the liver by eventual oxidation or excretion.

  2. Prolonged weightlessness, reference frames and visual symmetry detection.

    PubMed

    Leone, G; de Schonen, S; Lipshits, M

    1998-01-01

    We evaluated the influence of prolonged weightlessness on the performance of three cosmonauts to bilateral symmetry detection in the course of a 15-day-long Russian-French mission CASSIOPEE 96 aboard the MIR station. We tested the influence of weightlessness on subjects' performance as a function of the retinal orientation of axis of symmetry. as a function of type of stimuli (closed versus multi-elements shapes) and as a function of visual field presentation (at fixation, left visual field. right visual field). The results indicate firstly a difference between presentation at fixation versus away of fixation. Away of fixation, no effect of microgravity on performance was shown. A hypothesis of hemispheric specialization for symmetry detection was not supported as well. At fixation, an effect of micro-gravity was shown and more interestingly, the effect was quite different as a function of type of shapes used. suggesting that symmetry detection is a multiple-stage process.

  3. Slow recovery in desert perennial vegetation following prolonged human disturbance

    USGS Publications Warehouse

    Guo, Q.

    2004-01-01

    The study shows an exceptionally long-term recovery of perennial vegetation from prolonged heavy grazing and other human impacts. Since protection in 1906, overall species richness and habitat heterogeneity at the study site continued to increase until the 1960s when diversity, density and cover stabilized. During the same period, overall plant density and cover also increased. Species turnover increased gradually with time but no significant relation between any of the three community variables and precipitation or Palmer Drought Severity Index (PDSI) was detected. The increases in plant species richness, density, and cover of the perennial vegetation were mostly due to the increase of herbaceous species, especially palatable species. The lack of clear relationship between environment (e.g., precipitation) and community variables suggests that site history and plant life history must be taken into account in examining the nature of vegetation recovery process after disturbances.

  4. Prolonged intensive dominance behavior between gray wolves, Canis lupus

    USGS Publications Warehouse

    Mech, L. David; Cluff, H. Dean

    2010-01-01

    Dominance is one of the most pervasive and important behaviors among wolves in a pack, yet its significance in free-ranging packs has been little studied. Insights into a behavior can often be gained by examining unusual examples of it. In the High Arctic near Eureka, Nunavut, Canada, we videotaped and described an unusually prolonged and intensive behavioral bout between an adult male Gray Wolf (Canis lupus) and a male member of his pack, thought to be a maturing son. With tail raised, the adult approached a male pack mate about 50 m from us and pinned and straddled this packmate repeatedly over 6.5 minutes, longer than we had ever seen in over 50 years of studying wolves. We interpreted this behavior as an extreme example of an adult wolf harassing a maturing offspring, perhaps in prelude to the offspring?s dispersal.

  5. Media Impacts on Women's Fertility Desires: A Prolonged Exposure Experiment.

    PubMed

    Knobloch-Westerwick, Silvia; Willis, Laura E; Kennard, Ashley R

    2016-06-01

    Media exposure may have implications for family planning, a public health issue of key importance. Drawing on social comparison theory and social identity theory, a prolonged exposure experiment examined whether media portrayals of women's social roles affect fertility desires among 166 American, nonstudent, never married, childless women ages 21-35 years old. After sign-up and baseline sessions, participants viewed magazine pages five days in a row. Stimuli presented women in either mother/homemaker roles, beauty ideal roles, or professional roles. Three days later, participants again indicated their number of desired children and time planned until first birth. Exposure to mother/homemaker and beauty ideal portrayals increased the number of desired children across time. Exposure to professional portrayals increased the time planned until 1st birth compared to beauty ideal portrayals-this impact was partially mediated by a shift toward more progressive gender norms (per social identity theory) and assimilation (per social comparison theory).

  6. Prolonged remission of leukemia associated with polycythemia vera.

    PubMed

    Hazani, A; Tatarsky, I; Barzilai, D

    1977-09-01

    A patient with polycythemia vera (PV) received successive treatment by phlebotomies, radioactive phosphorus, myleran and cyclophosphamide. Sixteen years after the diagnosis, he developed acute myeloblastic leukemia. A complete remission was achieved following two courses of COAP (cyclophosphamide, vincristine, Cytosine Arabinoside, and prednisone) therapy. Four months later, while still in leukemic remission, he became mildly polycythemic again and the treatment with phlebotomies and cyclophosphamide was resume. The patient has subsequently been in complete remission of leukemia for over three years and his polycythemia is controlled by small doses of cyclophosphamide. This appears to be a unique case of such a prolonged remission of leukemia in the course of PV, with a return to a mild polycythemia state.

  7. Drivers' misjudgement of vigilance state during prolonged monotonous daytime driving.

    PubMed

    Schmidt, Eike A; Schrauf, Michael; Simon, Michael; Fritzsche, Martin; Buchner, Axel; Kincses, Wilhelm E

    2009-09-01

    To investigate the effects of monotonous daytime driving on vigilance state and particularly the ability to judge this state, a real road driving study was conducted. To objectively assess vigilance state, performance (auditory reaction time) and physiological measures (EEG: alpha spindle rate, P3 amplitude; ECG: heart rate) were recorded continuously. Drivers judged sleepiness, attention to the driving task and monotony retrospectively every 20 min. Results showed that prolonged daytime driving under monotonous conditions leads to a continuous reduction in vigilance. Towards the end of the drive, drivers reported a subjectively improved vigilance state, which was contrary to the continued decrease in vigilance as indicated by all performance and physiological measures. These findings indicate a lack of self-assessment abilities after approximately 3h of continuous monotonous daytime driving.

  8. Muscle regeneration in the prolonged absence of myostatin.

    PubMed

    Wagner, Kathryn R; Liu, Xiaosong; Chang, Xiaoli; Allen, Ronald E

    2005-02-15

    Myostatin is an endogenous inhibitor of muscle conserved across diverse species. In the absence of myostatin, there is massive muscle growth in mice, cattle, and humans. Previous studies in the mdx mouse model of muscular dystrophy demonstrate that inhibiting myostatin attenuates several features of dystrophic muscle. These findings have encouraged the development of human therapies to block myostatin. However, little is known of the long-term effects on muscle of myostatin blockade. To evaluate potential sequelae from the prolonged absence of myostatin, senescent myostatin null (mstn-/-) mice were studied. Senescent mstn-/- mice continue to have normal muscle with increased mass and strength relative to controls. Muscles of senescent mstn-/- mice regenerate robustly from both chronic and acute injury. Early markers of regeneration are enhanced in the absence of myostatin, suggesting a mechanism for the attenuation of dystrophic features found in mdx mice lacking myostatin.

  9. Prolonged QT interval in a man with anorexia nervosa

    PubMed Central

    Macías-Robles, María Dolores; Perez-Clemente, Ana María; Maciá-Bobes, Carmen; Alvarez-Rueda, María Asunción; Pozo-Nuevo, Sergio

    2009-01-01

    Anorexia nervosa is an eating disorder characterized by the avoidance of food intake, which usually leads to a weight loss. Cardiac co-morbility is common and we can find sometimes a mass loss from the left ventricle, which can be seen by echocardiography. But the commonest complications are rhythm variations, typically bradycardia with a prolonged QT interval in up to a 40% of the cases, which altogether elevates ventricular tachycardia and sudden death risk. We present the case of a male who was diagnosed with anorexia nervosa and developed asthenia, a long QT interval and also a severe both hypokalaemia and hypomagnesaemia. We intend to discuss the pathogenic paths as well as prophylactic and therapeutic measures to this potentially-lethal pathology. PMID:19646241

  10. Apparent life-threatening prolonged infant apnea in Saskatchewan.

    PubMed Central

    Sunkaran, K; McKenna, A; O'Donnell, M; Ninan, A; Kasian, G; Skwarchuk, J; Bingham, W T

    1989-01-01

    Life-threatening events such as prolonged apnea and severe bradycardia are uncommon in infants. When such events occur in a family, however, the results may be disastrous. Over a period of 3 years ending June 1986, we have looked after 111 such infants aged 4 weeks to 40 weeks with a mean age of 14 weeks (male-female ratio 1.26:1). Of these infants, 33 had an identifiable cause and were treated according to the diagnoses. A structural approach to this problem yielded good results. Only 10 infants were treated with a home monitor (4 prescribed by physician and 6 by parental request). Sleep and pneumogram (polysomnogram) studies showed fewer apneic episodes with advancing age (P less than .01). Giving theophylline seemed to abolish pneumogram abnormalities. No infants died. PMID:2735034

  11. Elevated rates of prolonged grief disorder in African Americans.

    PubMed

    Goldsmith, B; Morrison, R S; Vanderwerker, L C; Prigerson, H G

    2008-01-01

    The prevalence of Prolonged Grief Disorder (PGD) in non-Whites is currently unknown. This study was performed to explore the prevalence of PGD in African Americans (AAs). Multivariable analysis of two studies of recently bereaved individuals found AAs to have significantly higher rates of PGD than Whites (21% [14 of 66] vs. 12% [55 of 471], respectively; p = 0.03). Experiencing a loved one's death as sudden or unexpected was also significantly associated with PGD over and above the effects of race/ethnicity. AAs may be at increased risk for the development of PGD. The development of effective interventions to treat PGD highlights the need to identify high-risk individuals and refer them to therapy and suggests the potential need for such therapies to adopt culturally sensitive approaches to care.

  12. Does prolonged breastfeeding adversely affect a child's nutritional status?

    PubMed

    Brakohiapa, L A; Yartey, J; Bille, A; Harrison, E; Quansah, E; Armar, M A; Kishi, K; Yamamoto, S

    1988-08-20

    In 202 children who visited a children's hospital in the city of Accra, Ghana, breastfeeding beyond the age of 19 months was found to be associated with malnutrition. The effect of weaning on food intake was then studied in 15 breastfed malnourished children in a rural community. Before weaning (complete cessation of breast-feeding) protein and energy intakes of all the malnourished children were about half those of 5 normal children. 10 of the malnourished children were weaned, and their intakes rose to the levels of the normal children; the 5 who continued breastfeeding maintained their low intakes. These results indicate that prolonged breastfeeding can reduce total food intake and thus predispose to malnutrition. They also suggest that in Ghana and other developing countries the proper weaning age may be about 18 months.

  13. PIGMENT DEPOSITION IN VISCERA ASSOCIATED WITH PROLONGED CHLORPROMAZINE THERAPY.

    PubMed

    GREINER, A C; NICOLSON, G A

    1964-09-19

    Twelve physically healthy young adult mental hospital patients died unexpectedly while on prolonged chlorpromazine therapy. Five of them had clinically obvious pigmentation of the exposed skin. Two of these had impairment of vision as well. Autopsies were performed on all 12 patients. Extensive deposits of pigment (exhibiting the physical and histochemical properties of melanin) were present in macrophages in the dermis and throughout the reticuloendothelial system, and in the parenchymal cells of internal organs. The dopa tyrosinase reaction indicated increased melanocyte activity in the epidermis.The possible mechanism of production of this pigment is discussed, and the belief is expressed that the increased melanin production is due, at least partly, to the effect of chlorpromazine on the autonomic nervous system, blocking the production of pigment-lightening factors, of which melatonin is the most important. A short outline of contemplated further investigation is given.

  14. Some measures to reduce effects of prolonged sleep deprivation.

    PubMed

    Lagarde, D; Batejat, D

    1995-01-01

    Prolonged sleep deprivation is an exceptional situation, encountered in special environments such as sports, civilian and military, and which induces deficits in vigilance and performance. Among the array of measures which may be used to counteract these effects, the authors described a protocol using the combination of small naps, and administration of a pharmacological aid. A detailed description of advantages and drawbacks of each one of these measures is given, illustrated by several examples extracted from different studies. Four aspects of pharmacological aid are reviewed: the effects of amphetamines and amphetamine-like substances, caffeine, eugregoric substances, and the effect of the association small nap + eugregoric substances. The use of these various aids is discussed, and findings show that each one of them finds an application in a specific context.

  15. Regulation of calcium metabolism during prolonged antiorthostatic hypokinesia

    NASA Technical Reports Server (NTRS)

    Grigoryev, A. I.; Morukov, B. V.; Dorokhova, B. R.; Rustamyan, L. A.

    1988-01-01

    Characteristics of the regulation of calcium exchange in healthy persons exposed to 182 days of antiorthostatic hypokinesia are investigated. Total calcium concentrations, ionized calcium activities and parathyroid hormone concentrations in blood serum were determined, before, during, and up to 15 days after a 182-day period of strict bed rest at a head down tilt of 4 deg; and tests of blood urine responses to a calcium lactate stress were performed to study the role of the kidneys. An increase in calcium ion activity is observed during the period of hypokinesia, while total calcium concentrations changed to a lesser degree. Plasma parathyroid hormone levels are found to significantly exceed background levels during hypokinesia and in the recovery period immediately following. Finally, the increase in calcium excretion in the urine during prolonged limitations of muscular activity is found to be connected with both an enhancement of calcium filtration and a decrease in its reabsorption in the kidneys, possibly due to changes in hormonal regulation.

  16. Factors associated with prolonged length of stay in older patients

    PubMed Central

    Toh, Hui Jin; Lim, Zhen Yu; Yap, Philip; Tang, Terence

    2017-01-01

    INTRODUCTION Prolonged stay in acute hospitals increases the risk of hospital-acquired infections in older patients, and disrupts patient flow and access to care due to bed shortages. We aimed to investigate the factors associated with prolonged length of stay (pLOS) among older patients (aged ≥ 78 years) in a tertiary hospital, to identify the potentially modifiable risk factors that could direct interventions to reduce length of stay (LOS). METHODS During a three-month period from January 2013 to March 2013, we identified 72 patients with pLOS (LOS ≥ 21 days) and compared their demographic and clinical variables with that of 281 randomly selected control patients (LOS < 21 days) using univariate and multivariate logistic regression analyses. RESULTS The mean age of the patients was 85.30 ± 5.34 years; 54% of them were female and 72% were of Chinese ethnicity. Logistic regression revealed the following significant factors for increased LOS: discharge to intermediate and long-term care services (odds ratio [OR] 9.22, 95% confidence interval [CI] 3.56–23.89; p < 0.001); increased severity of illness (OR 2.41, 95% CI 1.12–5.21; p = 0.025); and presence of caregiver stress (OR 3.85, 95% CI 1.67–8.91; p = 0.002). CONCLUSION Presence of caregiver stress and nursing home placement are potential modifiable risk factors of pLOS among older patients. Early identification and management of caregiver stress, as well as expediting discharge planning, may help to reduce the length of stay for this cohort. PMID:27609507

  17. Prolonged fasting increases glutathione biosynthesis in postweaned northern elephant seals.

    PubMed

    Vázquez-Medina, José Pablo; Zenteno-Savín, Tania; Forman, Henry Jay; Crocker, Daniel E; Ortiz, Rudy M

    2011-04-15

    Northern elephant seals experience prolonged periods of absolute food and water deprivation (fasting) while breeding, molting or weaning. The postweaning fast in elephant seals is characterized by increases in the renin-angiotensin system, expression of the oxidant-producing protein Nox4, and NADPH oxidase activity; however, these increases are not correlated with increased oxidative damage or inflammation. Glutathione (GSH) is a potent reductant and a cofactor for glutathione peroxidases (GPx), glutathione-S transferases (GST) and 1-cys peroxiredoxin (PrxVI) and thus contributes to the removal of hydroperoxides, preventing oxidative damage. The effects of prolonged food deprivation on the GSH system are not well described in mammals. To test our hypothesis that GSH biosynthesis increases with fasting in postweaned elephant seals, we measured circulating and muscle GSH content at the early and late phases of the postweaning fast in elephant seals along with the activity/protein content of glutamate-cysteine ligase [GCL; catalytic (GCLc) and modulatory (GCLm) subunits], γ-glutamyl transpeptidase (GGT), glutathione disulphide reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), GST and PrxVI, as well as plasma changes in γ-glutamyl amino acids, glutamate and glutamine. GSH increased two- to four-fold with fasting along with a 40-50% increase in the content of GCLm and GCLc, a 75% increase in GGT activity, a two- to 2.5-fold increase in GR, G6PDH and GST activities and a 30% increase in PrxVI content. Plasma γ-glutamyl glutamine, γ-glutamyl isoleucine and γ-glutamyl methionine also increased with fasting whereas glutamate and glutamine decreased. Results indicate that GSH biosynthesis increases with fasting and that GSH contributes to counteracting hydroperoxide production, preventing oxidative damage in fasting seals.

  18. Management of Prolonged Pulmonary Air Leaks With Endobronchial Valve Placement

    PubMed Central

    Doelken, Peter; Pupovac, Stevan; Ata, Ashar; Fabian, Tom

    2016-01-01

    Background: Prolonged pulmonary air leaks (PALs) are associated with increased morbidity and extended hospital stay. We sought to investigate the role of bronchoscopic placement of 1-way valves in treating this condition. Methods: We queried a prospectively maintained database of patients with PAL lasting more than 7 days at a tertiary medical center. Main outcome measures included duration of chest tube placement and hospital stay before and after valve deployment. Results: Sixteen patients were eligible to be enrolled from September 2012 through December 2014. One patient refused to give consent, and in 4 patients, the source of air leak could not be identified with bronchoscopic balloon occlusion. Eleven patients (9 men; mean age, 65 ± 15 years) underwent bronchoscopic valve deployment. Eight patients had postoperative PAL and 3 had a secondary spontaneous pneumothorax. The mean duration of air leak before valve deployment was 16 ± 12 days, and the mean number of implanted valves was 1.9 (median, 2). Mean duration of hospital stay before and after valve deployment was 18 and 9 days, respectively (P = .03). Patients who had more than a 50% decrease in air leak on digital monitoring had the thoracostomy tube removed within 3–6 days. There were no procedural complications related to deployment or removal of the valves. Conclusions: Bronchoscopic placement of 1-way valves is a safe procedure that could help manage patients with prolonged PAL. A prospective randomized trial with cost-efficiency analysis is necessary to better define the role of this bronchoscopic intervention and demonstrate its effect on air leak duration. PMID:27647978

  19. Thrombolytic-Enhanced Extracorporeal Cardiopulmonary Resuscitation After Prolonged Cardiac Arrest

    PubMed Central

    Spinelli, Elena; Davis, Ryan P.; Ren, Xiaodan; Sheth, Parth S.; Tooley, Trevor R.; Iyengar, Amit; Sowell, Brandon; Owens, Gabe E.; Bocks, Martin L.; Jacobs, Teresa L.; Yang, Lynda J.; Stacey, William C.; Bartlett, Robert H.; Rojas-Peña, Alvaro; Neumar, Robert W.

    2016-01-01

    Objective To investigate the effects of the combination of extracorporeal cardiopulmonary resuscitation (ECPR) and thrombolytic therapy on the recovery of vital organ function after prolonged cardiac arrest. Design Laboratory investigation Setting University Laboratory Subjects Pigs Interventions Animals underwent 30-minute untreated ventricular fibrillation cardiac arrest followed by extracorporeal cardiopulmonary resuscitation (ECPR) for 6 hours. Animals were allocated into two experimental groups: t-ECPR, which received Streptokinase 1 MU and c-ECPR which did not receive Streptokinase. In both groups the resuscitation protocol included the following physiologic targets: mean arterial pressure (MAP) > 70 mmHg, Cerebral perfusion pressure (CerPP) > 50 mmHg, PaO2 150 ± 50 mmHg, PaCO2 40 ± 5 mmHg and core temperature 33 ± 1 °C. Defibrillation was attempted after 30 minutes of ECPR. Measurements and Main Results A cardiac resuscitability score was assessed on the basis of: success of defibrillation; return of spontaneous heart beat; weanability form ECPR; and left ventricular systolic function after weaning. The addition of thrombolytic to ECPR significantly improved cardiac resuscitability (3.7 ± 1.6 in t-ECPR vs 1.0 ± 1.5 in c-ECPR). Arterial lactate clearance was higher in t-ECPR than in c-ECPR (40 ± 15% VS 18 ± 21 %). At the end of the experiment, the intracranial pressure was significantly higher in c-ECPR than in t-ECPR. Recovery of brain electrical activity, as assessed by quantitative analysis of EEG signal, and ischemic neuronal injury on histopathologic examination did not differ between groups. Animals in t-ECPR group did not have increased bleeding complications, including intracerebral hemorrhages. Conclusions In a porcine model of prolonged cardiac arrest, thrombolytic-enhanced ECPR improved cardiac resuscitability and reduced brain edema, without increasing bleeding complications. However, early EEG recovery and ischemic neuronal injury were

  20. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade.

    PubMed

    Movafegh, Ali; Razazian, Mehran; Hajimaohamadi, Fatemeh; Meysamie, Alipasha

    2006-01-01

    Different additives have been used to prolong regional blockade. We designed a prospective, randomized, double-blind study to evaluate the effect of dexamethasone added to lidocaine on the onset and duration of axillary brachial plexus block. Sixty patients scheduled for elective hand and forearm surgery under axillary brachial plexus block were randomly allocated to receive either 34 mL lidocaine 1.5% with 2 mL of isotonic saline chloride (control group, n = 30) or 34 mL lidocaine 1.5% with 2 mL of dexamethasone (8 mg) (dexamethasone group, n = 30). Neither epinephrine nor bicarbonate was added to the treatment mixture. We used a nerve stimulator and multiple stimulations technique in all of the patients. After performance of the block, sensory and motor blockade of radial, median, musculocutaneous, and ulnar nerves were recorded at 5, 15, and 30 min. The onset time of the sensory and motor blockade was defined as the time between last injection and the total abolition of the pinprick response and complete paralysis. The duration of sensory and motor blocks were considered as the time interval between the administration of the local anesthetic and the first postoperative pain and complete recovery of motor functions. Sixteen patients were excluded because of unsuccessful blockade. The duration of surgery and the onset times of sensory and motor block were similar in the two groups. The duration of sensory (242 +/- 76 versus 98 +/- 33 min) and motor (310 +/- 81 versus 130 +/- 31 min) blockade were significantly longer in the dexamethasone than in the control group (P < 0.01). We conclude that the addition of dexamethasone to lidocaine 1.5% solution in axillary brachial plexus block prolongs the duration of sensory and motor blockade.

  1. Skeletal muscle water and electrolytes following prolonged dehydrating exercise.

    PubMed

    Mora-Rodríguez, R; Fernández-Elías, V E; Hamouti, N; Ortega, J F

    2015-06-01

    We studied if dehydrating exercise would reduce muscle water (H2Omuscle ) and affect muscle electrolyte concentrations. Vastus lateralis muscle biopsies were collected prior, immediately after, and 1 and 4 h after prolonged dehydrating exercise (150 min at 33 ± 1 °C, 25% ± 2% humidity) on nine endurance-trained cyclists (VO2max  = 54.4 ± 1.05 mL/kg/min). Plasma volume (PV) changes and fluid shifts between compartments (Cl(-) method) were measured. Exercise dehydrated subjects 4.7% ± 0.3% of body mass by losing 2.75 ± 0.15 L of water and reducing PV 18.4% ± 1% below pre-exercise values (P < 0.05). Right after exercise H2Omuscle remained at pre-exercise values (i.e., 398 ± 6 mL/100 g dw muscle(-1)) but declined 13% ± 2% (342 ± 12 mL/100 g dw muscle(-1); P < 0.05) after 1 h of supine rest. At that time, PV recovered toward pre-exercise levels. The Cl(-) method corroborated the shift of fluid between extracellular and intracellular compartments. After 4 h of recovery, PV returned to pre-exercise values; however, H2Omuscle remained reduced at the same level. Muscle Na(+) and K(+) increased (P < 0.05) in response to the H2Omuscle reductions. Our findings suggest that active skeletal muscle does not show a net loss of H2O during prolonged dehydrating exercise. However, during the first hour of recovery H2Omuscle decreases seemly to restore PV and thus cardiovascular stability.

  2. Prolonged Remission of Psoriasis with Azathioprine Pulse Therapy

    PubMed Central

    Gupta, Ramji

    2015-01-01

    Background: Although various therapies used for the treatment of psoriasis are able to produce remission, yet relapses, a common problem, remains frequent. It was observed that treatment with intermittent high dose (IHD) and continuous low dose (CLD) azathioprine can produce prolonged and durable remission in psoriasis. Aims: To see the long term effect of azathioprine pulse therapy (APT) in psoriasis. Methods: Ten patients with psoriasis who has completed more than 5 years in remission with azathioprine pulse therapy are being taken in the study. They were given IHD azathioprine (500 mg on 3 consecutive days which is repeated every month) with CLD azathioprine (100 mg orally) daily in between IHD. The entire treatment schedule was divided into four phases. During phase I, treatment with IHD and CLD azathioprine was started and continued till complete clearance of lesions after which, patients proceeded to Phase II. In phase II, they continued to get treatment with IHD and CLD. After continued remission for a period of nine months, they entered into phase III, when the treatment with IHD was stopped, but CLD continued. If there was no recurrence after nine months of phase III treatment, CLD was also withdrawn, and patients were followed-up without any treatment (Phase IV). Results: All 10 patients completed treatment and are in remission for more than five years without any treatment. Conclusions: Out of 60 patients in phase IV, 10 patients were in continuous remission for more than five years, after all treatment had been stopped. Thus, azathioprine pulse therapy regimen produces prolonged remission in psoriasis. PMID:26288403

  3. Molecular mechanisms of drug addiction.

    PubMed

    Nestler, Eric J

    2004-01-01

    Regulation of gene expression is one mechanism by which drugs of abuse can induce relatively long-lasting changes in the brain to cause a state of addiction. Here, we focus on two transcription factors, CREB (cAMP response element binding protein) and DeltaFosB, which contribute to drug-induced changes in gene expression. Both are activated in the nucleus accumbens, a major brain reward region, but mediate different aspects of the addicted state. CREB mediates a form of tolerance and dependence, which dampens an individual's sensitivity to subsequent drug exposure and contributes to a negative emotional state during early phases of withdrawal. In contrast, DeltaFosB mediates a state of relatively prolonged sensitization to drug exposure and may contribute to the increased drive and motivation for drug, which is a core symptom of addictive disorders. A major goal of current research is to identify the many target genes through which CREB and DeltaFosB mediate these behavioral states. In addition, future work needs to understand how CREB and DeltaFosB, acting in concert with numerous other drug-induced molecular changes in nucleus accumbens and many other brain regions, interact with one another to produce the complex behavioral phenotype that defines addiction.

  4. Light activated liposomes: Functionality and prospects in ocular drug delivery.

    PubMed

    Lajunen, Tatu; Nurmi, Riikka; Kontturi, Leena; Viitala, Lauri; Yliperttula, Marjo; Murtomäki, Lasse; Urtti, Arto

    2016-12-28

    Ocular drug delivery, especially to the retina and choroid, is a major challenge in drug development. Liposome technology may be useful in ophthalmology in enabling new routes of delivery, prolongation of drug action and intracellular drug delivery, but drug release from the liposomes should be controlled. For that purpose, light activation may be an approach to release drug at specified time and site in the eye. Technical advances have been made in the field of light activated drug release, particularly indocyanine green loaded liposomes are a promising approach with safe materials and effective light triggered release of small and large molecules. This review discusses the liposomal drug delivery with light activated systems in the context of ophthalmic drug delivery challenges.

  5. Prolonged cytotoxic effect of colchicine released from biodegradable microspheres.

    PubMed

    Muvaffak, Asli; Gurhan, Ismet; Hasirci, Nesrin

    2004-11-15

    One the main problems of cancer chemotherapy is the unwanted damage to normal cells caused by the high toxicities of anticancer drugs. Any system of controlled drug delivery that would reduce the total amount of drug required, and thus reduce the side effects, would potentially help to improve chemotherapy. In this respect, biodegradable gelatin microspheres were prepared by water/oil emulsion polymerization and by crosslinking with glutaraldehyde (GTA) as the drug-carrier system. Microspheres were loaded with colchicine, a model antimitotic drug, which was frequently used as an antimitotic agent in cancer research involving cell cultures. Microsphere sizes, swelling and degradation properties, drug-release kinetics, and cytotoxities were studied. Swelling characteristics of microspheres changed upon changing GTA concentration. A decrease in swelling values was recorded as GTA crosslink density was increased. In vitro drug release in PBS (0.01M, pH 7.4) showed rapid colchicine release up to approximately 83% (at t = 92 h) for microspheres with low GTA (0.05% v/v), whereas a slower release profile (only approximately 39%) was obtained for microspheres with high GTA (0.50% v/v) content, for the same period. Cytotoxicity tests with MCF-7, HeLa and H-82 cancer cell lines showed that free colchicine was very toxic, showing an approximately 100% lethal effect in both HeLa and H-82 cell lines and more than 50% decrease in viability in MCF-7 cells in 4 days. Indeed, entrapped colchicine indicated similar initial high toxic effect on cell viability in MCF-7 cell line and this effect became more dominant as colchicine continued to be released from microspheres in the same period. In conclusion, the control of the release rate of colchicine from gelatin microspheres was achieved under in vitro conditions by gelatin through the alteration of crosslinking conditions. Indeed, the results suggested the potential application of gelatin microspheres crosslinked with GTA as a

  6. Nanoparticles and nanofibers for topical drug delivery

    PubMed Central

    Goyal, Ritu; Macri, Lauren K.; Kaplan, Hilton M.; Kohn, Joachim

    2016-01-01

    This review provides the first comprehensive overview of the use of both nanoparticles and nanofibers for topical drug delivery. Researchers have explored the use of nanotechnology, specifically nanoparticles and nanofibers, as drug delivery systems for topical and transdermal applications. This approach employs increased drug concentration in the carrier, in order to increase drug flux into and through the skin. Both nanoparticles and nanofibers can be used to deliver hydrophobic and hydrophilic drugs and are capable of controlled release for a prolonged period of time. The examples presented provide significant evidence that this area of research has—and will continue to have — a profound impact on both clinical outcomes and the development of new products. PMID:26518723

  7. [Psychotropic drug therapy using maintenance dosage pumps].

    PubMed

    Smulevich, A B; Vorob'ev, V Iu; Tarasova, T P; Abrosimov, A I

    1987-01-01

    The article deals with questions related to the use of paracorporal automatic drug-administering devices designed for the prolonged administration of psychotropic drugs. This is the first ever experience with the use of artificial systems for drug administration in psychiatry. The authors have developed a scheme of drug administration and determined the optimal rate of injection and daily doses. Possible complications and side effects associated with this method of treatment, as well as the methods for their prevention and control are described in detail. According to preliminary data the administration of psychotropic drugs with the help of automatic devices may contribute significantly to the improvement of social adaptation of patients with minor mental disturbances and make easier the provision of psychotherapy, in particular it may considerably simplify functional training of patients with phobic abnormalities. The method appears to be especially promising with regard to maintenance therapy.

  8. COPD - control drugs

    MedlinePlus

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

  9. Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate.

    PubMed

    Britton, Gabrielle B; Bethancourt, José A

    2009-10-01

    Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light-dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations.

  10. Drug treatment of hyperprolactinemia.

    PubMed

    Chanson, P; Borson-Chazot, F; Chabre, O; Estour, B

    2007-06-01

    Medical treatment of hyperprolactinemia is based upon use of dopamine agonists (DA): bromocriptine, lisuride, quinagolide and cabergoline. In over 80% of cases, these drugs induce normal prolactinemia and ovulatory cycles. In resistant cases, the DA should be changed. Tolerance may occasionally be poor, particularly with bromocriptine, which appears less well-tolerated than quinagolide and than cabergoline above all. In the event of intolerance to a given DA, another should be tried. In patients with macroprolactinoma treated with DA, MRI monitoring should be carried out after 3 months of treatment to verify tumor size reduction, then after 1 year, yearly for the next 5 years and once every 5 years if adenoma size is stable. In cases of microprolactinoma, control under treatment is pointless. MRI may be performed after 1 year and then after 5 years. Once normal prolactin levels have been achieved, attempts may be made to stop the treatment. When a prolonged treatment is interrupted, especially with cabergoline, progressive increase in serum prolactin and return of hyperprolactinemia symptoms are seen in only around 20-30% of cases, particularly when residual adenoma exists after prolonged treatment. Nevertheless, prolactin levels should continue to be monitored after discontinuation of DA, possibly with MRI monitoring, since prolactin levels may rise again after a number of months or years. When normal prolactin levels have been achieved with DA, another solution consists in reducing the dose or dosing frequency of DA in steps to the lowest effective dose consistent with maintenance of normal prolactin levels and stable adenoma size. For drug-induced hyperprolactinemia, where the causative medication cannot be withdrawn, it is often pointless and possibly even dangerous to administer a DA. It is therefore necessary to check for absence of pituitary adenoma and where necessary, begin treatment with sex steroids so as to ensure satisfactory impregnation with sex

  11. Drug Research

    NASA Technical Reports Server (NTRS)

    1989-01-01

    NBOD2, a program developed at Goddard Space Flight Center to solve equations of motion coupled N-body systems is used by E.I. DuPont de Nemours & Co. to model potential drugs as a series of elements. The program analyses the vibrational and static motions of independent components in drugs. Information generated from this process is used to design specific drugs to interact with enzymes in designated ways.

  12. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation

    PubMed Central

    Chang, Tien-Jyun; Tseng, Hsing-Chi; Liu, Meng-Wei; Chang, Yi-Cheng; Hsieh, Meng-Lun; Chuang, Lee-Ming

    2016-01-01

    Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated. PMID:26997114

  13. Corrected QT interval prolongation after an overdose of escitalopram, morphine, oxycodone, zopiclone and benzodiazepines.

    PubMed

    Baranchuk, Adrian; Simpson, Christopher S; Methot, Michelle; Gibson, Kara; Strum, David

    2008-07-01

    Escitalopram is the recently marketed S-enantiomer of the widely used antidepressant citalopram. Data from intentional overexposure to this medication are limited. Twelve-lead electrocardiogram (ECG) effects from racemic citalopram have been described; however, the present report is the first, to the best of the authors' knowledge, that describes all the reported abnormalities in a single patient receiving escitalopram. A 52-year-old man with a history of depression treated with escitalopram 10 mg/day, extended-release morphine 30 mg/day and zopiclone 15 mg/day was found unconscious at his home. He was known to have attempted suicide three weeks previously. Partially emptied bottles of escitalopram, morphine, oxycodone, zopiclone, lorazepam and diazepam were found close to the patient. He was transferred to the emergency department, where airway management and other supportive care were initiated. The patient was transferred to the intensive care unit. The initial 12-lead ECG demonstrated junctional rhythm at 48 beats/min, a wide complex escape (145 ms) with right bundle branch morphology and a prolonged corrected QT interval at 650 ms. Cardiac monitoring was undertaken. No ventricular arrhythmias or torsade de pointes were detected. No specific treatment for shortening the QT was implemented. Another 12-lead ECG performed 48 h later demonstrated sinus tachycardia with a normal corrected QT, normal PR interval and normal QRS duration. The effects of the overdose of escitalopram on the ECG and its interactions with other drugs are reviewed.

  14. Achilles' heel of pluripotent stem cells: genetic, genomic and epigenetic variations during prolonged culture.

    PubMed

    Rebuzzini, Paola; Zuccotti, Maurizio; Redi, Carlo Alberto; Garagna, Silvia

    2016-07-01

    Pluripotent stem cells differentiate into almost any specialized adult cell type of an organism. PSCs can be derived either from the inner cell mass of a blastocyst-giving rise to embryonic stem cells-or after reprogramming of somatic terminally differentiated cells to obtain ES-like cells, named induced pluripotent stem cells. The potential use of these cells in the clinic, for investigating in vitro early embryonic development or for screening the effects of new drugs or xenobiotics, depends on capability to maintain their genome integrity during prolonged culture and differentiation. Both human and mouse PSCs are prone to genomic and (epi)genetic instability during in vitro culture, a feature that seriously limits their real potential use. Culture-induced variations of specific chromosomes or genes, are almost all unpredictable and, as a whole, differ among independent cell lines. They may arise at different culture passages, suggesting the absence of a safe passage number maintaining genome integrity and rendering the control of genomic stability mandatory since the very early culture passages. The present review highlights the urgency for further studies on the mechanisms involved in determining (epi)genetic and chromosome instability, exploiting the knowledge acquired earlier on other cell types.

  15. Cell Permeable Peptide Conjugated Nanoerythrosomes of Fasudil Prolong Pulmonary Arterial Vasodilation in PAH Rats

    PubMed Central

    Gupta, Nilesh; Patel, Brijeshkumar; Nahar, Kamrun; Ahsan, Fakhrul

    2014-01-01

    In this study, we tested the hypothesis that a cell permeable peptide, CARSKNKDC (CAR), conjugated nanoerythrosomes (NERs) containing fasudil, a rho-kinase (ROCK) inhibitor, produces prolonged pulmonary preferential vasodilation. CAR conjugated NERs containing fasudil were prepared by hypotonic lysis and extrusion method, optimized for various physicochemical properties in-vitro. The formulations were then used to study the hemodynamic efficacy in a monocrotaline-induced rodent model of pulmonary arterial hypertension (PAH). CAR-NERs-Fasudil was spherical in shape with an average vesicle size and entrapment efficiency of 161.3±1.37nm and 48.81±1.96%, respectively. Formulations were stable for ~3 weeks when stored at 4°C and the drug was released in a controlled fashion for >48 hrs. The uptake of CAR-NERs-Fasudil by TGF-β activated pulmonary arterial smooth muscle cell was ~1.5 fold greater than the uptake of NERs-Fasudil. CAR-NERs-Fasudil inhibited ROCK activity and 5-hydroxytryptamine induced cell proliferation. In terms of reduction of pulmonary arterial pressure, intratracheal administration of CAR-NERs-Fasudil was ~2-fold more specific to the lungs compared with plain fasudil. Overall, CAR peptide grafted nanoerythrosomes offers a new platform for improving the therapeutic efficacy of a rho-kinase inhibitor, fasudil, without affecting peripheral vasodilation. PMID:25460151

  16. Effects of prolonged hypoxia on the growth and radiation sensitivity of mammalian cells in culture

    SciTech Connect

    Shrieve, D.C.

    1982-01-01

    The purpose of this study was to characterize a model system in which to study hypoxic cell biology in vitro as a function of time under growth and metabolism resulting from prolonged hypoxia affect cellular radiation sensitivity. EMT6/SF cells were grown in monolayers on glass 60 mm petri dishes that had been modified to permit the addition of hypoxic solutions of test drugs or radiolabeled compounds without breaking the system open to air. These dishes were then sealed in aluminum chambers that were evacuated and re-filled eight times with 95% nitrogen/5% carbon dioxide (O/sub 2/ < 10 ppm). EMT6/SF cells that were maintained at 37 C under hypoxic conditions showed no increase in cell number for up to 70 h. The mitotic index of hypoxic cultures was less than 0.1%, compared to 2.3-3.0% in aerated cultures. The plating efficiency of hypoxic cells decreased with time to 20-30% of control values by 70 h. Aerated cultures consumed glucose more rapidly than hypoxic ones, but, on a per cell basis, hypoxic and aerated cells consumed glucose at equal rates (ca. 1.2 x 10/sup -4/ ..mu..g/cell/h). Virtually 100% of the glucose consumed was converted into lactic acid in both aerated and hypoxic cultures.

  17. [Effect of trihexyphenidyl-HCL on posttraumatic prolonged disturbance of consciousness: report of two cases].

    PubMed

    Kaijima, M; Fukuda, H; Tomabechi, M; Hodozuka, A

    1989-05-01

    Cases involving two patients who presented post-traumatic prolonged disturbance of consciousness (PTPDC), namely akinetic mutism, and recovered from it after treatment with trihexyphenidyl were reported. Case 1: A seventy-one-year-old farmer. Five months after head injury, when he was first admitted to us, he was stable with signs of oligokinesia, katatonic posture, speechlessness, rigid muscle tones and positive cog-wheel phenomenon. One week after administration of the drug, his speech and voluntary movement improved remarkably. Two months after the treatment, he was able to walk, and was discharged from the hospital. Case 2: A forty-six-year-old man sustained major head trauma. In the acute stage, he was comatose with decerebrate posture. On the 15th hospital day, he showed a state of akinetic mutism with normal sleep - wakefulness cycle. Evacuation of the collected subdural fluid was done one month after the injury, which resulted in no change in his clinical state. Five months after the injury, trihexyphenidyl treatment was begun. A few days after the treatment, his motor activity and his facial expression obviously improved. One week after, he mimicked the word 'o-ha-yo (good morning)' after the physician's greeting. CT scan and magnetic resonance imaging in the chronic state of these patients showed bifrontal cerebral white matter lesions, which indicated old cerebral contusion. No brain stem lesions were detected with these examinations. Our two cases clearly did not belong to the category of post-traumatic parkinsonism because of their clinical courses, and their features shown in radiological examinations. However the anti-parkinsonian drug, trihexyphenidyl was effective.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Drug Addiction

    MedlinePlus

    ... mental health disorders, several factors may contribute to development of drug addiction and dependence. The main factors are: Environment. Environmental factors, including your family's beliefs and attitudes ...

  19. Drugged Driving

    MedlinePlus

    ... Naloxone Pain Prevention Treatment Trends & Statistics Women and Drugs Publications Funding Funding Opportunities Clinical Research Post-Award Concerns General Information Grant & Contract Application ...

  20. Club Drugs

    MedlinePlus

    ... Naloxone Pain Prevention Treatment Trends & Statistics Women and Drugs Publications Funding Funding Opportunities Clinical Research Post-Award Concerns General Information Grant & Contract Application ...

  1. Role of QT interval prolongation in the creation of spiral wave type reentry.

    PubMed

    Shibata, N; Watanabe, H; Sakuma, I; Kodama, I; Niwa, R; Fukui, Y; Toyama, J; Hosoda, S

    1997-01-01

    The inducibility of reentry was compared for four QT patterns in a heart conduction simulation model. Local (L) and gradual (G) QT prolongation models are more susceptible to reentry induction than the no (N) QT prolongation model (reentry induced episodes for N, L, and G numbered 90, 120, and 122, respectively). This increased vulnerability was diminished when the QT interval was prolonged at all simulation sites (reentry induced episodes for the diffuse QT prolongation model, D model, numbered 82). Decreased QT dispersion might be important for the prevention of reentry induction regardless of whether the QT interval is increased.

  2. Adhesive polydopamine coated avermectin microcapsules for prolonging foliar pesticide retention.

    PubMed

    Jia, Xin; Sheng, Wen-bo; Li, Wei; Tong, Yan-bin; Liu, Zhi-yong; Zhou, Feng

    2014-11-26

    In this work, we report a conceptual strategy for prolonging foliar pesticide retention by using an adhesive polydopamine (PDA) microcapsule to encapsulate avermectin, thereby minimizing its volatilization and improving its residence time on crop surfaces. Polydopamine coated avermectin (Av@PDA) microcapsules were prepared by emulsion interfacial-polymerization and characterized by Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, field-emission scanning electron microscope, and transmission electron microscopy. The in situ synthesis route confers Av@PDA microcapsules with remarkable avermectin loading ability of up to 66.5% (w/w). Kinetic study of avermectin release demonstrated that Av@PDA microcapsules exhibit sustained- and controlled-release properties. The adhesive property of Av@PDA microcapsules on different surfaces was verified by a comparative study between Av@PDA and passivated Av@SiO2 and Av@PDA@SiO2 capsules with silica shell. Moreover, PDA shell could effectively shield UV irradiation and so protect avermectin from photodegradation, making it more applicable for foliar spraying. Meanwhile, it is determinated that Av@PDA microcapsules have good mechanical stability property.

  3. Exercise as a countermeasure for physiological adaptation to prolonged spaceflight

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.

    1996-01-01

    Exercise represents the primary countermeasure used during spaceflight to maintain or restore maximal aerobic capacity (VO2max), musculoskeletal structure, and orthostatic function. However, no single exercise or combination of prescriptions has proven entirely effective in restoring cardiovascular and musculoskeletal functions to preflight levels following prolonged spaceflight. As human spaceflight exposures increase in duration, assessment and development of various effective exercise-based protective procedures become paramount. This must involve improvement in specific countermeasure prescription as well as development of additional approaches that will allow space travelers greater flexibility and medical safety during long flights. Effective exercise prescription will be based on identification of basic physiological stimuli that maintain normal function in terrestrial gravity and understanding of how specific combinations of exercise characteristics e.g., duration, frequency, intensity, mode) can mimic these stimuli and affect the overall process of adaptation to microgravity. This can be accomplished only with greater emphasis of research on ground-based experiments. Future attention must be directed to improving exercise compliance while minimizing both crew time and the impact of the exercise on life-support resources.

  4. Significant prolongation of segmental pancreatic allograft survival in two species

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.

    1988-06-01

    A study was conducted to assess the suppression of segmental pancreatic allograft rejection by cyclosporine (CSA) alone in baboons and dogs, and subtotal marrow irradiation (TL1) alone and TL 1 in combination with CSA in baboons. Total pancreatectomy in the dog and primate provided a reliable diabetic model, induced an absolute deficiency of insulin and was uniformly lethal if not treated. Continuous administration of CSA in baboons resulted in modest allograft survival. As in baboons, dogs receiving CSA 25 mg/kg/d rendered moderate graft prolongation but a dose of 40 mg/kg/d resulted in significant graft survival (greater than 100 days) in 5 of 8 allograft recipients. Irradiation alone resulted in minimal baboon pancreatic allograft survival of 20 baboons receiving TL1 1,000 rad and CSA, 3 had graft survival greater than of 100 days. Of 15 baboons receiving TL1 800 rad and CSA, 6 had graft survival of greater than 100 days. In conclusion, CSA administration in dogs and TL1 in combination with CSA in baboons resulted in highly significant segmental pancreatic allograft survival.

  5. Examining potential contraindications for prolonged exposure therapy for PTSD

    PubMed Central

    van Minnen, Agnes; Harned, Melanie S.; Zoellner, Lori; Mills, Katherine

    2012-01-01

    Although prolonged exposure (PE) has received the most empirical support of any treatment for post-traumatic stress disorder (PTSD), clinicians are often hesitant to use PE due to beliefs that it is contraindicated for many patients with PTSD. This is especially true for PTSD patients with comorbid problems. Because PTSD has high rates of comorbidity, it is important to consider whether PE is indeed contraindicated for patients with various comorbid problems. Therefore, in this study, we examine the evidence for or against the use of PE with patients with problems that often co-occur with PTSD, including dissociation, borderline personality disorder, psychosis, suicidal behavior and non-suicidal self-injury, substance use disorders, and major depression. It is concluded that PE can be safely and effectively used with patients with these comorbidities, and is often associated with a decrease in PTSD as well as the comorbid problem. In cases with severe comorbidity, however, it is recommended to treat PTSD with PE while providing integrated or concurrent treatment to monitor and address the comorbid problems. PMID:22893847

  6. Predictors of Prolonged Mechanical Ventilation after Open Heart Surgery

    PubMed Central

    Totonchi, Ziae; Baazm, Farah; Chitsazan, Mitra; Seifi, Somayeh; Chitsazan, Mandana

    2014-01-01

    Introduction: Due to the importance of prolonged mechanical ventilation (PMV) as a postoperative complication, predicting "high-risk" patients by identifying predisposing risk factors is of important issue. The present study was aimed to identify perioperative variables associated with PMV in patients undergoing open heart surgery. Methods: A total of 743 consecutive patients, American Society of Anesthesiologists (ASA) physical status class III, who were scheduled to undergo open heart surgery using cardiopulmonary bypass were included in this observational study. Perioperative variables were compared between the patients with and without PMV, as defined by an extubation time of >48 h. Results: PMV occurred in 45 (6.1%) patients. On univariate analysis, pre-operative variables; including gender, history of chronic obstructive pulmonary disease (COPD); chronic kidney disease and endocarditis, intra-operative variables; including type of surgery, operation time, pump time, transfusion in operating room and postoperative variables; including bleeding and inotrope-dependency were significantly different between patients with and without PMV (all P<0.001, except for COPD and transfusion in operating room; P=0.004 and P=0.017, respectively). Conclusion: Our findings reinforce that risk stratification for predicting delayed extubation should be an important aspect of preoperative clinical evaluation in all anesthesiology settings. PMID:25610551

  7. Catecholaminergic effects of prolonged head-down bed rest

    NASA Technical Reports Server (NTRS)

    Goldstein, D. S.; Vernikos, J.; Holmes, C.; Convertino, V. A.

    1995-01-01

    Prolonged head-down bed rest (HDBR) provides a model for examining responses to chronic weightlessness in humans. Eight healthy volunteers underwent HDBR for 2 wk. Antecubital venous blood was sampled for plasma levels of catechols [norepinephrine (NE), epinephrine, dopamine, dihydroxyphenylalanine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid] after supine rest on a control (C) day and after 4 h and 7 and 14 days of HDBR. Urine was collected after 2 h of supine rest during day C, 2 h before HDBR, and during the intervals 1-4, 4-24, 144-168 (day 7), and 312-336 h (day 14) of HDBR. All subjects had decreased plasma and blood volumes (mean 16%), atriopeptin levels (31%), and peripheral venous pressure (26%) after HDBR. NE excretion on day 14 of HDBR was decreased by 35% from that on day C, without further trends as HDBR continued, whereas plasma levels were only variably and nonsignificantly decreased. Excretion rates of dihydroxyphenylglycol and dihydroxyphenylalanine decreased slightly during HDBR; excretion rates of epinephrine, dopamine, and dihydroxyphenylacetic acid and plasma levels of catechols were unchanged. The results suggest that HDBR produces sustained inhibition of sympathoneural release, turnover, and synthesis of NE without affecting adrenomedullary secretion or renal dopamine production. Concurrent hypovolemia probably interferes with detection of sympathoinhibition by plasma levels of NE and other catechols in this setting. Sympathoinhibition, despite decreased blood volume, may help to explain orthostatic intolerance in astronauts returning from spaceflights.

  8. Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus.

    PubMed

    Behl, Tapan; Kotwani, Anita; Kaur, Ishneet; Goel, Heena

    2015-05-15

    Nephrogenic diabetes insipidus is a clinical sub-type of a diversely expounded disorder, named diabetes insipidus. It is characterized by inability of the renal cells to sense and respond to the stimulus of vasopressin. Amongst its various etiologies, one of the most inevitable causes includes lithium-induced instigation. Numerous studies reported marked histological damage to the kidneys upon long-term treatment with lithium. The recent researches have hypothesized many lithium-mediated mechanisms to explain the damage and dysfunction caused in the kidneys following lithium exposure. These mechanisms, widely, intend to justify the lithium-induced electrolyte imbalance, its interference with some vital proteins and a specific steroidal hormone, obstruction caused to a certain imperative transducer pathway and the renal tubular acidification defect produced on its prolonged therapy. Thorough study of such mechanisms aids in better understanding of the role of lithium in the pathophysiology of this disorder. Hence, the ameliorated knowledge regarding disease-pathology might prove beneficial in developing therapies that aim on disrupting the various lithium-mediated pathways. Hence, this may effectively lead to the demonstration of a novel treatment for nephrogenic diabetes insipidus, which is, at present, limited to the use of diuretics which block lithium reuptake into the body.

  9. Prolonged Adaptive Evolution of a Defensive Gene in the Solanaceae.

    PubMed

    Rausher, Mark D; Huang, Jie

    2016-01-01

    Although plants and their natural enemies may coevolve for prolonged periods, little is known about how long individual plant defensive genes are involved in the coevolutionary process. We address this issue by examining patterns of selection on the defensive gene threonine deaminase (TD). Tomato (Solanum lycopersicum) has two copies of this gene. One performs the canonical housekeeping function in amino acid metabolism of catalyzing the first reaction in the conversion of threonine to isoleucine. The second copy functions as an antinutritive defense against lepidopteran herbivores by depleting threonine in the insect gut. Wild tobacco (Nicotiana attenuata) also contains a defensive copy. We show that a single copy of TD underwent two or three duplications near the base of the Solanaceae. One copy retains the housekeeping function, whereas a second copy evolved defensive functions. Positive selection occurred on the branch of the TD2 gene tree subtending the common ancestor of the Nicotianoideae and Solanoideae. It also occurred within the Solanoideae clade but not within the Nicotianoideae clade. Finally, it occurred on most branches leading from the common ancestor to S. lycopersicum. Based on recent calibrations of the Solanaceae phylogeny, TD2 experienced adaptive substitutions for a period of 30-50 My. We suggest that the most likely explanation for this result is fluctuating herbivore abundances: When herbivores are rare, relaxed selection increases the likelihood that slightly disadvantageous mutations will be fixed by drift; when herbivores are common, increased selection causes the evolution of compensatory adaptive mutations. Alternative explanations are also discussed.

  10. Haploinsufficiency of Akt1 Prolongs the Lifespan of Mice

    PubMed Central

    Nojima, Aika; Yamashita, Masakatsu; Yoshida, Yohko; Shimizu, Ippei; Ichimiya, Harumi; Kamimura, Naomi; Kobayashi, Yoshio; Ohta, Shigeo; Ishii, Naoaki; Minamino, Tohru

    2013-01-01

    There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan; however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1+/– mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt-1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases. PMID:23935948

  11. Quality assessment of palm products upon prolonged heat treatment.

    PubMed

    Tarmizi, Azmil Haizam Ahmad; Lin, Siew Wai

    2008-01-01

    Extending the frying-life of oils is of commercial and economic importance. Due to this fact, assessment on the thermal stability of frying oils could provide considerable savings to the food processors. In this study, the physico-chemical properties of five palm products mainly palm oil, single-fractionated palm olein, double-fractionated palm olein, red palm olein and palm-based shortening during 80 hours of heating at 180 degrees C were investigated. Heating properties of these products were then compared with that of high oleic sunflower oil, which was used as reference oil. The indices applied in evaluating the quality changes of oils were free fatty acid, smoke point, p-anisidine value, tocols, polar and polymer compounds. Three palm products i.e. palm oil, single-fractionated palm olein and double-fractionated palm olein were identified to be the most stable in terms of lower formation of free fatty acid, polar and polymer compounds as well as preserving higher smoke point and tocols content compared to the other three oils. The low intensity of hydrolytic and oxidative changes due to prolonged heating, suggests that these palm products are inherently suitable for frying purposes.

  12. Characterization of renal response to prolonged immersion in normal man

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Denunzio, A. G.; Ramachandran, M.

    1980-01-01

    ?jDuring the initial phase of space flight, there is a translocation of fluid from the lower parts of the body to the central vascular compartment with a resultant natriuresis, diuresis, and weight loss. Because water immersion is regarded as an appropriate model for studying the redistribution of fluid that occurs in weightlessness, an immersion study of relatively prolonged duration was carried out in order to characterize the temporal profile of the renal adaptation to central hypervolemia. Twelve normal male subjects underwent an immersion study of 8-h duration in the sodium-replete state. Immersion resulted in marked natriuresis and diuresis which were sustained throughout the immersion period. The failure of that natriuresis and diuresis of immersion to abate or cease despite marked extracellular fluid volume contraction as evidenced by a mean weight loss of -2.2 + or - 0.3 kg suggests that central blood volume was not restored to normal and that some degree of central hypervolemia probably persisted.

  13. Massive and prolonged deep carbon emissions associated with continental rifting

    NASA Astrophysics Data System (ADS)

    Lee, Hyunwoo; Muirhead, James D.; Fischer, Tobias P.; Ebinger, Cynthia J.; Kattenhorn, Simon A.; Sharp, Zachary D.; Kianji, Gladys

    2016-02-01

    Carbon from Earth’s interior is thought to be released to the atmosphere mostly via degassing of CO2 from active volcanoes. CO2 can also escape along faults away from active volcanic centres, but such tectonic degassing is poorly constrained. Here we use measurements of diffuse soil CO2, combined with carbon isotopic analyses to quantify the flux of CO2 through fault systems away from active volcanoes in the East African Rift system. We find that about 4 Mt yr-1 of mantle-derived CO2 is released in the Magadi-Natron Basin, at the border between Kenya and Tanzania. Seismicity at depths of 15-30 km implies that extensional faults in this region may penetrate the lower crust. We therefore suggest that CO2 is transferred from upper-mantle or lower-crustal magma bodies along these deep faults. Extrapolation of our measurements to the entire Eastern rift of the rift system implies a CO2 flux on the order of tens of megatonnes per year, comparable to emissions from the entire mid-ocean ridge system of 53-97 Mt yr-1. We conclude that widespread continental rifting and super-continent breakup could produce massive, long-term CO2 emissions and contribute to prolonged greenhouse conditions like those of the Cretaceous.

  14. Rare bacterium of new genus isolated with prolonged enrichment culture.

    PubMed

    Hashizume, Akiko; Fudou, Ryosuke; Jojima, Yasuko; Nakai, Ryohsuke; Hiraishi, Akira; Tabuchi, Akira; Sen, Kikuo; Shibai, Hiroshiro

    2004-01-01

    Dynamic change in microbial flora was monitored with an oxygen electrode. The 1st phase microorganisms, which first grew well in LB medium, were followed by the 2nd phase microorganisms, which supposedly assimilated microbial cells of the 1st phase and their metabolites. In a similar way, a change in microbial flora was observed from the 1st phase to the 4th phase in 84 hr. Based on this observation, prolonged enrichment culture was done for as long as two months to increase the ratio of existence of rare microorganisms. From these culture liquids, four slow-growing bacteria (provisionally named Shinshu-ah1, -ah2, -ah3, and -ah4), which formed scarcely visible small colonies, were isolated. Sequence analysis of their 16S rDNA showed that Shinshu-ah1 had 97% homology with Bradyrhizobium japonicum and uncultured alpha proteobacterium clone blaii 16, Shinshu-ah2 91% with Rasbo bacterium, Alpha proteobacterium 34619, Bradyrhizobium genosp. P, Afipia felis and an unidentified bacterium, Shinshu-ah3 99% with Methylobacterium mesophilicum, and Shinshu-ah4 95% with Agromyces ramosus DSM 43045. Phylogenetic study indicated that Shinshu-ah2 had a possibility to form a new family, Shinshu-ah1 a new genus, and Shinshu-ah4 a new species.

  15. Radiation burdens for humans on prolonged exomagnetospheric voyages.

    PubMed

    Moore, F D

    1992-03-01

    The severity of radiation exposure for astronauts outside the magnetosphere poses a critical unanswered question bearing on the use of manned vehicles in extended exploration of the solar system (moon, Mars). Such prolonged exomagnetospheric voyages (1-3 years) enter a radiologic environment more severe than that of low earth orbit, an annual dose equivalent in the range of 0.3-0.5 Sv (30-50 rem), and a lifetime excess cancer fatality risk of 3-5% due to low linear-energy-transfer components of galactic cosmic radiation alone. To this calculus must be added estimates for high-atomic-number, high-energy particles, the probability of solar particle events, and the limited effectiveness of shielding. For a 3-year Mars voyage these could elevate the dose equivalent to 1.5-2.25 Sv (150-225 rem) total (0.5-0.75 Sv [50-75 rem] annual) and risks to 5-9% excess cancer fatality. Both the mission (civilian scientific research) and the alternatives (unmanned robotic devices) enter the policy decision here. This paper presents a brief review of pertinent physical and biological data and of research urgently needed before reaching a decision on this question.

  16. Depth perception after prolonged usage of night vision goggles.

    PubMed

    Sheehy, J B; Wilkinson, M

    1989-06-01

    The present study was initiated following a report that a few helicopter pilots had failed a test of stereoscopic depth perception after a prolonged training flight employing night vision goggles (NVGs). In order to determine the cause of the loss, 12 helicopter pilots/copilots were assessed for depth perception, lateral and vertical phoria, and contrast sensitivity before and after training flights requiring the pilots to wear night vision goggles for the duration of the flight. Pilots flew one to three missions while wearing either PVS-5A or AN/AVS-6 goggles. Mission duration ranged from 1 to 4 h. The results indicate that contrast sensitivity and depth perception when monocular cues are present did not degrade over the course of the mission. Lateral phoria, however, did demonstrate an average exophoric shift of 1.5 prism diopters for 12 out of the 24 missions. The results indicate that the original report of a loss of depth perception based on a test of depth requiring stereopsis might have been caused by a shift in lateral phoria. It would be expected that as additional fusional effort is required, the minimum resolvable disparity degrades due to the increase in accommodation brought about through vergence accommodation. Possible causes for the phoria shift and future testing are discussed.

  17. Effect of prolonged space flight on cardiac function and dimensions

    NASA Technical Reports Server (NTRS)

    Henry, W. L.; Epstein, S. E.; Griffith, J. M.; Goldstein, R. E.; Redwood, D. R.

    1974-01-01

    Echocardiographic studies were performed preflight 5 days before launch and on recovery day and 1, 2, 4, 11, 31 and 68 days postflight. From these echocardiograms measurements were made. From these primary measurements, left ventricular end-diastolic volume, end-systolic volume, stroke volume, and mass were derived using the accepted assumptions. Findings in the Scientist Pilot and Pilot resemble those seen in trained distance runners. Wall thickness measurements were normal in all three crewmembers preflight. Postflight basal studies were unchanged in the Commander on recovery day through 68 days postflight in both the Scientist Pilot and Pilot, however, the left ventricular end-diastolic volume, stroke volume, and mass were decreased slightly. Left ventricular function curves were constructed for the Commander and Pilot by plotting stroke volume versus end-diastolic volume. In both astronauts, preflight and postflight data fell on the same straight line demonstrating that no deterioration in cardiac function had occurred. These data indicate that the cardiovascular system adapts well to prolonged weightlessness and suggest that alterations in cardiac dimensions and function are unlikely to limit man's future in space.

  18. Association between Muscle Synergy and Stability during Prolonged Walking

    PubMed Central

    Suzuki, Keisuke; Nishida, Yusuke; Mitsutomi, Kazuhiko

    2014-01-01

    [Purpose] The purpose of this study was to examine whether changes in muscle synergy could affect gait stability or muscle activity by comparing muscle activity before and after prolonged walking. [Subjects and Methods] Twelve healthy male subjects walked on a treadmill for 10 min as a warm-up. Data were recorded from the participants during the first and last 1 min during 90 min of walking at 4.5 km/h. Electromyographic (EMG) activity was recorded for 7 leg muscles, and patterns of coordination were determined by principal component analysis (PCA). The patterns of activity within the anatomic muscle groups were additionally determined by repeating PCA. iEMG was calculated using the mean EMG for each cycle step during the 1 min walking periods. The largest Lyapunov exponent was calculated to quantify each subject’s inherent local dynamic stability. [Results] The patterns for each of the 7 muscles showed no change between the start and end periods. However, the end period showed a higher co-activation of the triceps surae, lower iEMG of the medial gastrocnemius, and a smaller largest Lyapunov exponent of the mediolateral and anteroposterior directions than those observed during the start period. [Conclusion] The increase in triceps surae co-activation may be associated with gait stability. PMID:25364133

  19. Mueller-Lyer decrement: practice or prolonged inspection?

    NASA Technical Reports Server (NTRS)

    Schiano, D. J.; Jordan, K.

    1990-01-01

    Noting the similarity between the illusion decrement and selective adaptation paradigms, Long has challenged the view that illusion decrement effects reflect a strategic--as opposed to a structural--underlying mechanism, and has called for further research on this issue. To investigate the confound between prolonged free inspection and repeated trials in the standard decrement procedure, the effects of three inspection conditions (continuous, intermittent, and immediate) on the magnitude of the overestimation Mueller-Lyer illusion have been assessed under two levels of trials (a total of two or six judgments). Significant illusion decline was found only under conditions of repeated trials, with either continuous or intermittent inspection. These findings do not support the predictions of purely structural theories (including neural adaptation and efferent readiness theories), according to which degree of decrement should be determined solely by viewing time. Instead, the data demonstrate that illusion decrement is a product of practice, providing converging evidence for the view of decrement as involving a cognitive 'recalibration' or learning process.

  20. Recovery in skeletal muscle contractile function after prolonged hindlimb immobilization

    NASA Technical Reports Server (NTRS)

    Fitts, R. H.; Brimmer, C. J.

    1985-01-01

    The effect of three-month hindlimb immobilization (IM) in rats on contractile properties of slow-twitch soleus (SOL), fast-twitch extensor digitorum longus, and fast-twitch superficial region of the vastus lateralis were measured after 0, 14, 28, 60, and 90 days of recovery on excized, horizontally suspended muscles stimulated electrically to maximal twitch tension. IM caused decreases in muscle-to-body weight ratios for all muscles, with no complete recovery even after 90 days. The contractile properties of the fast-twitch muscles were less affected by IM than those of the slow-twitch SOL. The SOL isometric twitch duration was shortened, due to reduced contraction and half-relaxation time, both of which returned to control levels after 14 days of recovery. The peak tetanic tension, P(O), g/sq cm,, decreased with IM by 46 percent in the SOL, but recovered by the 28th day. The maximum shortening velocity was not altered by IM in any of the muscles. Thus, normal contractile function could recover after prolonged limb IM.

  1. International Consensus on drug allergy.

    PubMed

    Demoly, P; Adkinson, N F; Brockow, K; Castells, M; Chiriac, A M; Greenberger, P A; Khan, D A; Lang, D M; Park, H-S; Pichler, W; Sanchez-Borges, M; Shiohara, T; Thong, B Y- H

    2014-04-01

    When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug-specific antibodies or T cells. DHRs may be allergic or nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life-threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under-reporting) and overdiagnosis (due to an overuse of the term ‘allergy’) are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more-expensive or less-effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class-induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of

  2. Mucoadhesive vaginal drug delivery systems.

    PubMed

    Acartürk, Füsun

    2009-11-01

    Vaginal delivery is an important route of drug administration for both local and systemic diseases. The vaginal route has some advantages due to its large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to many drugs and self-insertion. The traditional commercial preparations, such as creams, foams, gels, irrigations and tablets, are known to reside in the vaginal cavity for a relatively short period of time owing to the self-cleaning action of the vaginal tract, and often require multiple daily doses to ensure the desired therapeutic effect. The vaginal route appears to be highly appropriate for bioadhesive drug delivery systems in order to retain drugs for treating largely local conditions, or for use in contraception. In particular, protection against sexually-transmitted diseases is critical. To prolong the residence time in the vaginal cavity, bioadhesive therapeutic systems have been developed in the form of semi-solid and solid dosage forms. The most commonly used mucoadhesive polymers that are capable of forming hydrogels are synthetic polyacrylates, polycarbophil, chitosan, cellulose derivatives (hydroxyethycellulose, hydroxy-propylcellulose and hydroxypropylmethylcellulose), hyaluronic acid derivatives, pectin, tragacanth, carrageenan and sodium alginate. The present article is a comprehensive review of the patents related to mucoadhesive vaginal drug delivery systems.

  3. Polymeric Micelles, a Promising Drug Delivery System to Enhance Bioavailability of Poorly Water-Soluble Drugs

    PubMed Central

    Ling, Peixue; Zhang, Tianmin

    2013-01-01

    Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs) can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained. PMID:23936656

  4. Drugs@FDA: FDA Approved Drug Products

    MedlinePlus

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing options Linkedin Pin it Email Print Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  5. Nanostructure-based platforms-current prospective in ophthalmic drug delivery

    PubMed Central

    Sharma, Rakesh Kumar; Yassin, Alaa Eldeen B

    2014-01-01

    The topically applied drugs as drops are washed off from the eye in very short period, resulting in low ocular bioavailability of drugs. Number of approaches have been attempted to increase the bioavailability and the duration of action of ocular drugs. This review provides an insight into various novel approaches; hydrophilic nanogels, solid lipid nanoparticles, and nanosponges applied very recently in the delivery of insoluble drugs, prolonging the ocular residence time, minimize pre-corneal drug loss and, therefore, bioavailability and therapeutic efficacy of the drugs. Despite various scientific approaches, efficient ocular drug delivery remains a challenge for pharmaceutical scientists. PMID:25116766

  6. 78 FR 62427 - TRICARE; Removal of the Prohibition To Use Addictive Drugs in the Maintenance Treatment of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-22

    ... opioid treatment services. Medication assisted treatment, to include drug maintenance involving... medical evidence, this exclusion of medication assisted treatment of substance use dependence utilizing a... medications like buprenorphine and naloxone when used for either prolonged ambulatory detoxification...

  7. Prolonged ampakine exposure prunes dendritic spines and increases presynaptic release probability for enhanced long-term potentiation in the hippocampus.

    PubMed

    Chang, Philip K-Y; Prenosil, George A; Verbich, David; Gill, Raminder; McKinney, R Anne

    2014-09-01

    CX 546, an allosteric positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPARs), belongs to a drug class called ampakines. These compounds have been shown to enhance long-term potentiation (LTP), a cellular model of learning and memory, and improve animal learning task performance, and have augmented cognition in neurodegenerative patients. However, the chronic effect of CX546 on synaptic structures has not been examined. The structure and integrity of dendritic spines are thought to play a role in learning and memory, and their abnormalities have been implicated in cognitive disorders. In addition, their structural plasticity has been shown to be important for cognitive function, such that dendritic spine remodeling has been proposed as the morphological correlate for LTP. Here, we tested the effect of CX546 on dendritic spine remodeling following long-term treatment. We found that, with prolonged CX546 treatment, organotypic hippocampal slice cultures showed a significant reduction in CA3-CA1 excitatory synapse and spine density. Electrophysiological approaches revealed that the CA3-CA1 circuitry compensates for this synapse loss by increasing synaptic efficacy through enhancement of presynaptic release probability. CX546-treated slices showed prolonged and enhanced potentiation upon LTP induction. Furthermore, structural plasticity, namely spine head enlargement, was also more pronounced after CX546 treatment. Our results suggest a concordance of functional and structural changes that is enhanced with prolonged CX546 exposure. Thus, the improved cognitive ability of patients receiving ampakine treatment may result from the priming of synapses through increases in the structural plasticity and functional reliability of hippocampal synapses.

  8. Drug Education.

    ERIC Educational Resources Information Center

    Sardana, Raj K.

    This autoinstructional lesson deals with the study of such drugs as marijuana and LSD, with emphasis on drug abuse. It is suggested that it can be used in science classes at the middle level of school. No prerequisites are suggested. The teacher's guide lists the behavioral objectives, the equipment needed to complete the experience and suggests…

  9. Antineoplastic Drugs

    NASA Astrophysics Data System (ADS)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  10. High remission and low relapse with prolonged intensive DMARD therapy in rheumatoid arthritis (PRINT)

    PubMed Central

    Li, Ru; Zhao, Jin-Xia; Su, Yin; He, Jing; Chen, Li-Na; Gu, Fei; Zhao, Cheng; Deng, Xue-Rong; Zhou, Wei; Hao, Yan-Jie; Xue, Yu; Liu, Hua-Xiang; Zhao, Yi; Zou, Qing-Hua; Liu, Xiang-Yuan; Zhu, Ping; Sun, Ling-Yun; Zhang, Zhuo-Li; Zou, He-Jian; Li, Xing-Fu; Liu, Yi; Fang, Yong-Fei; Keystone, Edward; McInnes, Iain B.; Li, Zhan-Guo

    2016-01-01

    Abstract Objectives: To determine whether prolonged intensive disease-modifying antirheumatic drug (DMARD) treatment (PRINT) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis (RA). Methods: In this multicenter, randomized and parallel treatment trial, 346 patients with active RA (disease activity score (28 joints) [DAS28] (erythrocyte sedimentation rate [ESR]) > 5.1) were enrolled from 9 centers. In phase 1, patients received intensive treatment with methotrexate, leflunomide, and hydroxychloroquine, up to 36 weeks, until remission (DAS28 ≤ 2.6) or a low disease activity (2.6 < DAS28 ≤ 3.2) was achieved. In phase 2, patients achieving remission or low disease activity were followed up with randomization to 1 of 2 step-down protocols: leflunomide plus hydroxychloroquine combination or leflunomide monotherapy. The primary endpoints were good European League Against Rheumatism (EULAR) response (DAS28 (ESR) < 3.2 and a decrease of DAS28 by at least 1.2) during the intensive treatment and the disease state retention rate during step-down maintenance treatment. Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought. Results: A good EULAR response was achieved in 18.7%, 36.9%, and 54.1% of patients at 12, 24, and 36 weeks, respectively. By 36 weeks, 75.4% of patients achieved good and moderate EULAR responses. Compared with those achieving low disease activity and a high health assessment questionnaire (HAQ > 0.5), patients achieving remission (DAS28 ≤ 2.6) and low HAQ (≤ 0.5) had a significantly higher retention rate when tapering the DMARDs treatment (P = 0.046 and P = 0.01, respectively). There was no advantage on tapering to combination rather than monotherapy. Conclusions: Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy. Low disease activity at the start of disease taper leads to less subsequent

  11. Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease.

    PubMed

    Zoja, C; Corna, D; Benedetti, G; Morigi, M; Donadelli, R; Guglielmotti, A; Pinza, M; Bertani, T; Remuzzi, G

    1998-03-01

    As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P < 0.005; 10 months: 53% vs. 80%) and significantly (P < 0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 +/- 3 vs. 127 +/- 42; 10 months, 53 +/-5 vs. 140 +/- 37 mg/dl). Appearance of anti-DNA antibodies was retarded and survival significantly (P < 0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7 - 12-fold in 8- 10-month-old mice vs. 2-month-old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies

  12. Predictors of Prolonged TB Treatment in a Dutch Outpatient Setting

    PubMed Central

    Daskapan, Alper; Kosterink, Jos G. W.; van der Werf, Tjip S.; van den Hof, Susan; Alffenaar, Jan-Willem C.

    2016-01-01

    Introduction Standard treatment duration for drug-susceptible tuberculosis (TB) treatment is 6 months. Treatment duration is often extended—and for various different reasons. The aim of this study was to determine the prevalence and to assess risk factors associated with extended TB treatment. Methods A cross-sectional study was conducted. Data including demographic, clinical, radiological and microbiological information from the Netherlands TB Register (NTR) of 90 patients with smear and culture positive pulmonary TB of the region Haaglanden, The Netherlands, was eligible for analysis. Results Treatment was extended to ≥ 200 days by 46 (51%) patients. Extended TB treatment was associated with a higher frequency of symptoms, presumed to be due to adverse drug reactions (ADR; OR 2.39 95% CI: 1.01–5.69), drug-induced liver injury (DILI) (OR: 13.51; 95% CI: 1.66–109.82) and longer than 2 month smear and culture conversion rate (OR: 11.00; 95% CI: 1.24–97.96 and OR: 8.56; 95% CI: 1.53–47.96). In the multivariable logistic analysis, development of DILI emerged as the single statistically strong risk factor necessitating extension of TB treatment. Conclusion This finding will need further confirmation in a prospective study, exploring the possible mutual role of pharmacokinetic and pharmacogenetic determinants of DILI among TB patients. PMID:27832142

  13. Achilles tendon mechanical properties after both prolonged continuous running and prolonged intermittent shuttle running in cricket batting.

    PubMed

    Houghton, Laurence; Dawson, Brian; Rubenson, Jonas

    2013-08-01

    Effects of prolonged running on Achilles tendon properties were assessed after a 60 min treadmill run and 140 min intermittent shuttle running (simulated cricket batting innings). Before and after exercise, 11 participants performed ramp-up plantar flexions to maximum-voluntary-contraction before gradual relaxation. Muscle-tendon-junction displacement was measured with ultrasonography. Tendon force was estimated using dynamometry and a musculoskeletal model. Gradients of the ramp-up force-displacement curves fitted between 0-40% and 50-90% of the preexercise maximal force determined stiffness in the low- and high-force-range, respectively. Hysteresis was determined using the ramp-up and relaxation force-displacement curves and elastic energy storage from the area under the ramp-up curve. In simulated batting, correlations between tendon properties and shuttle times were also assessed. After both protocols, Achilles tendon force decreased (4% to 5%, P < .050), but there were no changes in stiffness, hysteresis, or elastic energy. In simulated batting, Achilles tendon force and stiffness were both correlated to mean turn and mean sprint times (r = -0.719 to -0.830, P < .050). Neither protocol resulted in fatigue-related changes in tendon properties, but higher tendon stiffness and plantar flexion force were related to faster turn and sprint times, possibly by improving force transmission and control of movement when decelerating and accelerating.

  14. Diffuse alveolar damage in a patient with rheumatoid arthritis under prolonged leflunomide treatment: A Case Report and Literature Review.

    PubMed

    Keng, Li-Ta; Lin, Mong-Wei; Huang, Hsien-Neng; Chung, Kuei-Pin

    2016-06-01

    Patients with rheumatoid arthritis (RA) often have pulmonary involvement, and interstitial lung disease (ILD) is the primary manifestation, in which diffuse alveolar damage (DAD) is a rare histopathologic pattern. Leflunomide (LEF) is a frequently prescribed disease-modifying antirheumatic drug for treating RA. LEF-related ILD in the form of DAD has been reported in patients with RA, with the duration of LEF treatment before symptom onset ranging from 6 to 1204 days.We present a case of elderly woman with RA under prolonged LEF treatment for >9 years (3291 days), who had acute respiratory failure with the initial presentation of exertional dyspnea, fever, chills, and productive cough for 2 days. The histopathologic result of surgical lung biopsy was compatible with DAD. She was diagnosed as having LEF-related ILD, based on correlated clinical history, compatible histopathologic examination and excluding possible infection after extensive survey.Although the causative role of LEF cannot be confirmed, this case still hints that LEF-related DAD may occur even if LEF has been prescribed for a prolonged period.

  15. Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice.

    PubMed

    Lewis, Eli C; Shapiro, Leland; Bowers, Owen J; Dinarello, Charles A

    2005-08-23

    Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human alpha1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-control-treated graft recipients, which rejected islets at day 10, AAT-treated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro, several islet responses to IL-1beta/IFNgamma stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 alpha and expressed 63% fewer surface MHC class II molecules. TNFalpha release from IL-1beta/IFNgamma-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNFalpha on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.

  16. Intrasplenic transplantation of allogeneic hepatocytes prolongs survival in anhepatic rats.

    PubMed

    Arkadopoulos, N; Lilja, H; Suh, K S; Demetriou, A A; Rozga, J

    1998-11-01

    To examine whether hepatocytes transplanted in the spleen can function as an ectopic liver, we performed hepatocyte transplantation in rats that were rendered anhepatic. Total hepatectomy was performed by using a novel single-stage technique. Following hepatectomy, Group 1 rats (n = 16) were monitored until death to determine survival time without prior intervention. Group 2 anhepatic rats (n = 20) were sacrificed at various times to measure blood hepatocyte growth factor (HGF) and transforming growth factor beta1 (TGF-beta1) levels. Group 3 (n = 16) rats received intrasplenic injection of isolated hepatocytes (2.5 x 10(7) cells/rat) followed by total hepatectomy after 3 days. Group 4 (n = 12) sham-transplanted rats received intrasplenic saline infusion, and after 3 days they were rendered anhepatic. Group 2, 3, and 4 rats were maintained on daily Cyclosporine A (10 mg/kg; intramuscularly). Group 1 anhepatic rats survived for 22.4 +/- 5.2 hours (standard deviation). The anhepatic state was associated with a progressive and statistically significant rise in blood HGF and TGF-beta1 levels. Rats that received hepatocyte transplantation before total hepatectomy had a significantly longer survival time than sham-transplanted anhepatic controls (34.1 +/- 8.5 vs. 15.5 +/- 4.8 hrs, P < .01). Additionally, at 12 hours post-hepatectomy, transplanted rats had significantly lower blood ammonia, prothrombin time, international normalized ratio, and TGF-beta1 levels when compared with sham-transplanted controls. In conclusion, intrasplenic transplantation of allogeneic hepatocytes prolonged survival, improved blood chemistry, and lowered blood TGF-beta1 levels in rats rendered anhepatic.

  17. Predictors of Prolonged Hospitalization in Patients with Fever

    PubMed Central

    2016-01-01

    Objective: The study was conducted to analyze the predictors of prolonged hospitalization in patients with fever. Patients and Methods: This was a prospective cohort study conducted from July - December 2015 at Ayub Teaching Hospital, Pakistan. Convenience sampling was used to enroll the patients who visited the hospital during the study duration. A sample size of 115 patients was calculated. It included patients who presented with a new onset fever which started in the last month, and the cause of fever was undiagnosed at the time of admission. Critical patients were excluded. Data for more than 30 variables was collected on a pro forma. Univariate regression methods were used to analyze the data in the Statistical Package for Social Sciences (SPSS), version 23. Results: A total of 115 patients were analyzed. Males constituted 66/115 (57.4%). The mean age for patients was 43.6 years (standard deviation (SD) = 20.2). On admission, low platelet counts (p = 0.001), high erythrocyte sedimentation rate (ESR) counts (p = 0.007), a high total leukocyte count (TLC) (p = 0.029), and involvement of nervous (p = 0.021), cardiovascular (p = 0.04), respiratory (p = 0.043), gastroenterological (p = 0.042), hematological (p = 0.028), or urogenital system (p = 0.016) were associated with a longer stay in the hospital. Conclusion: Patients with an undiagnosed and new onset fever will have a longer hospital stay if, on admission, they have low platelet counts, a higher ESR, a high TLC, or involvement of nervous, cardiovascular, respiratory, gastrointestinal, hematological, or urogenital systems. An early identification of risk factors can lead to better treatment and may also lead to a decreased hospital stay. PMID:27774357

  18. Altered locus coeruleus-norepinephrine function following single prolonged stress.

    PubMed

    George, Sophie A; Knox, Dayan; Curtis, Andre L; Aldridge, J Wayne; Valentino, Rita J; Liberzon, Israel

    2013-03-01

    Data from preclinical and clinical studies have implicated the norepinephrine system in the development and maintenance of post-traumatic stress disorder. The primary source of norepinephrine in the forebrain is the locus coeruleus (LC); however, LC activity cannot be directly measured in humans, and previous research has often relied upon peripheral measures of norepinephrine to infer changes in central LC-norepinephrine function. To directly assess LC-norepinephrine function, we measured single-unit activity of LC neurons in a validated rat model of post-traumatic stress disorder - single prolonged stress (SPS). We also examined tyrosine hydroxylase mRNA levels in the LC of SPS and control rats as an index of norepinephrine utilisation. For electrophysiological recordings, 92 LC neurons were identified from 19 rats (SPS, 12; control, 7), and spontaneous and evoked responses to a noxious event (paw compression) were recorded. Baseline and restraint stress-evoked tyrosine hydroxylase mRNA expression levels were measured in SPS and control rats (n = 16 per group) in a separate experiment. SPS rats showed lower spontaneous activity but higher evoked responses, leading to an enhanced signal-to-noise ratio of LC neurons, accompanied by impaired recovery from post-stimulus inhibition. In concert, tyrosine hydroxylase mRNA expression in the LC of SPS rats tended to be lower at baseline, but was exaggerated following restraint stress. These data demonstrate persistent changes in LC function following stress/trauma in a rat model of post-traumatic stress, as measured by differences in both the electrophysiological properties of LC neurons and tyrosine hydroxylase mRNA transcription.

  19. Prolonged cannabis withdrawal in young adults with lifetime psychiatric illness.

    PubMed

    Schuster, Randi Melissa; Fontaine, Madeleine; Nip, Emily; Zhang, Haiyue; Hanly, Ailish; Eden Evins, A

    2017-02-27

    Young adults with psychiatric illnesses are more likely to use cannabis and experience problems from use. It is not known whether those with a lifetime psychiatric illness experience a prolonged cannabis withdrawal syndrome with abstinence. Participants were fifty young adults, aged 18-25, recruited from the Boston-area in 2015-2016, who used cannabis at least weekly, completed the Structured Clinical Interview for DSM-IV to identify Axis I psychiatric diagnoses (PD+ vs PD-), and attained cannabis abstinence with a four-week contingency management protocol. Withdrawal symptom severity was assessed at baseline and at four weekly abstinent visits using the Cannabis Withdrawal Scale. Cannabis dependence, age of initiation, and rate of abstinence were similar in PD+ and PD- groups. There was a diagnostic group by abstinent week interaction, suggesting a difference in time course for resolution of withdrawal symptoms by group, F(4,46)=3.8, p=0.009, controlling for sex, baseline depressive and anxiety symptoms, and frequency of cannabis use in the prior 90days. In post hoc analyses, there was a difference in time-course of cannabis withdrawal. PD- had significantly reduced withdrawal symptom severity in abstinent week one [t(46)=-2.2, p=0.03], while PD+ did not report improved withdrawal symptoms until the second abstinent week [t(46)=-4.1, p=0.0002]. Cannabis withdrawal symptoms improved over four weeks in young people with and without a lifetime psychiatric diagnosis. However, those with a psychiatric illness reported one week delayed improvement in withdrawal symptom severity. Longer duration of cannabis withdrawal may be a risk factor for cannabis dependence and difficulty quitting.

  20. Triathlete characterization and response to prolonged strenuous competition.

    PubMed

    Holly, R G; Barnard, R J; Rosenthal, M; Applegate, E; Pritikin, N

    1986-02-01

    The purpose of this study was to characterize triathletes and to assess their responses to prolonged, strenuous competition. Nine triathletes (6 males, 3 females) participated. Mean V0(2)max and percentage of body fat were 72.0 ml X kg-1 X min-1 and 7.1%, respectively, in the four males who finished in the top 15. This compared to values of 58.4 ml X kg-1 X min-1/10.2% and 58.7 ml X kg-1 X min-1/12.6% in the other males and females, respectively. In the 5 wk preceding competition (Hawaii "Ironman Triathlon World Championship") the average daily training of the four top 15 male competitors consisted of swimming 2720 m, running 13.6 km, and biking 84.0 km. This was approximately 1.5 times greater than that of the other athletes. The average training diet was 59% carbohydrate, 21% fat, and 20% protein. Immediately following competition, SGOT, SGPT, and serum LDH were increased 700, 262, and 222% (P less than 0.004), respectively, and still remained marginally elevated 5-6 d later (P less than 0.02). Immediately following competition, serum triglycerides remained unchanged, while serum glucose, glycerol, and nonesterified fatty acids increased 52, 248, and 191% (P less than 0.005), respectively. By 5-6 d post-competition glucose had returned to normal, while triglycerides were elevated 94% (P less than 0.005) and nonsterified fatty acids were decreased 58% (P less than 0.01).

  1. Central and regional hemodynamics in prolonged space flights

    NASA Astrophysics Data System (ADS)

    Gazenko, O. G.; Shulzhenko, E. B.; Turchaninova, V. F.; Egorov, A. D.

    This paper presents the results of measuring central and regional (head, forearm, calf) hemodynamics at rest and during provocative tests by the method of tetrapolar rheography in the course of Salyut-6-Soyuz and Salyut-7-Soyuz missions. The measurements were carried out during short-term (19 man-flights of 7 days in duration) and long-term (21 man-flights of 65-237 days in duration) manned missions. At rest, stroke volume (SV) and cardiac output (CO) as well as heart rate (HR) decreased insignificantly (in short-term flights) or remained essentially unchanged (in long-term flights). In prolonged flights CO increased significantly in response to exercise tests due to an increase in HR and the lack of changes in SV. After exercise tests SV and CO decreased as compared to the preflight level. During lower body negative pressure (LBNP) tests HR and CO were slightly higher than preflight. Changes in regional hemodynamics included a distinct decrease of pulse blood filling (PBF) of the calf, a reduction of the tone of large vessels of the calf and small vessels of the forearm. Head examination (in the region of the internal carotid artery) showed a decrease of PBF of the left hemisphere (during flight months 2-8) and a distinct decline of the tone of small vessels, mainly, in the right hemisphere. During LBNP tests the tone of pre- and postcapillary vessels of the brain returned to normal while PBF of the right and left hemisphere vessels declined. It has been shown that regional circulation variations depend on the area examined and are induced by a rearrangement of total hemodynamics of the human body in microgravity. This paper reviews the data concerning changes in central and regional circulation of men in space flights of different duration.

  2. Prolonged administration of antithymocyte serum in mice. II. Histopathological investigation

    PubMed Central

    Simpson, Elizabeth; Nehlsen, Sandra L.

    1971-01-01

    Prolonged administration of ATS to mice resulted in depletion of small lymphocytes in the thymus-dependent (paracortical) areas of lymph nodes in all mice. Small lymphocyte depletion of the thymus-dependent periarteriolar region of the spleen was present in most mice, although this feature was masked by plasmacytosis in this region in some. Depletion of small lymphocytes in the thymus-dependent areas of Peyer's patches was evident in some of the younger mice. None of these changes in lymphoid organs were seen in control mice, untreated or given NRS. The thymus was unaffected except in some ATS- or NRS-treated mice which were sick and/or old, in which the narrowing of the thymic cortex was attributed to non-specific stress. Plasmacytosis was seen in the medullae of lymph nodes of both ATS- and NRS-treated mice, although it was more intense in the latter. In non-lymphoid organs the most striking changes were seen in the kidneys of mice treated both with ATS and NRS. Complex-type nephritis followed by amyloidosis was seen in a large proportion of mice over 6 months old in both these groups and in these mice amyloid was seen frequently in other organs, including spleen and liver. Tumours occurred in fifty-four ATS-treated mice, but in no other group. Fifty-two of these tumours were attributable to polyoma virus; two other were lymphoblastomas. Reticulum cell hyperplasia was seen in two further mice. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13Fig. 14Fig. 15Fig. 16Fig. 17Fig. 18 PMID:4326920

  3. Does prolonged biliary obstructive jaundice sensitize the liver to endotoxemia?

    PubMed

    Iida, Ayako; Yoshidome, Hiroyuki; Shida, Takashi; Kimura, Fumio; Shimizu, Hiroaki; Ohtsuka, Masayuki; Morita, Yasuhiro; Takeuchi, Dan; Miyazaki, Masaru

    2009-04-01

    Biliary obstructive jaundice (OJ) is an important clinical consideration concerning high bacteremic risk. Hepatocyte apoptosis is one of the causes of cholestatic liver injury. The aim of the current study was to examine the precise pathway and time course of hepatocyte apoptosis during OJ with LPS administration and to determine if OJ sensitizes the liver to endotoxemia. Male C57BL/6 mice were subjected to bile duct ligation and division and were administered with LPS at 3 (OJ3) or 14 (OJ14) days after surgery. Fas ligand expression, poly (adenosine diphosphate-ribose) polymerase p85 fragment immunohistochemistry, activation of caspases 3, 8, and 9, serum alanine aminotransferase levels, and hepatic adenosine triphosphate (ATP) contents were examined. Survival after LPS administration in male C57BL/6 or gld/gld (Fas ligand-deficient) mice was determined. The expression of Fas ligand increased during OJ. After LPS administration, the expression of cleaved caspases 3 and 8 increased in Sham3, Sham14, OJ3, and OJ14 mice, and it significantly increased in OJ14 compared with other mice. Poly (adenosine diphosphate-ribose) polymerase p85 immunohistochemistry showed significant hepatocyte apoptosis after LPS administration in OJ14 mice relative to OJ3. In OJ14 with LPS administration, ATP contents significantly decreased and alanine aminotransferase levels increased. Hepatocyte apoptosis was decreased in gld/gld OJ14 mice compared with C57BL/6 OJ14. All C57BL/6 OJ14 mice with LPS died, but survival in gld/gld OJ14 significantly ameliorated. In prolonged OJ with LPS administration, hepatocyte apoptosis depending on Fas ligand expression significantly increased in association with a decrease in ATP contents, thus resulting in liver necrapoptosis.

  4. [Club drugs].

    PubMed

    Guerreiro, Diogo Frasquilho; Carmo, Ana Lisa; da Silva, Joaquim Alves; Navarro, Rita; Góis, Carlos

    2011-01-01

    Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma-hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse.

  5. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective.

    PubMed

    van Leeuwen, Roelof W F; van Gelder, Teun; Mathijssen, Ron H J; Jansman, Frank G A

    2014-07-01

    In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice.

  6. Multistep, effective drug distribution within solid tumors

    PubMed Central

    Shemi, Amotz; Khvalevsky, Elina Zorde; Gabai, Rachel Malka; Domb, Abraham; Barenholz, Yechezkel

    2015-01-01

    The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such ‘priming’ enables drug penetration to successive cell layers. Tumor ‘void volume’ (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by ‘mixing’, powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER™ system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER™ was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients. PMID:26416413

  7. Treatment of drug-induced seizures.

    PubMed

    Chen, Hsien-Yi; Albertson, Timothy E; Olson, Kent R

    2016-03-01

    Seizures are a common complication of drug intoxication, and up to 9% of status epilepticus cases are caused by a drug or poison. While the specific drugs associated with drug-induced seizures may vary by geography and change over time, common reported causes include antidepressants, stimulants and antihistamines. Seizures occur generally as a result of inadequate inhibitory influences (e.g., gamma aminobutyric acid, GABA) or excessive excitatory stimulation (e.g. glutamate) although many other neurotransmitters play a role. Most drug-induced seizures are self-limited. However, status epilepticus occurs in up to 10% of cases. Prolonged or recurrent seizures can lead to serious complications and require vigorous supportive care and anticonvulsant drugs. Benzodiazepines are generally accepted as the first line anticonvulsant therapy for drug-induced seizures. If benzodiazepines fail to halt seizures promptly, second line drugs include barbiturates and propofol. If isoniazid poisoning is a possibility, pyridoxine is given. Continuous infusion of one or more anticonvulsants may be required in refractory status epilepticus. There is no role for phenytoin in the treatment of drug-induced seizures. The potential role of ketamine and levetiracetam is promising but not established.

  8. Breathable Medicine: Pulmonary Mode of Drug Delivery.

    PubMed

    Gandhimathi, Chinnasamy; Venugopal, Jayarama Reddy; Sundarrajan, Subramanian; Sridhar, Radhakrishnan; Tay, Samuel Sam Wah; Ramakrishna, Seeram; Kumar, Srinivasan Dinesh

    2015-04-01

    Pharmaceutically active compounds require different modes of drug delivery systems to accomplish therapeutic activity without loss of its activity and lead to exhibit no adverse effects. Originating from ancient days, pulmonary mode of drug delivery is gaining much importance compared to other modes of drug delivery systems with respect to specific diseases. Pulmonary drug delivery is a non-invasive route for local and systemic therapies together with more patient convenience, compliance and is a needleless system. In this review, we addressed the vaccine delivery via non- or minimally invasive routes. Polymeric nanoparticles are preferred for use in the pulmonary delivery devices owing to a prolonged retention in lungs. Small site for absorption, mucociliary clearance, short residence time and low bioavailability are some of the limitations in pulmonary drug delivery have been resolved by generating micro- and nano-sized aerosol particles. We have classified the breathable medicine on the basis of available devices for inhalation and also prominent diseases treated through pulmonary mode of drug delivery. Owing to increasing toxicity of pharmacological drugs, the use of natural medicines has been rapidly gaining importance recently. The review article describes breathability of medicines or the pulmonary mode of drug delivery system and their drug release profile, absorption, distribution and efficacy to cure asthma and diabetes.

  9. Corticosteroid Treatment for Prolonged Fever in Hepatosplenic Cat-Scratch Disease.

    PubMed

    Phan, Amanda; Castagnini, Luis A

    2016-12-01

    Hepatosplenic cat-scratch disease (CSD) may cause prolonged fever. We present the case of a 4-year-old boy with confirmed hepatosplenic CSD with fever lasting 3 months despite use of multiple different antimicrobial agents. The patient became afebrile soon after corticosteroid therapy was started. Our case indicates corticosteroids may be useful in patients with hepatosplenic CSD and prolonged fever.

  10. Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children.

    PubMed

    Sahin, Mustafa; Menache, Caroline C; Holmes, Gregory L; Riviello, James J

    2003-08-12

    High-dose suppressive therapy (HDST) is used to treat refractory status epilepticus (RSE). Prolonged therapy is required in some cases, and prognosis is important in making therapeutic decisions. The authors therefore studied the long-term outcome in previously normal children who survived prolonged HDST for acute symptomatic RSE. All have intractable epilepsy, and none returned to baseline.

  11. Imagining the Alternatives to Life Prolonging Treatments: Elders' Beliefs about the Dying Experience

    ERIC Educational Resources Information Center

    Winter, Laraine; Parker, Barbara; Schneider, Melissa

    2007-01-01

    Deciding for or against a life-prolonging treatment represents a choice between prolonged life and death. When the death alternative is not described, individuals must supply their own assumptions. How do people imagine the experience of dying? The authors asked 40 elderly people open-ended questions about dying without 4 common life-prolonging…

  12. Prolonged Exposure for Treating PTSD Among Female Methadone Patients Who Were Survivors of Sexual Abuse in Israel.

    PubMed

    Schiff, Miriam; Nacasch, Nitsa; Levit, Shabtay; Katz, Noam; Foa, Edna B

    2015-01-01

    The aims of this pilot study were: (a) to test the feasibility of prolonged exposure (PE) therapy conducted by a social worker staff on female patients in methadone program clinics who were survivors of child sexual abuse or rape and (b) to examine preliminary outcomes of PE on posttraumatic stress disorder (PTSD), depression, and illicit drug use at pre- and posttreatment, and up to 12-month follow-ups. Twelve female methadone patients who were survivors of child sexual abuse or rape diagnosed with PTSD were enrolled in 13-19 weekly individual PE sessions. Assessments were conducted at pre-, mid-, and posttreatment, as well as at 3, 6, and 12-month follow-ups. The treatment outcomes measures included PTSD symptoms, depressive symptoms, and illicit drug use. Ten of the 12 study patients completed treatment. PTSD and depressive symptoms showed significant reduction. No relapse to illicit drug use was detected. These preliminary results suggest that PE may be delivered by methadone social workers with successful outcomes. Further research should test the efficacy of PE among methadone patients in a randomized control trial with standard care as the control condition.

  13. Prolonged Hypocalcemic Effect by Pulmonary Delivery of Calcitonin Loaded Poly(Methyl Vinyl Ether Maleic Acid) Bioadhesive Nanoparticles

    PubMed Central

    Varshosaz, J.; Minaiyan, M.; Forghanian, M.

    2014-01-01

    The purpose of the present study was to design a pulmonary controlled release system of salmon calcitonin (sCT). Therefore, poly(methyl vinyl ether maleic acid) [P(MVEMA)] nanoparticles were prepared by ionic cross-linking method using Fe2+ and Zn2+ ions. Physicochemical properties of nanoparticles were studied in vitro. The stability of sCT in the optimized nanoparticles was studied by electrophoretic gel method. Plasma calcium levels until 48 h were determined in rats as pulmonary-free sCT solution or nanoparticles (25 μg·kg−1), iv solution of sCT (5 μg·kg−1), and pulmonary blank nanoparticles. The drug remained stable during fabrication and tests on nanoparticles. The optimized nanoparticles showed proper physicochemical properties. Normalized reduction of plasma calcium levels was at least 2.76 times higher in pulmonary sCT nanoparticles compared to free solution. The duration of hypocalcemic effect of pulmonary sCT nanoparticles was 24 h, while it was just 1 h for the iv solution. There was not any significant difference between normalized blood calcium levels reduction in pulmonary drug solution and iv injection. Pharmacological activity of nanoparticles after pulmonary delivery was 65% of the iv route. Pulmonary delivery of P(MVEMA) nanoparticles of sCT enhanced and prolonged the hypocalcemic effect of the drug significantly. PMID:24701588

  14. [The formulation aspects of drug liberation].

    PubMed

    Rácz, I

    1993-05-01

    Author raised problems and showed through research data some simple possibilities to achieve controlled release drug liberation. The dosage form developed during drug formulation work may influence the biological effects exerted by the active ingredients and therefore may alter the therapeutic efficacy, too. The dosage from itself includes all the chemical properties of active ingredients (salt-, ester form, polar-apolar material etc.), the physical state (crystal, amorphous, polymorphous, particle size, surface area, solvated state etc.), the value of stability and the parameters of auxiliary materials and manufacturing processes. The aim of formulation -among others-is to achieve the optimal liberation and bioavailability of drugs. The article reviews the possibilities through examples (theophylline, nitrofurantoin, phenacetin, antacids) how to make production prescriptions with high reproducibility used for the preparation of prolonged action systems with controlled release drug liberation.

  15. Use of formal and informal care among people with prolonged fatigue: a review of the literature.

    PubMed Central

    Elliott, H

    1999-01-01

    Prolonged fatigue is a common symptom in the community and a common complaint in GPs' surgeries. The current consensus is that prolonged fatigue is most appropriately managed within primary care but that quality of care is patchy. Diagnosis is difficult and there is no conclusive evidence about effective treatment. This can lead to confusion and controversy among lay people and health professionals alike. Although the value of a positive doctor-patient relationship is emphasized, general practice consultations are frequently experienced as difficult by both parties. Moreover, little is known about how people access other sources of care and information about prolonged fatigue, such as alternative medicine, self-help groups, lay others, and self care, in conjunction with or as an alternative to care from health professionals. This paper reviews the literature on the nature and extent of the problem prolonged fatigue represents for primary care, and on the use of formal and informal care for prolonged fatigue. PMID:10326269

  16. Drug dependence

    MedlinePlus

    ... starts using drugs to try to self-treat mental illness. Support Groups Many support groups are available in ... American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Arlington, VA: American Psychiatric Publishing. 2013. ...

  17. Drug Facts

    MedlinePlus Videos and Cool Tools

    ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth ( ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  18. Drug abuse

    MedlinePlus

    ... 5th ed. Arlington, VA: American Psychiatric Publishing. 2013. Weiss RD. Drugs of abuse. In: Goldman L, ... Hospice and Palliative Medicine, Atlanta, GA. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the ...

  19. Study Drugs

    MedlinePlus

    ... may have withdrawal symptoms like depression, thoughts of suicide, intense drug cravings, sleep problems, and fatigue. The ... some proven ways to boost concentration and beat stress: Meditation . Even a few minutes of meditation each ...

  20. Drug-drug interactions: antiretroviral drugs and recreational drugs.

    PubMed

    Staltari, Orietta; Leporini, Christian; Caroleo, Benedetto; Russo, Emilio; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2014-01-01

    With the advances in antiretroviral (ARV) therapy, patients with Human Immunodeficiency Virus (HIV) infection are living longer, however, some patients encounter co- morbidities which sometimes require treatment. Therefore, during the treatment with ARV drugs these patients could take several recreational drugs (e.g. amphetamines, hallucinogenes, opiates, or alcohol) with a possible development of drug-drug interactions (DDIs). In particular, Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are mainly excreted through the kidney and are not substrates of the cytochrome P450 or P-glycoprotein, therefore the DDIs during this treatment are minimal. In contrast, the other ARV drugs (i.e. non-nucleoside reversetranscriptase inhibitors, Protease inhibitors, Integrase inhibitors, chemokine receptor 5 antagonists and HIV-fusion inhibitors) are an important class of antiretroviral medications that are frequent components of HAART regimens but show several DDIs related to interaction with the cytochrome P450 or P-glycoprotein. In this paper we will review data concerning the possibility of DDI in HIV patients treated with ARV and taking recreational drugs.

  1. Causes of Death Associated With Prolonged TV Viewing

    PubMed Central

    Keadle, Sarah K.; Moore, Steven C.; Sampson, Joshua N.; Xiao, Qian; Albanes, Demetrius; Matthews, Charles E.

    2015-01-01

    Introduction TV viewing is the most prevalent sedentary behavior and is associated with increased risk of cardiovascular disease and cancer mortality, but the association with other leading causes of death is unknown. This study examined the association between TV viewing and leading causes of death in the U.S. Methods A prospective cohort of 221,426 individuals (57% male) aged 50–71 years who were free of chronic disease at baseline (1995–1996), 93% white, with an average BMI of 26.7 (SD=4.4) kg/m2 were included. Participants self-reported TV viewing at baseline and were followed until death or December 31, 2011. Hazard ratios (HRs) and 95% CIs for TV viewing and cause-specific mortality were estimated using Cox proportional hazards regression. Analyses were conducted in 2014–2015. Results After an average follow-up of 14.1 years, adjusted mortality risk for a 2-hour/day increase in TV viewing was significantly higher for the following causes of death (HR [95% CI]): cancer (1.07 [1.03, 1.11); heart disease (1.23 [1.17, 1.29]); chronic obstructive pulmonary disease (1.28 [1.14, 1.43]); diabetes (1.56 [1.33, 1.83]); influenza/pneumonia (1.24 [1.02, 1.50]); Parkinson disease (1.35 [1.11, 1.65]); liver disease (1.33 [1.05, 1.67]); and suicide (1.43 [1.10, 1.85]. Mortality associations persisted in stratified analyses with important potential confounders, reducing causation concerns. Conclusions This study shows the breadth of mortality outcomes associated with prolonged TV viewing, and identifies novel associations for several leading causes of death. TV viewing is a prevalent discretionary behavior that may be a more important target for public health intervention than previously recognized. Trial Registration ClinicalTrials.gov number, NCT00340015 PMID:26215832

  2. Prolonged Culture of Aligned Skeletal Myotubes on Micromolded Gelatin Hydrogels

    PubMed Central

    Bettadapur, Archana; Suh, Gio C.; Geisse, Nicholas A.; Wang, Evelyn R.; Hua, Clara; Huber, Holly A.; Viscio, Alyssa A.; Kim, Joon Young; Strickland, Julie B.; McCain, Megan L.

    2016-01-01

    In vitro models of skeletal muscle are critically needed to elucidate disease mechanisms, identify therapeutic targets, and test drugs pre-clinically. However, culturing skeletal muscle has been challenging due to myotube delamination from synthetic culture substrates approximately one week after initiating differentiation from myoblasts. In this study, we successfully maintained aligned skeletal myotubes differentiated from C2C12 mouse skeletal myoblasts for three weeks by utilizing micromolded (μmolded) gelatin hydrogels as culture substrates, which we thoroughly characterized using atomic force microscopy (AFM). Compared to polydimethylsiloxane (PDMS) microcontact printed (μprinted) with fibronectin (FN), cell adhesion on gelatin hydrogel constructs was significantly higher one week and three weeks after initiating differentiation. Delamination from FN-μprinted PDMS precluded robust detection of myotubes. Compared to a softer blend of PDMS μprinted with FN, myogenic index, myotube width, and myotube length on μmolded gelatin hydrogels was similar one week after initiating differentiation. However, three weeks after initiating differentiation, these parameters were significantly higher on μmolded gelatin hydrogels compared to FN-μprinted soft PDMS constructs. Similar results were observed on isotropic versions of each substrate, suggesting that these findings are independent of substrate patterning. Our platform enables novel studies into skeletal muscle development and disease and chronic drug testing in vitro. PMID:27350122

  3. Diazepam withdrawal syndrome: its prolonged and changing nature.

    PubMed Central

    Mellor, C. S.; Jain, V. K.

    1982-01-01

    The diazepam withdrawal syndrome was studied in 10 patients who had abused the drug for 3 to 14 years. In the previous 6 months their consumption of diazepam had ranged from 60 to 120 mg daily; none had used other drugs during this period. The withdrawal period lasted about 6 weeks. The intensity of the symptoms and signs was high initially, fell during the first 2 weeks, then rose again in the third week, before finally declining. Three groups of symptoms and signs were identified. Group A symptoms occurred throughout withdrawal and included tremor, anorexia, insomnia and myoclonus. Group B symptoms and signs were largely confined to the first 10 days and were those of a toxic psychosis. Group C symptoms reached a peak in the third and fourth weeks of withdrawal and were characterized by sense perceptions that were either heightened or lowered. The symptom groups, the presence of tremor and myoclonus, and the relief of symptoms by a test dose permit diazepam withdrawal to be distinguished from anxiety. The biphasic course of the symptoms is probably related to the pharmacokinetics of diazepam. PMID:7139456

  4. Prolonged Culture of Aligned Skeletal Myotubes on Micromolded Gelatin Hydrogels

    NASA Astrophysics Data System (ADS)

    Bettadapur, Archana; Suh, Gio C.; Geisse, Nicholas A.; Wang, Evelyn R.; Hua, Clara; Huber, Holly A.; Viscio, Alyssa A.; Kim, Joon Young; Strickland, Julie B.; McCain, Megan L.

    2016-06-01

    In vitro models of skeletal muscle are critically needed to elucidate disease mechanisms, identify therapeutic targets, and test drugs pre-clinically. However, culturing skeletal muscle has been challenging due to myotube delamination from synthetic culture substrates approximately one week after initiating differentiation from myoblasts. In this study, we successfully maintained aligned skeletal myotubes differentiated from C2C12 mouse skeletal myoblasts for three weeks by utilizing micromolded (μmolded) gelatin hydrogels as culture substrates, which we thoroughly characterized using atomic force microscopy (AFM). Compared to polydimethylsiloxane (PDMS) microcontact printed (μprinted) with fibronectin (FN), cell adhesion on gelatin hydrogel constructs was significantly higher one week and three weeks after initiating differentiation. Delamination from FN-μprinted PDMS precluded robust detection of myotubes. Compared to a softer blend of PDMS μprinted with FN, myogenic index, myotube width, and myotube length on μmolded gelatin hydrogels was similar one week after initiating differentiation. However, three weeks after initiating differentiation, these parameters were significantly higher on μmolded gelatin hydrogels compared to FN-μprinted soft PDMS constructs. Similar results were observed on isotropic versions of each substrate, suggesting that these findings are independent of substrate patterning. Our platform enables novel studies into skeletal muscle development and disease and chronic drug testing in vitro.

  5. [Possible ramifications of prolonged standing at the workplace and its association with the development of chronic venous insufficiency].

    PubMed

    Shai, Avi; Karakis, Isabella; Shemesh, David

    2007-09-01

    The issue of working conditions and their health ramifications have recently been raised on the public agenda in Israel with special emphasis on occupations requiring prolonged standing. This review article discusses the physiological and medical aspects of prolonged standing in the workplace. Searching the literature, 19 studies were found which specifically examined the effect of prolonged standing versus prolonged sitting at work. Most of these studies suggested that prolonged standing may result in the development and aggravation of chronic venous insufficiency. The association between prolonged standing and venous insufficiency was found to be more pronounced in women than in men.

  6. CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation.

    PubMed

    Kumar, Yingying; Kung, Simon; Shinozaki, Gen

    2014-12-01

    Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects.

  7. Injectable microparticle-gel system for prolonged and localized lidocaine release. II. In vivo anesthetic effects.

    PubMed

    Chen, Pen-Chung; Kohane, Daniel S; Park, Yoon Jeong; Bartlett, Robert H; Langer, Robert; Yang, Victor C

    2004-09-01

    Current treatment protocols for postoperative pain are beset by either the short duration of the anesthetic effect or requirement of hospitalization of the patients. We reported herein a novel treatment by applying to the surgical site a biodegradable microparticle-gel system for prolonged and localized release of encapsulated anesthetic drugs. In a previous publication, lidocaine-loaded poly(D,L-lactic acid) microspheres were fabricated and their formulations were optimized. In vitro characterization of these lidocaine-loaded microspheres, however, revealed a shortcoming of this system; that is, microspheres tend to fuse physically. Fusion of the microspheres could hinder their clinical applications, as it would clog the needle. In this article, we demonstrated that fabricating microspheres with high molecular weight (approximately 60 KDa) poly(lactic-co-glycolic acid) would increase the glass transition temperature of the microspheres after lidocaine loading, thereby increasing their mechanical stability and eliminating their fusion during storage. Such microspheres containing 31% (w/w) lidocaine in the presence or absence of 25% (w/v) poloxamer 407 gel were then evaluated in vivo by monitoring the sensory and motor functions of the rats after sciatic nerve block, using the previously established hot-plate and weight-bearing testing methods. Results showed that microspheres formulated with poloxamer 407 gel yielded the longest duration of sensory and motor block for a period of approximately 8.5 h, compared to 5 h by microspheres in saline, 5 h by lidocaine in poloxamer 407 gel, and 2 h by lidocaine in saline. This study suggests that the microsphere-gel system containing lidocaine could potentially be applied clinically to the treatment of postoperative pain.

  8. Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats

    PubMed Central

    Eagle, Andrew L.; Singh, Robby; Kohler, Robert J.; Friedman, Amy L.; Liebowitz, Chelsea P.; Galloway, Matthew P.; Enman, Nicole M.; Jutkiewicz, Emily M.; Perrine, Shane A.

    2017-01-01

    Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague–Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0,10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, asexpected. However, compared to control ratson Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. PMID:25712697

  9. Intractable restless legs syndrome: role of prolonged-release oxycodone–naloxone

    PubMed Central

    de Biase, Stefano; Valente, Mariarosaria; Gigli, Gian Luigi

    2016-01-01

    Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs accompanied by uncomfortable sensations that occur at night or at time of rest. Pharmacological therapy should be limited to patients who suffer from clinically relevant symptoms. Chronic RLS is usually treated with either a dopamine agonist (pramipexole, ropinirole, rotigotine) or an α2δ calcium-channel ligand (gabapentin, gabapentin enacarbil, pregabalin). Augmentation is the main complication of long-term dopaminergic treatment, and frequently requires a reduction of current dopaminergic dose or a switch to non-dopaminergic medications. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a recent Phase III trial, oxycodone–naloxone prolonged release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatments. The adverse-event profile was consistent with the safety profile of opioids. The most frequent adverse events were fatigue, constipation, nausea, headache, hyperhidrosis, somnolence, dry mouth, and pruritus. Adverse events were usually mild or moderate in intensity. No cases of augmentation were reported. Oxycodone–naloxone PR is approved for the second-line symptomatic treatment of adults with severe to very severe idiopathic RLS after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone–naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and α2δ ligands are needed. PMID:26966363

  10. Adolescent pre-exposure to ethanol or MDMA prolongs the conditioned rewarding effects of MDMA.

    PubMed

    Do Couto, B Ribeiro; Rodríguez-Arias, M; Fuentes, S; Gagliano, H; Armario, A; Miñarro, J; Aguilar, M A

    2011-07-06

    Adolescents often take ethanol (EtOH) in combination with MDMA (3,4-methylenedioxymethylamphetamine). In the present work we studied the effect of repeated intermittent adolescent pre-exposure to both drugs on the behavioral and neurochemical effects of MDMA in mice. Sixteen days after pre-treatment, the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm were evaluated, along with the levels of biogenic amines, basal motor activity and corticosterone response to different challenges. Pre-exposure to EtOH, MDMA or EtOH+MDMA did not affect the CPP induced by 10mg/kg of MDMA. However, adolescent exposure to EtOH or MDMA increased the duration of the conditioned rewarding effects of MDMA. Following extinction of the CPP, a priming dose of 5mg/kg of MDMA elicited reinstatement in all the groups, with the duration of this reinstated CPP being longer in mice pre-treated with MDMA. After reinstatement, an increase in monoamine levels was observed in mice pre-exposed to EtOH (DA, DOPAC and 5-HT in the striatum and 5-HIAA in the cortex and hippocampus) or MDMA (5-HT in the hippocampus). Basal motor activity and basal levels of corticosterone were not affected by any of these pre-treatments, but the group pre-exposed to MDMA showed higher levels of corticosterone in response to the administration of 10mg/kg of MDMA. Behavioral and hormonal effects of adolescent exposure to MDMA were reversed by co-administration of EtOH. Our results suggest that exposure to EtOH or MDMA during adolescence prolongs the rewarding properties of MDMA.

  11. Prolonged reduction of motion sickness sensitivity by visual-vestibular interaction

    PubMed Central

    Raphan, Ted; Cohen, Bernard

    2011-01-01

    The angular vestibulo-ocular reflex (aVOR) and optokinetic nystagmus (OKN) were elicited simultaneously at low frequencies to study effects of habituation of the velocity storage time constant in the vestibular system on motion sickness. Twenty-nine subjects, eleven of whom were susceptible to motion sickness from common transportation, were habituated by sinusoidal rotation at 0.017 Hz at peak velocities from 5 to 20°/s, while they watched a full-field OKN stimulus. The OKN stripes rotated in the same direction and at the same frequency as the subjects, but at a higher velocity. This produced an OKN opposite in direction to the aVOR response. Motion sickness sensitivity was evaluated with off-vertical axis rotation (OVAR) and by the response to transportation before and after 5 days of visual-vestibular habituation. Habituation did not induce motion sickness or change the aVOR gains, but it shortened the vestibular time constants in all subjects. This greatly reduced motion sickness produced by OVAR and sensitivity to common transport in the motion susceptible subjects, which persisted for up to 18 weeks. Two motion susceptible subjects who only had aVOR/OKN habituation without being tested with OVAR also became asymptomatic. Normal subjects who were not habituated had no reduction in either their aVOR time constants or motion sickness sensitivity. The opposing aVOR/OKN stimulation, which has not been studied before, was well tolerated, and for the first time was an effective technique for rapid and prolonged habituation of motion sickness without exposure to drugs or other nauseating habituation stimuli. PMID:21287155

  12. Survey of colourings and preservatives in drugs.

    PubMed Central

    Pollock, I.; Young, E.; Stoneham, M.; Slater, N.; Wilkinson, J. D.; Warner, J. O.

    1989-01-01

    OBJECTIVE--To assess the prevalence of colourings and preservatives in drug formulations in the United Kingdom. DESIGN--Postal survey. PARTICIPANTS--All pharmaceutical manufacturers in the United Kingdom were requested to supply data on drug formulations with particular regard to the content of colourings and preservatives. MAIN OUTCOME MEASURE--Prevalence in proprietary drugs of colourings or preservatives, or both, that have been implicated in adverse reactions. Computation of a list of formulations of bronchodilators, antihistamines, and antibiotics that are free of such additives. RESULTS--A total of 118 out of 120 pharmaceutical companies supplied the data requested. In all, 2204 drug formulations were analysed and found to contain 419 different additives, of which 52 were colourings and preservatives that have been implicated in adverse reactions; 930 formulations contained such an additive. Tartrazine was the fourth most commonly occurring colouring, being present in 124 drug formulations. CONCLUSION--Many drugs contain additives that help to identify them and prolong their shelf life but are implicated in adverse reactions in some people. Some form of labelling of drug additives would enable these people to avoid drugs containing such additives. PMID:2508849

  13. Nanoparticles in the ocular drug delivery

    PubMed Central

    Zhou, Hong-Yan; Hao, Ji-Long; Wang, Shuang; Zheng, Yu; Zhang, Wen-Song

    2013-01-01

    Ocular drug transport barriers pose a challenge for drug delivery comprising the ocular surface epithelium, the tear film and internal barriers of the blood-aqueous and blood-retina barriers. Ocular drug delivery efficiency depends on the barriers and the clearance from the choroidal, conjunctival vessels and lymphatic. Traditional drug administration reduces the clinical efficacy especially for poor water soluble molecules and for the posterior segment of the eye. Nanoparticles (NPs) have been designed to overcome the barriers, increase the drug penetration at the target site and prolong the drug levels by few internals of drug administrations in lower doses without any toxicity compared to the conventional eye drops. With the aid of high specificity and multifunctionality, DNA NPs can be resulted in higher transfection efficiency for gene therapy. NPs could target at cornea, retina and choroid by surficial applications and intravitreal injection. This review is concerned with recent findings and applications of NPs drug delivery systems for the treatment of different eye diseases. PMID:23826539

  14. Development of a novel prolonged-release nicotine transdermal patch.

    PubMed

    Davaran, Soodabeh; Rashidi, Mohammad R; Khandaghi, Reza; Hashemi, Mahdi

    2005-03-01

    A transdermal patch for delivering nicotine for periods of 12-48h was designed. An inclusion complex formed between the nicotine and beta-cyclodextrine (beta-CD) was used in drug depot. The usefulness of a specially cross-linked polyvinyl alcohol (cross-PVA) membrane was investigated as a rate controlling membrane. The influence of carbopol polymers, type C-934P and C-940 and propylene glycol on transdermal permeation of nicotine through the rat skin was investigated. The results indicated a maximum flux of 42 microgcm(-2)h(-1) after 48 h from the patches made from C-934P when the propylene glycol concentration was 15% and the nicotine-beta-CD mole ratio in the inclusion complex was 3:1. These nicotine transdermal patches can be fabricated to obtain a controlled release, zero order systems.

  15. Detrimental role of prolonged sleep deprivation on adult neurogenesis

    PubMed Central

    Fernandes, Carina; Rocha, Nuno Barbosa F.; Rocha, Susana; Herrera-Solís, Andrea; Salas-Pacheco, José; García-García, Fabio; Murillo-Rodríguez, Eric; Yuan, Ti-Fei; Machado, Sergio; Arias-Carrión, Oscar

    2015-01-01

    Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis. PMID:25926773

  16. Symptom Severity Predicts Prolonged Recovery after Sport-Related Concussion: Age and Amnesia Do Not

    PubMed Central

    Meehan, William P.; Mannix, Rebekah C.; Stracciolini, Andrea; Elbin, R.J.; Collins, Michael W.

    2013-01-01

    Objective To identify predictors of prolonged symptoms for athletes who sustain concussions. Study design We conducted a multi-center, prospective, cohort study of patients in 2 sport concussion clinics. Possible predictors of prolonged symptoms from concussion were compared between two groups: those whose symptoms resolved within 28 days and those whose symptoms persisted beyond 28 days. Candidate predictor variables were entered into a logistic regression model that was used to generate adjusted odds ratios. Results During the study period, 182 patients met inclusion criteria. The mean age was 15.2 years (SD 3.04 years). Over a third (N=65) of patients underwent computerized neurocognitive testing on their initial visit. In univariate analyses, Post Concussion Symptom Scale (PCSS) score and all composite scores on computerized neurocognitive testing appeared to be associated with prolonged symptom duration. Sex, age, loss of consciousness at time of injury and amnesia at time of injury were not associated with prolonged symptom duration. After adjusting for potential confounding, however, only total score on the PCSS score was associated with the odds of suffering prolonged symptoms. Conclusions After adjusting for other potential confounding variables, only total score on the PCSS was associated with the odds of suffering prolonged symptoms from sport-related concussions; age and amnesia were not. Further efforts to develop clinical tools for predicting which athletes will suffer prolonged recoveries after concussion should focus on initial symptom score. PMID:23628374

  17. Prolonged bradycardia, asystole and outcome of high spinal cord injury patients: Risk factors and management

    PubMed Central

    Shaikh, Nissar; Rhaman, M. A.; Raza, Ali; Shabana, Adel; Malstrom, Mahommad Faisal; Al-Sulaiti, Ghanem

    2016-01-01

    Background: High spinal cord injury (HSCI) is one of the devastating traumatic injuries. 80% of these patients are young male, and 93% will have major neurological disabilities. There is a paucity of literature about prolonged bradycardia in HSCI patients. The aim of this study was to know the prevalence, risk factors, precipitating factors for prolonged bradycardia in the HSCI patients. Materials and Methods: All patients who were admitted to the Intensive Care Unit (ICU) of a tertiary hospital, with spinal cord injury above level of dorsal (D4) were enrolled in this study prospectively. Patient's demographic data, mechanism, level and type of spinal injury, associated injuries, injury severity score (ISS), spinal shock, vasopressors used, time of occurrence of bradycardia, treatment for bradycardia, precipitating as well as risk factors and outcome were recorded. Results: During the study period, a total of 138 patients were admitted to the ICU with HSCI. Majority of patients were male. The most frequently associated injury in these patients was skeletal fractures (38.4%). Most common complication was pneumonia 56 (41%). Forty-five (33%) of the total patients had prolonged bradycardia; 87% of these patients had pneumonia when bradycardia occurred. 53.4% had cardiac asystole. 29 (21%) patients had bradycardia at the time of endotracheal suctioning, whereas 27 (20%) patients developed bradycardia at the time of positioning. Majority of the patients were managed conservatively. Those HSCI patients who developed prolonged bradycardia, their ISS score was statistically higher, ICU and hospital stay was significantly higher compared with those HSCI patient who did not have prolonged bradycardia. Multivariate analysis revealed that hypotension on admission; pneumonia, and tracheostomy were risk factors for the development of prolonged bradycardia in HSCI patients. Conclusion: Prolonged bradycardia was associated with significantly higher incidence of asystole

  18. The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue

    PubMed Central

    Thein, Tun-Linn; Leo, Yee-Sin; Lye, David C.

    2016-01-01

    Dengue fever is gaining importance in Singapore with an increase in the number of cases and mortality in recent years. Although prolonged and saddleback fever have been reported in dengue fever, there are no specific studies on their significance in dengue. This study aims to examine the prevalence of prolonged and saddleback fever in dengue as well as their associations with dengue severity. A total of 2843 polymerase-chain reaction (PCR) confirmed dengue patients admitted to Tan Tock Seng Hospital from 2004 to 2008 were included in the study. Sixty-nine percent of them were male with a median age of 34 years. Prolonged fever (fever > 7 days duration) was present in 572 (20.1%) of patients. Dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and severe dengue (SD) were significantly more likely to occur in patients with prolonged fever. Mucosal bleeding, anorexia, diarrhea, abdominal pain, nausea or vomiting, lethargy, rash, clinical fluid accumulation, hepatomegaly, nosocomial infection, leukopenia, higher neutrophil count, higher hematocrit, higher alanine transaminase (ALT) and aspartate transaminase (AST), higher creatinine, lower protein and prolonged activated partial thromboplastin time (APTT) were significantly associated with prolonged fever but not platelet count or prothrombin time (PT). Saddleback fever was present in 165 (5.8%). Although DHF and SD were more likely to occur in patients in those with saddleback fever, DSS was not. Compared with prolonged fever, saddleback fever did not show many significant associations except for diarrhea, abdominal pain, clinical fluid accumulation, hematocrit and platelet change, and lower systolic blood pressure. This study demonstrates that prolonged fever may be associated with various warning signs and more severe forms of dengue (SD, DSS, DHF), while saddleback fever showed associations with DHF and SD but not DSS. The presence of prolonged or saddleback fever in dengue patients should therefore prompt

  19. Population-Based Study of QT Interval Prolongation in Patients with Rheumatoid Arthritis

    PubMed Central

    Chauhan, Krati; Ackerman, Michael J.; Crowson, Cynthia S.; Matteson, Eric L.; Gabriel, Sherine E.

    2015-01-01

    Background Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular morbidity and mortality. Heart rate corrected QT interval (QTc) (which is obtained from a 12-lead electrocardiogram (ECG) and reflects ventricular repolarization duration) is a strong predictor of cardiovascular mortality. Our primary purpose is to determine the impact of QTc prolongation on mortality in RA patients. Methods A population-based inception cohort of patients with RA fulfilling 1987 ACR criteria in 1988–2007 was identified, with an age- and sex-matched comparison cohort and followed until death, migration or 12-31-2008. Data were collected on ECG variables, medications known to prolong QT interval, electrolytes, cardiovascular risk factors and disease status and RA disease characteristics. Cox proportional hazards models were used to examine QTc prolongation as predictor of mortality. Results QTc prolongation prior to RA incidence/index date was similar in RA (15%) and non-RA (18%) subjects. During follow-up, the cumulative incidence of QTc prolongation was higher among RA (48% at 20 years after RA incidence) than non-RA (38% at 20 years after index date; p= 0.004). Idiopathic QTc prolongation (excluding prolongations explained by ECG changes, medications, etc.) was marginally associated with all-cause mortality (HR: 1.28; 95% CI: 0.91–1.81, p=0.16), but was not associated with cardiovascular mortality (HR: 1.10; 95% CI:0.43–2.86, p= 0.83) in RA. Conclusion RA patients have a significantly elevated risk of developing QTc prolongation. However, idiopathic prolonged QTc was only marginally associated with all-cause mortality in RA patients. The clinical implications of these findings in RA require further study. PMID:25572282

  20. Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin.

    PubMed

    Hajak, Göran; Lemme, Kathrin; Zisapel, Nava

    2015-01-01

    Surveillance studies are useful to evaluate how a new medicinal product performs in everyday treatment and how the patient who takes it feels and functions, thereby determining the benefit/risk ratio of the drug under real-life conditions. Prolonged-release melatonin (PRM; Circadin) was approved in Europe for the management of primary insomnia patients age 55 years or older suffering from poor quality of sleep. With traditional hypnotics (e.g. benzodiazepine-receptor agonists), there are concerns about rebound insomnia and/or withdrawal symptoms. We report data from a postmarketing surveillance study in Germany on the effects of 3 weeks of treatment with PRM on sleep in patients with insomnia during treatment and at early (1-2 days) and late (around 2 weeks) withdrawal. In total, 653 patients (597 evaluable) were recruited at 204 sites (mean age 62.7 years, 68% previously treated with hypnotics, 65% women). With PRM treatment, the mean sleep quality (on a scale of 1-5 on which 1 is very good and 5 is very bad) improved from 4.2 to 2.6 and morning alertness improved from 4.0 to 2.5. The improvements persisted over the post-treatment observation period. Rebound insomnia, defined as a one-point deterioration in sleep quality below baseline values, was found in 3.2% (early withdrawal) and 2.0% (late withdrawal). Most of the patients (77%) who used traditional hypnotics before PRM treatment had stopped using them and only 5.6% of naive patients started such drugs after PRM discontinuation. PRM was well tolerated during treatment and the most frequently reported adverse events were nausea (10 patients, 1.5%), dizziness, restlessness and headache (five patients each, <1%). There were no serious adverse events and no adverse events were reported after discontinuation. The persisting treatment effect and very low rebound rate suggest a beneficial role of sleep-wake cycle stabilization with PRM in the treatment of insomnia.

  1. Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin

    PubMed Central

    Hajak, Göran; Lemme, Kathrin

    2015-01-01

    Surveillance studies are useful to evaluate how a new medicinal product performs in everyday treatment and how the patient who takes it feels and functions, thereby determining the benefit/risk ratio of the drug under real-life conditions. Prolonged-release melatonin (PRM; Circadin) was approved in Europe for the management of primary insomnia patients age 55 years or older suffering from poor quality of sleep. With traditional hypnotics (e.g. benzodiazepine-receptor agonists), there are concerns about rebound insomnia and/or withdrawal symptoms. We report data from a postmarketing surveillance study in Germany on the effects of 3 weeks of treatment with PRM on sleep in patients with insomnia during treatment and at early (1–2 days) and late (around 2 weeks) withdrawal. In total, 653 patients (597 evaluable) were recruited at 204 sites (mean age 62.7 years, 68% previously treated with hypnotics, 65% women). With PRM treatment, the mean sleep quality (on a scale of 1–5 on which 1 is very good and 5 is very bad) improved from 4.2 to 2.6 and morning alertness improved from 4.0 to 2.5. The improvements persisted over the post-treatment observation period. Rebound insomnia, defined as a one-point deterioration in sleep quality below baseline values, was found in 3.2% (early withdrawal) and 2.0% (late withdrawal). Most of the patients (77%) who used traditional hypnotics before PRM treatment had stopped using them and only 5.6% of naive patients started such drugs after PRM discontinuation. PRM was well tolerated during treatment and the most frequently reported adverse events were nausea (10 patients, 1.5%), dizziness, restlessness and headache (five patients each, <1%). There were no serious adverse events and no adverse events were reported after discontinuation. The persisting treatment effect and very low rebound rate suggest a beneficial role of sleep–wake cycle stabilization with PRM in the treatment of insomnia. PMID:25054634

  2. Sleep-prolonging effect of Coriandrum sativum hydro-alcoholic extract in mice.

    PubMed

    Rakhshandeh, Hassan; Sadeghnia, Hamid Reza; Ghorbani, Ahmad

    2012-01-01

    The present study was planned to investigate sleep-prolonging effect of C. sativum. The hydro-alcoholic extract (HAE) and its three fractions namely water (WF), ethyl acetate (EAF) and N-butanol (NBF) were prepared from C. sativum aerial parts and administrated to mice. Also, the possible cytotoxicity of the extracts was tested using cultured PC12 cells. The HAE, EAF and NBF significantly prolonged sleep duration. Only the NBF could significantly decrease sleep latency. No decrease in the neuronal surviving was observed either by HAE or by its fractions. The present data indicate that C. sativum exert sleep-prolonging action without major neurotoxic effect.

  3. Drug watch.

    PubMed

    Whitson, S

    1999-01-01

    Recent developments on new anti-HIV agents and drugs for opportunistic infections are highlighted. Information is provided on the infusion inhibitor T-20; DuPont's second generation non-nukes, DPC 961 and DPC 963; Papirine (PEN203) for the human papilloma virus; Sporanox for treating fungal infections; and the antiretroviral protein, lysozyme. In addition, information is given on a plant found in the Bolivian rainforest that may contain compounds to prevent HIV infection by blocking the enzyme, integrase. Other promising new drugs addressed at the 6th Conference on Retroviruses and Opportunistic Infections are listed in a table. Contact information for US clinical trials is provided.

  4. Effect of long-term phenothiazine treatment on drug metabolism.

    PubMed Central

    Kolakowska, T; Franklin, M; Alapin, B

    1975-01-01

    1 The half-life of plasma antipyrine was measured in twelve chronic schizophrenic patients during long-term phenothiazine treatment and again following 4-5 weeks on placebo. 2 The mean antipyrine half-life was low during phenothiazine administration (6.1 +/- 4.2 h), rising after withdrawal of drugs to the range reported for untreated subjects by other authors (9.5 +/- 4.2 h). The prolongation of antipyrine half-life following the drug-free period occurred in nine of twelve subjects and the difference was significant for the group at P less than 0.05. 3 The finding suggests that prolonged administration of phenothiazines stimulates the rate of drug metabolism. PMID:1234485

  5. Sudden cardiac death secondary to antidepressant and antipsychotic drugs.

    PubMed

    Sicouri, Serge; Antzelevitch, Charles

    2008-03-01

    A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use.

  6. Antineoplastic Drugs.

    ERIC Educational Resources Information Center

    Morris, Sara; Michael, Nancy, Ed.

    This module on antineoplastic drugs is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  7. Club Drugs

    MedlinePlus

    ... Drug Gamma-hydroxybutyrate (GHB), also known as G, Liquid Ecstasy, and Soap Ketamine, also known as Special K, K, Vitamin K, and Jet Rohypnol, also known as Roofies Methamphetamine, also known as Speed, Ice, Chalk, Meth, Crystal, Crank, and Glass Lysergic Acid Diethylamide (LSD), also ...

  8. Promazine and chlorpromazine for prolonged spinal anesthesia in rats.

    PubMed

    Chen, Yu-Wen; Chu, Chin-Chen; Chen, Yu-Chung; Kan, Chung-Dann; Wang, Jhi-Joung

    2012-07-19

    Though promazine and chlorpromazine elicited cutaneous anesthesia, no study of spinal anesthesia with chlorpromazine and promazine has been reported. This study was to examine whether chlorpromazine and promazine produce spinal anesthesia. Using a rat model via intrathecal injection, we tested spinal blockades of motor function and nociception by promazine, chlorpromazine or bupivacaine, and so were dose-response studies and durations. We demonstrated that chlorpromazine and promazine elicited dose-dependent spinal blockades in motor function and nociception. On the 50% effective dose (ED(50)) basis, the rank of potency of these drugs was bupivacaine>promazine>chlorpromazine (P<0.05 for the differences). On an equipotent basis (25% effective dose [ED(25)], ED(50), and ED(75)), the block duration caused by chlorpromazine or promazine was longer than that caused by the long-lasting local anesthetic bupivacaine (P<0.01 for the differences). Chlorpromazine and promazine, as well as bupivacaine, showed longer duration of sensory block than that of motor block. Our data reported that intrathecal promazine and chlorpromazine with a more sensory-selective action over motor blockade had less potent and longer-lasting spinal blockades when compared with bupivacaine.

  9. Some features of the bioelectric activity of the muscles with prolonged hypokinesia

    NASA Technical Reports Server (NTRS)

    Belaya, N. A.; Amirov, R. Z.; Shaposhnikov, Y. A.; Lebedeva, I. P.; Sologub, B. S.

    1978-01-01

    The effects of prolonged hypokinesia, brought on by confinement to bed and the attendant lack of motor activity, on the bioelectric activity of muscles are studied. Electromyographic measurements of amplitude and frequency indicators of muscular bioelectric activity were analyzed.

  10. The Mind-Body Connection - Can Prolonged Stress Affect Whether Breast Cancer Returns?

    MedlinePlus

    ... Past Issues The Mind-Body Connection Can Prolonged Stress Affect Whether Breast Cancer Returns? Past Issues / Winter ... traumatic life events. The categories ranged from traumatic stress to some stress to no significant stress. According ...

  11. Underutilization of Mental Health Services Among Bereaved Caregivers With Prolonged Grief Disorder

    PubMed Central

    Lichtenthal, Wendy G.; Nilsson, Matthew; Kissane, David W.; Breitbart, William; Kacel, Elizabeth; Jones, Eric C.; Prigerson, Holly G.

    2013-01-01

    Objective This study examined grief and mental health service use among 86 bereaved caregivers of advanced cancer patients. Methods Caregivers were assessed before (median=3.1 months) and after (median=6.6 months) patients’ deaths for prolonged grief disorder, axis I psychiatric disorders, mental health service use, suicidality, and health-related quality of life. Results Sixteen percent of the bereaved sample met criteria for prolonged grief disorder, which was significantly associated with suicidality and poorer health-related quality of life, but not with mental health service use. The majority of bereaved caregivers with prolonged grief disorder did not access mental health services. In multivariable analyses, having discussed psychological concerns with a health care professional when the patient was ill was the only significant predictor of mental health service use during bereavement. Conclusions Because bereaved caregivers with prolonged grief disorder underutilize mental health services, connecting them with services while the patient is still alive may be beneficial. PMID:21969652

  12. Prolonged oculogyric crisis on addition of nifedipine to neuroleptic medication regime.

    PubMed

    Singh, I

    1987-01-01

    Extrapyramidal symptoms, including oculogyric crisis, are well recognised side-effects of clopenthixol medication, but precipitation of prolonged oculogyric crisis on addition of nifedipine to an ongoing clopenthixol regime has not so far been reported.

  13. Resuscitation of prolonged cardiac arrest from massive pulmonary embolism by extracorporeal membrane oxygenation.

    PubMed

    Kim, Yun Seok; Choi, Wookjin; Hwang, Jaecheol

    2017-01-10

    Extracorporeal cardiopulmonary resuscitation can be used as a rescue strategy in cases of prolonged cardiac arrest caused by massive pulmonary embolism. We present a case of a male patient who was in prolonged cardiac arrest following massive pulmonary embolism. Veno-arterial extracorporeal membrane oxygenation was initiated approximately 93 min after prolonged cardiopulmonary resuscitation. After resuscitation, bedside echocardiography and a chest computed tomography angiogram revealed a massive pulmonary embolism during extracorporeal membrane oxygenation support. The patient received transcatheter mechanical thrombectomy without haemodynamic instability in extracorporeal membrane oxygenation support. He was also treated with therapeutic hypothermia to improve neurological outcome. Renal replacement therapy for acute kidney injury was continued for 36 days. The patient was discharged at 60 days after admission with no serious complications. This case demonstrates that veno-arterial extracorporeal membrane oxygenation and therapeutic hypothermia are an effective treatment strategy for prolonged cardiac arrest caused by massive pulmonary embolism.

  14. A review on proniosomal drug delivery system for targeted drug action

    PubMed Central

    Radha, G. V.; Rani, T. Sudha; Sarvani, B.

    2013-01-01

    Proniosomes are dry formulation of water soluble carrier particles that are coated with surfactant. They are rehydrated to form niosomal dispersion immediately before use on agitation in hot aqueous media within minutes. Proniosomes are physically stable during the storage and transport. Drug encapsulated in the vesicular structure of proniosomes prolong the existence of drug in the systematic circulation and enhances the penetration into target tissue and reduce toxicity. From a technical point of view, niosomes are promising drug carriers as they possess greater chemical stability and lack of many disadvantages associated with liposomes, such as high- cost and variable purity problems of phospholipids. The present review emphasizes on overall methods of preparation characterization and applicability of proniosomes in targeted drug action. PMID:24808669

  15. Transporter-mediated drug-drug interactions.

    PubMed

    Müller, Fabian; Fromm, Martin F

    2011-07-01

    Drug-drug interactions are a serious clinical issue. An important mechanism underlying drug-drug interactions is induction or inhibition of drug transporters that mediate the cellular uptake and efflux of xenobiotics. Especially drug transporters of the small intestine, liver and kidney are major determinants of the pharmacokinetic profile of drugs. Transporter-mediated drug-drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. In this article, we focus on probe drugs lacking significant metabolism to highlight mechanisms of interactions of selected intestinal, hepatic and renal drug transporters (e.g., organic anion transporting polypeptide [OATP] 1A2, OATP2B1, OATP1B1, OATP1B3, P-gp, organic anion transporter [OAT] 1, OAT3, breast cancer resistance protein [BCRP], organic cation transporter [OCT] 2 and multidrug and toxin extrusion protein [MATE] 1). Genotype-dependent drug-drug interactions are also discussed.

  16. Development of a prolonged-release gastroretentive tablet formulation of ciprofloxacin hydrochloride: pharmacokinetic characterization in healthy human volunteers.

    PubMed

    Mostafavi, Abolfazl; Emami, Jaber; Varshosaz, Jaleh; Davies, Neal M; Rezazadeh, Mahboubeh

    2011-05-16

    The fluroquinolone anti-biotic ciprofloxacin is primarily dissolved and absorbed from the upper part of the GI tract. We, therefore, aimed to develop a prolonged release gastroretentive (GT) formulation of ciprofloxacin that could be administered once daily with a conventional tablet (CT). A variety of polymers and effervescent properties were utilized to optimize the desired disposition profile. Tablets were prepared by the direct compression technique and evaluated for physical properties, swelling, floating, and drug release. In vivo studies were also carried out on the optimized GT formulation and CT in healthy volunteers. A very sensitive and reliable HPLC method was developed to measure plasma concentration of ciprofloxacin. The duration of floating times were predominantly >24 h and floating lag times <20 s. The drug release mechanism followed zero order kinetics. C(max), T(max), and AUC(0-∞) of GT vs CT were 0.945±0.29 vs 2.1±0.46 μg/ml, 6.0±1.42 vs 1.42±0.59 h and 8.54±1.87 vs 9.45±2.12 μg/ml/h, respectively. Pharmacokinetic parameters indicate that the developed GT formulation extended the pharmacokinetic profile achieved with CT. The C(max)/MIC and AUC(0-∞)/MIC, which are indicative of eradication of pathogens, following co-administration of GT with CT were comparable to those of twice-daily administration of CT alone.

  17. The molecular basis for the prolonged blood circulation of lipidated incretin peptides: Peptide oligomerization or binding to serum albumin?

    PubMed

    Wang, Ying; Lomakin, Aleksey; Kanai, Sonoko; Alex, Rainer; Belli, Sara; Donzelli, Massimiliano; Benedek, George B

    2016-11-10

    Hybrid incretin peptides are a new generation of drugs for the treatment of diabetes and obesity. Despite their biological potency, the effectiveness of these peptides as drugs is limited by their short circulation time in blood (typically within minutes). In this work, we show that lipid conjugated forms of a GLP-1/GIP/glucagon hybrid peptides stay in circulation for hours. We studied the oligomerization and albumin-binding of the unconjugated hybrid peptide as well as its lipidated variants. These lipidated peptides differ in the N-terminal mutation, the position of lipidation and the linkage to lipid. We found that these lipidated peptides form stable oligomers at concentrations above 1mg/mL. This concentration range is relevant to formulation and storage of the peptides. We observed no binding between the peptide oligomers and human serum albumin. However, at the expected therapeutic concentration range (~10-100ng/mL), the oligomers dissociate into monomers. The monomers of lipidated peptides bind to albumin. We have determined the dissociation constants of binding between the lipidated peptides and serum albumin. The dissociation constants of albumin-binding of our lipidated peptides are all very close and similar to that of the fatty acid binding of albumin. Our findings suggest that the monomeric lipidated peptides bind to HSA mainly by the fatty acid chain. Therefore, albumin binding is likely to be a universal mechanism of the prolonged circulating duration of lipidated pharmaceutical peptides.

  18. Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice

    PubMed Central

    Lee, Amy S.; Brandhorst, Sebastian; Rangel, Daisy F.; Navarrete, Gerardo; Cohen, Pinchas; Longo, Valter D.; Chen, Jeannie; Groshen, Susan; Morgan, Todd E.; Dubeau, Louis

    2017-01-01

    GRP78, a multifunctional protein with potent cytoprotective properties, is an emerging therapeutic target to combat cancer development, progression and drug resistance. The biological consequences of prolonged reduction in expression of this essential chaperone which so far has been studied primarily in young mice, was investigated in older mice, as older individuals are likely to be important recipients of anti-GRP78 therapy. We followed cohorts of Grp78+/+ and Grp78+/− male and female mice up to 2 years of age in three different genetic backgrounds and characterized them with respect to body weight, organ integrity, behavioral and memory performance, cancer, inflammation and chemotoxic response. Our results reveal that body weight, organ development and integrity were not impaired in aged Grp78+/− mice. No significant effect on cancer incidence and inflammation was observed in aging mice. Interestingly, our studies detected some subtle differential trends between the WT and Grp78+/− mice in some test parameters dependent on gender and genetic background. Our studies provide the first evidence that GRP78 haploinsufficiency for up to 2 years of age has no major deleterious effect in rodents of different genetic background, supporting the merit of anti-GRP78 drugs in treatment of cancer and other diseases affecting the elderly. PMID:28145503

  19. Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice.

    PubMed

    Lee, Amy S; Brandhorst, Sebastian; Rangel, Daisy F; Navarrete, Gerardo; Cohen, Pinchas; Longo, Valter D; Chen, Jeannie; Groshen, Susan; Morgan, Todd E; Dubeau, Louis

    2017-02-01

    GRP78, a multifunctional protein with potent cytoprotective properties, is an emerging therapeutic target to combat cancer development, progression and drug resistance. The biological consequences of prolonged reduction in expression of this essential chaperone which so far has been studied primarily in young mice, was investigated in older mice, as older individuals are likely to be important recipients of anti-GRP78 therapy. We followed cohorts of Grp78(+/+) and Grp78(+/-) male and female mice up to 2 years of age in three different genetic backgrounds and characterized them with respect to body weight, organ integrity, behavioral and memory performance, cancer, inflammation and chemotoxic response. Our results reveal that body weight, organ development and integrity were not impaired in aged Grp78(+/-) mice. No significant effect on cancer incidence and inflammation was observed in aging mice. Interestingly, our studies detected some subtle differential trends between the WT and Grp78(+/-) mice in some test parameters dependent on gender and genetic background. Our studies provide the first evidence that GRP78 haploinsufficiency for up to 2 years of age has no major deleterious effect in rodents of different genetic background, supporting the merit of anti-GRP78 drugs in treatment of cancer and other diseases affecting the elderly.

  20. Treatment of Metformin Intoxication Complicated by Lactic Acidosis and Acute Kidney Injury: The Role of Prolonged Intermittent Hemodialysis.

    PubMed

    Regolisti, Giuseppe; Antoniotti, Riccardo; Fani, Filippo; Greco, Paolo; Fiaccadori, Enrico

    2017-02-17

    Metformin intoxication with lactic acidosis, a potentially lethal condition, may develop in diabetic patients when the drug dose is inappropriate and/or its clearance is reduced. Diagnosis and therapy may be delayed due to nonspecific symptoms at presentation, with severe anion gap metabolic acidosis and elevated serum creatinine values being the most prominent laboratory findings. Confirmation requires measurement of serum metformin by high-performance liquid chromatography-tandem mass spectrometry, but this technique is available only at specialized institutions and cannot be relied on as a guide to immediate treatment. Thus, based on strong clinical suspicion, renal replacement therapy must be started promptly to achieve efficient drug clearance and correct the metabolic acidosis. However, because metformin accumulates in the intracellular compartment with prolonged treatment, a rebound in serum concentrations due to redistribution is expected at the end of dialysis. We report a case of metformin intoxication, severe lactic acidosis, and acute kidney injury in a diabetic patient with pre-existing chronic kidney disease stage 3, treated effectively with sustained low-efficiency dialysis. We discuss the pathophysiology, differential diagnosis, and treatment options and highlight specific pharmacokinetic issues that should be considered in selecting the appropriate modality of renal replacement therapy.

  1. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

    PubMed

    Gharibian, Katherine N; Mueller, Bruce A

    2016-07-01

    Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

  2. A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience.

    PubMed

    Gallimore, Andrew R; Strassman, Rick J

    2016-01-01

    The state of consciousness induced by N,N-dimethyltryptamine (DMT) is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel "alternate universe," often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient "beings." The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects-less than 20 min-militates against single dose administration as the ideal model for such enquiry. Using pharmacokinetic modeling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion. This is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery. Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent.

  3. A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience

    PubMed Central

    Gallimore, Andrew R.; Strassman, Rick J.

    2016-01-01

    The state of consciousness induced by N,N-dimethyltryptamine (DMT) is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel “alternate universe,” often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient “beings.” The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects—less than 20 min—militates against single dose administration as the ideal model for such enquiry. Using pharmacokinetic modeling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion. This is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery. Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent. PMID:27471468

  4. In vitro and in vivo effects of promethazine (Phenergan) on drug metabolism.

    PubMed

    Fernandez, G; Castro, J A

    1978-02-01

    Prolongation effects of promethazine on the pentobarbital sleeping time are not due to interactions of this drug with cytochrome P-450 or cytochrome c reductase or inhibition of drug metabolism because pentobarbital plasma levels in promethazine treated animals before awakening are not different than in controls. Results suggest additive effects of both drugs on the central nervous system. Those interactions do however play a role during in vitro studies.

  5. A review of ropinirole prolonged release in Parkinson’s disease

    PubMed Central

    Nashatizadeh, Muhammad M; Lyons, Kelly E; Pahwa, Rajesh

    2009-01-01

    Ropinirole prolonged release is a once-daily, 24-hour formulation of ropinirole, a non-ergot dopamine agonist. It is approved as monotherapy and as an adjunct to levodopa in the treatment of Parkinson’s disease (PD). Several potential advantages of ropinirole prolonged release compared to the immediate release formulation include maintaining more consistent dopaminergic activity with steadier plasma levels, increased tolerability, greater compliance from a simpler once-daily dosing regimen and ease in dose titration. In a randomized, double-blind, non-inferiority, crossover study, ropinirole prolonged release was shown to have comparable efficacy and tolerability to immediate release ropinirole in early PD patients, with significantly greater compliance. Subjects were converted overnight between ropinirole formulations without loss of efficacy and with good tolerability. In a randomized, double-blind, placebo-controlled study in advanced PD, daily “off” time was reduced by an average of 2.1 hours with ropinirole prolonged release compared to 0.4 hours with placebo. Patients on ropinirole prolonged release were also more likely to require less daily levodopa. Ropinirole prolonged release is well tolerated with a similar adverse effect profile to other non-ergot dopamine agonists. The most common adverse effects include dyskinesia, nausea, dizziness, hallucinations, somnolence, abdominal pain or discomfort and orthostatic hypotension. Ropinirole prolonged release is a safe and effective treatment option for both early and advanced PD. This manuscript briefly reviews the current pharmacological treatment options for PD and provides a more detailed review of the currently available data regarding ropinirole prolonged release as a treatment option for PD. PMID:19503779

  6. Subtleties in practical application of prolonged infusion of β-lactam antibiotics.

    PubMed

    De Waele, Jan J; Lipman, Jeffrey; Carlier, Mieke; Roberts, Jason A

    2015-05-01

    Prolonged infusion (PI) of β-lactam antibiotics is increasingly used in order to optimise antibiotic exposure in critically ill patients. Physicians are often not aware of a number of subtleties that may jeopardise the treatment. In this clinically based paper, we stress pragmatic issues, such as the importance of a loading dose before PI, and discuss a number of important practicalities that are mandatory to benefit from the pharmacokinetic advantages of prolonged β-lactam antibiotic administration.

  7. Metronidazole-induced encephalopathy after prolonged metronidazole course for treatment of C. difficile colitis

    PubMed Central

    Godfrey, Mark S; Finn, Arkadiy; Zainah, Hadeel; Dapaah-Afriyie, Kwame

    2015-01-01

    A 65-year-old woman with a diagnosis of Clostridium difficile colitis undergoing prolonged treatment with metronidazole was admitted to hospital for altered mentation, slurred speech and weakness. She was diagnosed with metronidazole-induced encephalopathy, confirmed with brain MRI and improved when the offending agent was removed. This case report highlights encephalopathy as a complication of prolonged metronidazole treatment, which has become more common in clinical practice for the treatment of C. difficile infection. PMID:25596288

  8. Prolongation anormale d'un bloc fémoral analgésique: cas Clinique

    PubMed Central

    Koné, Joseph; Bensghir, Mustapha; Boutayeb, El Houcine; Haimeur, Charki

    2015-01-01

    La prolongation anormale d'un bloc nerveux peut être définie comme un dépassement du délai habituel de récupération sensitive ou motrice. A travers un cas clinique d'une prolongation anormale d'un bloc analgésique et une revue de la littérature, les auteurs discutent les facteurs de risque et les moyens de prévention de cette complication. PMID:26918085

  9. Implementation of Prolonged Exposure in the Army: Is Consultation Necessary for Effective Dissemination

    DTIC Science & Technology

    2015-10-01

    in posttraumatic stress disorder . Journal of Nervous and Mental Disease, 201(8), 691-697. Foa, E. B., Hembree, E. A., Cahill, S. P., Rauch, S. A...M., Riggs, D. S., Feeny, N. C., & Yadin, E. (2005). Randomized trial of prolonged exposure for posttraumatic stress disorder with and without...dialectical behavior therapy prolonged exposure protocol for suicidal and self-injuring women with borderline personality disorder and PTSD

  10. Comparing Virtual Reality Exposure Therapy to Prolonged Exposure in the Treatment of Soldiers with PTSD

    DTIC Science & Technology

    2014-06-01

    researched psychotherapies for PTSD. Virtual reality exposure (VRE) has demonstrated growing support as an innovative method for activating the trauma...related trauma that met criteria for PTSD according to the CAPS. Participants also had to agree not to initiate other psychotherapy for PTSD or new...1. Psychotherapy that used prolonged or virtual reality-enhanced prolonged exposure (VR) would reduce the clinical symptoms of PTSD to a greater

  11. Metronidazole-induced encephalopathy after prolonged metronidazole course for treatment of C. difficile colitis.

    PubMed

    Godfrey, Mark S; Finn, Arkadiy; Zainah, Hadeel; Dapaah-Afriyie, Kwame

    2015-01-16

    A 65-year-old woman with a diagnosis of Clostridium difficile colitis undergoing prolonged treatment with metronidazole was admitted to hospital for altered mentation, slurred speech and weakness. She was diagnosed with metronidazole-induced encephalopathy, confirmed with brain MRI and improved when the offending agent was removed. This case report highlights encephalopathy as a complication of prolonged metronidazole treatment, which has become more common in clinical practice for the treatment of C. difficile infection.

  12. Recent advances in ophthalmic drug delivery

    PubMed Central

    Kompella, Uday B; Kadam, Rajendra S; Lee, Vincent HL

    2011-01-01

    Topical ocular drug bioavailability is notoriously poor, in the order of 5% or less. This is a consequence of effective multiple barriers to drug entry, comprising nasolacrimal drainage, epithelial drug transport barriers and clearance from the vasculature in the conjunctiva. While sustained drug delivery to the back of the eye is now feasible with intravitreal implants such as Vitrasert™ (~6 months), Retisert™ (~3 years) and Iluvien™ (~3 years), currently there are no marketed delivery systems for long-term drug delivery to the anterior segment of the eye. The purpose of this article is to summarize the resurgence in interest to prolong and improve drug entry from topical administration. These approaches include mucoadhesives, viscous polymer vehicles, transporter-targeted prodrug design, receptor-targeted functionalized nanoparticles, iontophoresis, punctal plug and contact lens delivery systems. A few of these delivery systems might be useful in treating diseases affecting the back of the eye. Their effectiveness will be compared against intravitreal implants (upper bound of effectiveness) and trans-scleral systems (lower bound of effectiveness). Refining the animal model by incorporating the latest advances in microdialysis and imaging technology is key to expanding the knowledge central to the design, testing and evaluation of the next generation of innovative ocular drug delivery systems. PMID:21399724

  13. Drug delivery system and breast cancer cells

    NASA Astrophysics Data System (ADS)

    Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

    2016-06-01

    Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

  14. Effects of the prolonged vertical tube on the separation performance of a cyclone.

    PubMed

    Qian, Fuping; Zhang, Jiguang; Zhang, Mingyao

    2006-08-25

    This article aims at the gas flow into the dustbin of conventional cyclones, the prolonged cyclone (attaching a vertical tube at the bottom of the dust outlet) is proposed by some researchers, which can make flow with dust enter into the tube and separate further. The Reynolds stress transport model (RSTM) has been employed to predict the gas flow fields of the conventional and prolonged cyclones. The tangential velocity, axial velocity profiles and turbulent kinetic energy profiles are presented, and the downward flow rates into the dustbin of the three cyclones are compared. The separation performances of these three cyclones are tested. The result indicates that the tangential velocity, axial velocity and turbulent kinetic energy in the dustbin reduce greatly when the prolonged vertical tube attaching into the dust outlet, which can avoid the re-entrainment of already separated dust effectively. Furthermore, the prolonged vertical tube increases the separation space of dusts. The downward flow rate into the dustbin of the prolonged cyclone decreases compared with the conventional cyclone. The experimental results show that the prolonged vertical tube can improve the separation efficiency by a slightly increased pressure drop. However, for an even longer tube, the separation efficiency is slightly reduced. Thus, there is an optimal tube length for a given cyclone.

  15. Drugs in pregnancy. Renal disease.

    PubMed

    Marsh, J E; Maclean, D; Pattison, J M

    2001-12-01

    The management of pregnant women with renal impairment presents a major challenge to obstetricians, nephrologists, and ultimately paediatricians. As renal failure progresses there is an increase in both maternal and fetal complications. Often these women have intercurrent medical conditions and, prior to conception, are receiving a broad range of prescribed medications. A successful obstetric outcome relies upon careful pre-pregnancy counselling and planning, obsessive monitoring during pregnancy, and close liaison between different specialist teams. Experience is mounting in the management of pregnant transplant recipients, but the introduction of newer immunosuppressive agents which have great promise in prolonging graft survival present new problems for those recipients of a kidney transplant who are planning to conceive. We review drug prescription for pregnant patients with renal impairment, end-stage renal failure, or a kidney transplant.

  16. Involvement of metabotropic glutamate receptor 5 in the inhibition of methamphetamine-associated contextual memory after prolonged extinction training.

    PubMed

    Huang, Chien-Hsuan; Yu, Yang-Jung; Chang, Chih-Hua; Gean, Po-Wu

    2016-04-01

    Addiction is thought to be a memory process between perception and environmental cues and addicted patients often relapse when they come into contact with the drug-related context once again. Here, we used a conditioned place preference protocol to seek a more effective extinction methodology of methamphetamine (METH) memory and delineate its underlying mechanism. Conditioning METH for 3 days in mice markedly increased the time spent in the METH-paired compartment. Then the mice were conditioned with saline for 6 days, from day 6 to day 11, a procedure termed extinction training. However, METH memory returned after a priming injection of METH. We prolonged extinction duration from 6 to 10 days and found that this extensive extinction (EE) training prevented priming effect. At the molecular level, we discovered that prolonged extinction training reversed the METH-conditioned place preference-induced increase in surface expression of GluA2 and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/NMDA ratio in the basolateral amygdala. In addition, we found that extinction with metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPA receptors AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH-primed reinstatement is mediated by the mGluR5. Conditioning mice with methamphetamine place preference (METH CPP) increases surface expression of AMPA receptors (AMPARs) in the basolateral amygdala. We found prolongation of extinction duration from 6 to 10 days prevented priming effect. At the molecular level, we discovered that extensive extinction (EE) reversed the METH CPP-induced increase in surface expression of GluA2 and AMPA/NMDA ratio. In addition, we found that extinction with the metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE

  17. Planar bioadhesive microdevices: a new technology for oral drug delivery.

    PubMed

    Fox, Cade B; Chirra, Hariharasudhan D; Desai, Tejal A

    2014-01-01

    The oral route is the most convenient and least expensive route of drug administration. Yet, it is accompanied by many physiological barriers to drug uptake including low stomach pH, intestinal enzymes and transporters, mucosal barriers, and high intestinal fluid shear. While many drug delivery systems have been developed for oral drug administration, the physiological components of the gastro intestinal tract remain formidable barriers to drug uptake. Recently, microfabrication techniques have been applied to create micron-scale devices for oral drug delivery with a high degree of control over microdevice size, shape, chemical composition, drug release profile, and targeting ability. With precise control over device properties, microdevices can be fabricated with characteristics that provide increased adhesion for prolonged drug exposure, unidirectional release which serves to avoid luminal drug loss and enhance drug permeation, and protection of a drug payload from the harsh environment of the intestinal tract. Here we review the recent developments in microdevice technology and discuss the potential of these devices to overcome unsolved challenges in oral drug delivery.

  18. Planar bioadhesive microdevices: a new technology for oral drug delivery

    PubMed Central

    Fox, Cade B.; Chirra, Hariharasudhan D.; Desai, Tejal A.

    2014-01-01

    The oral route is the most convenient and least expensive route of drug administration. Yet, it is accompanied by many physiological barriers to drug uptake including low stomach pH, intestinal enzymes and transporters, mucosal barriers, and high intestinal fluid shear. While many drug delivery systems have been developed for oral drug administration, the physiological components of the gastro intestinal tract remain formidable barriers to drug uptake. Recently, microfabrication techniques have been applied to create micron-scale devices for oral drug delivery with a high degree of control over microdevice size, shape, chemical composition, drug release profile, and targeting ability. With precise control over device properties, microdevices can be fabricated with characteristics that provide increased adhesion for prolonged drug exposure, unidirectional release which serves to avoid luminal drug loss and enhance drug permeation, and protection of a drug payload from the harsh environment of the intestinal tract. Here we review the recent developments in microdevice technology and discuss the potential of these devices to overcome unsolved challenges in oral drug delivery. PMID:25219863

  19. Microemulsion: New Insights into the Ocular Drug Delivery

    PubMed Central

    Hegde, Rahul Rama; Verma, Anurag; Ghosh, Amitava

    2013-01-01

    Delivery of drugs into eyes using conventional drug delivery systems, such as solutions, is a considerable challenge to the treatment of ocular diseases. Drug loss from the ocular surface by lachrymal fluid secretion, lachrymal fluid-eye barriers, and blood-ocular barriers are main obstacles. A number of ophthalmic drug delivery carriers have been made to improve the bioavailability and to prolong the residence time of drugs applied topically onto the eye. The potential use of microemulsions as an ocular drug delivery carrier offers several favorable pharmaceutical and biopharmaceutical properties such as their excellent thermodynamic stability, phase transition to liquid-crystal state, very low surface tension, and small droplet size, which may result in improved ocular drug retention, extended duration of action, high ocular absorption, and permeation of loaded drugs. Further, both lipophilic and hydrophilic characteristics are present in microemulsions, so that the loaded drugs can diffuse passively as well get significantly partitioned in the variable lipophilic-hydrophilic corneal barrier. This review will provide an insight into previous studies on microemulsions for ocular delivery of drugs using various nonionic surfactants, cosurfactants, and associated irritation potential on the ocular surface. The reported in vivo experiments have shown a delayed effect of drug incorporated in microemulsion and an increase in the corneal permeation of the drug. PMID:23936681

  20. Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs.

    PubMed

    Vicente, Jose; Stockbridge, Norman; Strauss, David G

    Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-Tpeak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block.

  1. Drugs@FDA: FDA Approved Drug Products

    MedlinePlus

    ... by Month Approvals, tentative approvals, and supplements Original New Drug Approvals (NDAs and BLAs) by Month All applications ... FDA. Does not include tentative approvals. Original Abbreviated New Drug Approvals (ANDAs) by Month Generic Drug Approvals. Does ...

  2. Long-term genotoxic effects of immunosuppressive drugs on lymphocytes of kidney transplant recipients.

    PubMed

    Lizotti Cilião, Heloísa; Batista de Oliveira Camargo-Godoy, Rossana; Mazzaron Barcelos, Gustavo Rafael; Zanuto, Amanda; Daher Alvares Delfino, Vinicius; de Syllos Cólus, Ilce Mara

    2016-08-01

    Immunosuppressive therapy can prevent rejection after organ transplantation. However, increased cancer risk is a serious complication among patients undergoing such therapy. We have evaluated whether prolonged use of immunosuppressive drugs is genotoxic. DNA instability was assessed, using the comet and micronucleus assays, in blood lymphocytes of 76 kidney transplant patients. DNA damage detected by the comet assay increased with time after transplantation. The estimated glomerular filtration rate of the patients did not influence the incidence of DNA damage. No association between micronucleated mononucleated cells and time elapsed after transplantation was observed. Our results suggest that prolonged use of immunosuppressive drugs in kidney transplant patients can induce genetic instability.

  3. Drug-Induced Liver Disease: Clinical Course.

    PubMed

    Saithanyamurthi, Hemamala; Faust, Alison Jazwinski

    2017-02-01

    Drug-induced liver injury (DILI) is a term used to describe a spectrum of clinical presentations and severity that ranges from mild elevation of liver enzymes on routine blood work to acute liver failure and death. Approximately 10% of all patients with DILI develop acute liver failure resulting in death or liver transplantation. DILI may be prolonged with persistence of elevated liver enzymes for longer than 6 months in approximately 5% to 20% of cases. Cirrhosis and long-term liver-related morbidity and mortality have also been described but are rare, occurring in 1% to 3% of cases.

  4. Antiplatelet Drugs

    PubMed Central

    Hirsh, Jack; Spencer, Frederick A.; Baglin, Trevor P.; Weitz, Jeffrey I.

    2012-01-01

    The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment. PMID:22315278

  5. Carry-over fluency induced by extreme prolongations: A new behavioral paradigm.

    PubMed

    Briley, P M; Barnes, M P; Kalinowski, J S

    2016-04-01

    Extreme prolongations, which can be generated via extreme delayed auditory feedback (DAF) (e.g., 250-500 ms) or mediated cognitively with timing applications (e.g., analog stopwatch) at 2 s per syllable, have long been behavioral techniques used to inhibit stuttering. Some therapies have used this rate solely to establish initial fluency, while others use extremely slowed speech to establish fluency and add other strategic techniques such as easy onsets and diaphragmatic breathing. Extreme prolongations generate effective, efficient, and immediate forward flowing fluent speech, removing the signature behaviors of discrete stuttering (i.e., syllable repetitions and audible and inaudible postural fixations). Prolonged use of extreme prolongations establishes carry-over fluency, which is spontaneous, effortless speech absent of most, if not all, overt and covert manifestations of stuttering. The creation of this immediate fluency and the immense potential of extreme prolongations to generate long periods of carry-over fluency have been overlooked by researchers and clinicians alike. Clinicians depart from these longer prolongation durations as they attempt to achieve the same fluent results at a near normal rate of speech. Clinicians assume they are re-teaching fluency and slow rates will give rise to more normal rates with less control, but without carry-over fluency, controls and cognitive mediation are always needed for the inherently unstable speech systems of persons who stutter to experience fluent speech. The assumption being that the speech system is untenable without some level of cognitive and motoric monitoring that is always necessary. The goal is omnipresent "near normal rate sounding fluency" with continuous mediation via cognitive and motoric processes. This pursuit of "normal sounding fluency" continues despite ever-present relapse. Relapse has become so common that acceptance of stuttering is the new therapy modality because relapse has come to be

  6. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies.

    PubMed

    Bauer, Renato A

    2015-09-01

    Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.

  7. Predicting Prolonged Stay in the ICU Attributable to Bleeding in Patients Offered Plasma Transfusion

    PubMed Central

    Ngufor, Che; Murphree, Dennis; Upadhyaya, Sudhi; Madde, Nageswar; Pathak, Jyotishman; Carter, Rickey; Kor, Daryl

    2016-01-01

    In blood transfusion studies, plasma transfusion (PPT) and bleeding are known to be associated with risk of prolonged ICU length of stay (ICU-LOS). However, as patients can show significant heterogeneity in response to a treatment, there might exists subgroups with differential effects. The existence and characteristics of these subpopulations in blood transfusion has not been well-studied. Further, the impact of bleeding in patients offered PPT on prolonged ICU-LOS is not known. This study presents a causal and predictive framework to examine these problems. The two-step approach first estimates the effect of bleeding in PPT patients on prolonged ICU-LOS and then estimates risks of bleeding and prolonged ICU-LOS. The framework integrates a classification model for risks prediction and a regression model to predict actual LOS. Results showed that the effect of bleeding in PPT patients significantly increases risk of prolonged ICU-LOS (55%, p=0.00) while no bleeding significantly reduces ICU-LOS (4%, p=0.046). PMID:28269892

  8. Prolongation Structure of a Generalised Inhomogeneous Gardner Equation in Plasmas and Fluids

    NASA Astrophysics Data System (ADS)

    Xie, Xi-Yang; Tian, Bo; Sun, Wen-Rong; Wang, Yun-Po

    2016-04-01

    In this article, the prolongation structure technique is applied to a generalised inhomogeneous Gardner equation, which can be used to describe certain physical situations, such as the stratified shear flows in ocean and atmosphere, ion acoustic waves in plasmas with a negative ion, interfacial solitary waves over slowly varying topographies, and wave motion in a non-linear elastic structural element with large deflection. The Lax pairs, which are derived via the prolongation structure, are more general than the Lax pairs published before. Under the Painlevé conditions, the linear-damping coefficient equals to zero, the quadratic non-linear coefficient is proportional to the dispersive coefficient c(t), the cubic non-linear coefficient is proportional to c(t), leaving no constraints on c(t) and the dissipative coefficient d(t). We establish the prolongation structure through constructing the exterior differential system. We introduce two methods to obtain the Lax pairs: (a) based on the prolongation structure, the Lax pairs are obtained, and (b) via the Lie algebra, we can derive the Pfaffian forms and Lax pairs when certain parameters are chosen. We set d(t) as a constant to discuss the influence of c(t) on the Pfaffian forms and Lax pairs, and to discuss the influence of d(t) on the Pfaffian forms and Lax pairs, we set c(t) as another constant. Then, we get different prolongation structure, Pfaffian forms and Lax pairs.

  9. Tolerability to prolonged lifting tasks. A validation of the recommended limits.

    PubMed

    Capodaglio, P; Bazzini, G

    1997-01-01

    Prolonged physical exertion is subjectively regulated by the perception of effort. This preliminary study was conducted to validate the use of subjective perceptions of effort in assessing objectively tolerable workloads for prolonged lifting tasks. Ten healthy male subjects tested their maximal lifting capacity (MLC) on a lift dynamometer (LidoLift, Loredan Biomed., West Sacramento, CA) and underwent incremental and 30-minute endurance lifting tests. Cardiorespiratory parameters were monitored with an oxygen uptake analyzer, mechanical parameters were calculated using a computerized dynamometer. Ratings of perceived exertion were given on Borg's 10-point scale. Physiological responses to repetitive lifting were matched with subjective perceptions. A single-variable statistical regression for power functions was performed to obtain the individual "iso-perception" curves as functions of the mechanical work exerted. We found that the "iso-perception" curve corresponding to a "moderate" perception of effort may represent the individual "tolerance threshold" for prolonged lifting tasks, since physiological responses at this level of intensity did not change significantly and the respiratory exchange ratio was less than one. The individually tolerable weight for lifting tasks lasting 30 min has been expressed as a percentage of the isoinertial MLC value and compared with the currently recommended limits for prolonged lifting tasks (Italian legislation D.L. 626/94). On the basis of our preliminary results a "tolerance threshold" of 20% MLC has been proposed for prolonged lifting tasks.

  10. Prolonged minor allograft survival in intravenously primed mice--a test of the veto hypothesis

    SciTech Connect

    Johnson, L.L.

    1987-07-01

    Experiments were performed to test the hypothesis that veto cells are responsible for the prolonged survival of minor allografts of skin that is observed in recipients primed intravenously with spleen cells from mice syngeneic with the skin donors. This prolonged survival was observed for each of several minor histocompatibility (H) antigens and is antigen-specific. Gamma radiation (3300 rads) abolished the ability of male spleen cells infused i.v. to delay the rejection of male skin grafts (H-Y antigen) on female recipients. However, depletion of Thy-1+ cells from the i.v. infusion failed to abolish the ability to prolong male skin graft survival. Furthermore, the prolonged survival accorded to B6 (H-2b) male skin grafts on CB6F1 (H-2b/H-2d) female recipients given i.v. infusions of B6 male spleen cells extended to BALB/c (H-2d) male skin grafts as well, indicating a lack of MHC restriction. Thus, prolongation of minor allograft survival by i.v. infusion of minor H antigen-bearing spleen cells appears not to depend on veto T cells that others have found to be responsible for the suppression of CTL generation.

  11. Impact of Prolonged Temporal Discrimination Threshold on Finger Movements of Parkinson’s Disease

    PubMed Central

    Lee, M. J.; Son, J. S.; Lee, J. H.; Kim, S. J.; Lyoo, C. H.; Lee, M. S.

    2016-01-01

    Introduction Sensory information is essential for the precise control of movement. Patients with Parkinson’s disease (PD) have higher-order sensory dysfunctions including prolonged temporal discrimination threshold (TDT). However, the impact of prolonged TDT on parkinsonian motor deficits is uncertain. Methods This study includes 33 PD patients and 24 healthy controls. TDT values were measured in the index finger. Using coin rotation task (CRT), dexterous finger movement was assessed. Using an inertial sensor, the speed, amplitude, and frequency of finger tapping were measured. The impact of prolonged index finger TDT on two different finger movements was analyzed using the general estimating equation. Results Compared to healthy controls, TDT was prolonged in the PD patients. There was no impact of TDT on mean values or decrement for amplitude and speed, as well as mean values, decrement and variability of tapping frequency. However, prolonged TDT had a significant impact on the variability in amplitude (B = 436.905 × 10−4, Wald χ2 = 9.140, p = 0.014) and speed (B = 425.655 × 10−4, Wald χ2 = 9.876, p = 0.014) of finger tapping. There was a marginal correlation between TDT and CRT. In addition, CRT correlated with variability in amplitude and speed of finger tapping. Conclusion In PD, cutaneous temporal discriminative sensory dysfunction appears to be related to increased variabilities in the speed and amplitude of fast repetitive finger movements and disturbed finger dexterity. PMID:27893840

  12. Metacognition, social cognition, and symptoms in patients with first episode and prolonged psychoses.

    PubMed

    Vohs, J L; Lysaker, P H; Francis, M M; Hamm, J; Buck, K D; Olesek, K; Outcalt, J; Dimaggio, G; Leonhardt, B; Liffick, E; Mehdiyoun, N; Breier, A

    2014-03-01

    While it has been documented that persons with prolonged schizophrenia have deficits in metacognition and social cognition, it is less clear whether these difficulties are already present during a first episode. To explore this issue we assessed and compared metacognition using the Metacognition Assessment Scale-Abbreviated (MAS-A) and social cognition using the Eyes, Hinting and Bell-Lysaker Emotional Recognition Tests (BLERT) in participants with first episode psychosis (FEP; n=26), participants with a prolonged psychosis (n=72), and a psychiatric control group consisting of persons with a substance use disorder and no history of psychosis (n=14). Analyses revealed that both psychosis cohorts scored lower than controls on the MAS-A total and all subscales except metacognitive mastery. Compared to the FEP group, the persons with prolonged psychosis demonstrated greater metacognitive capacities only in those MAS-A domains reflective of the ability to understand the mental state of others and to see that others may have motivations and desires separate from their own. Other domains of metacognition did not differ between psychosis groups. The Eyes, Hinting and BLERT scores of the two psychosis groups did not differ but were poorer than those produced by the control group. Exploratory correlations in the FEP group showed a pattern similar to that previously observed in prolonged psychosis. Taken together, these findings suggest that while certain domains of metacognition could improve with prolonged psychosis, difficulties with global metacognition and social cognition may be stable features of the disorder and perhaps unique to psychosis.

  13. Effect of prolonged exposure to organic solvents on the active site environment of subtilisin Carlsberg.

    PubMed

    Bansal, Vibha; Delgado, Yamixa; Fasoli, Ezio; Ferrer, Amaris; Griebenow, Kai; Secundo, Francesco; Barletta, Gabriel L

    2010-06-01

    The potential of enzyme catalysis as a tool for organic synthesis is nowadays indisputable, as is the fact that organic solvents affect an enzyme's activity, selectivity and stability. Moreover, it was recently realized that an enzyme's initial activity is substantially decreased after prolonged exposure to organic media, an effect that further hampers their potential as catalysts for organic synthesis. Regrettably, the mechanistic reasons for these effects are still debatable. In the present study we have made an attempt to explain the reasons behind the partial loss of enzyme activity on prolonged exposure to organic solvents. Fluorescence spectroscopic studies of the serine protease subtilisin Carlsberg chemically modified with polyethylene glycol (PEG-SC) and inhibited with a Dancyl fluorophore, and dissolved in two organic solvents (acetonitrile and 1,4-dioxane) indicate that when the enzyme is initially introduced into these solvents, the active site environment is similar to that in water; however prolonged exposure to the organic medium causes this environment to resemble that of the solvent in which the enzyme is dissolved. Furthermore, kinetic studies show a reduction on both V(max) and K(M) as a result of prolonged exposure to the solvents. One interpretation of these results is that during this prolonged exposure to organic solvents the active-site fluorescent label inhibitor adopts a different binding conformation. Extrapolating this to an enzymatic reaction we argue that substrates bind in a less catalytically favorable conformation after the enzyme has been exposed to organic media for several hours.

  14. Factors of working conditions and prolonged fatigue among teachers at public elementary and junior high schools.

    PubMed

    Shimizu, Midori; Wada, Koji; Wang, Guoqin; Kawashima, Masatoshi; Yoshino, Yae; Sakaguchi, Hiroko; Ohta, Hiroshi; Miyaoka, Hitoshi; Aizawa, Yoshiharu

    2011-01-01

    Prolonged fatigue among elementary and junior high school teachers not only damages their health but also affects the quality of education. The aim of this study was to determine the factors of working conditions associated with prolonged fatigue among teachers at public elementary and junior high schools. We distributed a self-reported, anonymous questionnaire to 3,154 teachers (1,983 in elementary schools, 1,171 in junior high schools) working in public schools in a city in Japan. They were asked to assess 18 aspects of their working conditions using a seven-point Likert scale. Prolonged fatigue was measured using the Japanese version of the checklist individual strength questionnaire. Multiple regression analysis was used to examine the association between working conditions and prolonged fatigue. Gender, age, and school type were introduced as confounders. In all, 2,167 teachers participated in this study. Results showed that qualitative and quantitative workload (time pressure due to heavy workload, interruptions, physically demanding job, extra work at home), communication with colleagues (poor communication, lack of support), and career factors (underestimation of performance by the board of education or supervisors, occupational position not reflecting training, lack of prospects for work, job insecurity) were associated with prolonged fatigue.

  15. Drugs Approved for Neuroblastoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  16. Drugs Approved for Retinoblastoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  17. Drugs Approved for Leukemia

    Cancer.gov

    This page lists cancer drugs approved by the FDA for use in leukemia. The drug names link to NCI's Cancer Drug Information summaries. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  18. Club Drug Use

    MedlinePlus

    ... different from other illicit drugs?What are the dangers of taking club drugs?What can I do ... Drug Use | Gamma-Hydroxybutyrate (GHB)Learn about the dangers of taking gamma-hydroxybutyrate (GHB), an illegal drug ...

  19. Effects of Drug Use

    MedlinePlus

    ... Used Drugs in the Past Drug Use Prevention Phone Numbers and Websites Search ... and the brain , sometimes forever. Learn more about: how drug use and mental health problems often happen together the link between drug use ...

  20. Urine drug screen

    MedlinePlus

    Drug screen -- urine ... detect the presence of illegal and some prescription drugs in your urine. Their presence indicates that you recently used these drugs. Some drugs may remain in your system for ...

  1. The use of hypromellose in oral drug delivery.

    PubMed

    Li, Chi L; Martini, Luigi G; Ford, James L; Roberts, Matthew

    2005-05-01

    Hypromellose, formerly known as hydroxypropylmethylcellulose (HPMC), is by far the most commonly employed cellulose ether used in the fabrication of hydrophilic matrices. Hypromellose provides the release of a drug in a controlled manner, effectively increasing the duration of release of a drug to prolong its therapeutic effect. This review provides a current insight into hypromellose and its applicability to hydrophilic matrices in order to highlight the basic parameters that affect its performance. Topics covered include the chemical, thermal and mechanical properties of hypromellose, hydration of the polymer matrices, the mechanism of drug release and the influence of tablet geometry on drug-release rate. The inclusion of drug-release modifiers within hypromellose matrices, the effects of dissolution media and the influence of both the external environment and microenvironment pH within the gel matrix on the properties of the polymer are also discussed.

  2. A Review on Composite Liposomal Technologies for Specialized Drug Delivery

    PubMed Central

    Mufamadi, Maluta S.; Pillay, Viness; Choonara, Yahya E.; Du Toit, Lisa C.; Modi, Girish; Naidoo, Dinesh; Ndesendo, Valence M. K.

    2011-01-01

    The combination of liposomes with polymeric scaffolds could revolutionize the current state of drug delivery technology. Although liposomes have been extensively studied as a promising drug delivery model for bioactive compounds, there still remain major drawbacks for widespread pharmaceutical application. Two approaches for overcoming the factors related to the suboptimal efficacy of liposomes in drug delivery have been suggested. The first entails modifying the liposome surface with functional moieties, while the second involves integration of pre-encapsulated drug-loaded liposomes within depot polymeric scaffolds. This attempts to provide ingenious solutions to the limitations of conventional liposomes such as short plasma half-lives, toxicity, stability, and poor control of drug release over prolonged periods. This review delineates the key advances in composite technologies that merge the concepts of depot polymeric scaffolds with liposome technology to overcome the limitations of conventional liposomes for pharmaceutical applications. PMID:21490759

  3. [The mucoadhesion phenomena and importance in drug application].

    PubMed

    Płaczek, Marcin; Sznitowska, Małgorzata

    2009-01-01

    The main assignment of the pharmaceutical sciences is to develop new, safer and more effective methods of pharmacotherapy. Among tools used to realize this goal are modern drug formulations, both for new and well known active substances. Different concepts have been proposed to achieve efficient drug delivery, and mucoadhesion has received a significant degree of attention during past years. Mucoadhesive systems, thanks to the presence of certain polymers, may attach for few hours to the mucosal membrane and therefore it is possible to obtain prolonged, local or systemic drug effect. This article contains an overview of data concerning the mucoadhesion phenomena and most important adhesion theories. Furthermore, methods that are frequently used to study the adhesion forces between drug and mucus as well as application of mucoadhesive hydrogels as drug carriers for different mucosal membranes are also discussed.

  4. Survival after prolonged pediatric extracorporeal membrane oxygenation support for adenoviral pneumonia.

    PubMed

    Allibhai, Taslim F; Spinella, Philip C; Meyer, Michael T; Hall, Brian H; Kofos, Daniel; DiGeronimo, Robert J

    2008-08-01

    Adenoviral pneumonia can cause significant pulmonary morbidity leading to extracorporeal membrane oxygenation (ECMO) rescue. Reported survival of adenoviral pneumonia requiring ECMO has been poor, and prolonged time on ECMO is associated with increased mortality. We present 2 pediatric cases of adenoviral pneumonia in patients who survived after greater than 30 days on ECMO and review the Extracorporeal Life Support Organization (ELSO) registry to describe the collective experience of children with viral pneumonia requiring prolonged ECMO. Although survival has improved over the past decade for pediatric adenoviral pneumonia, the ELSO database previously has had no surviving children reported with a primary diagnosis of adenovirus after more than 4 weeks on ECMO. Our experience suggests that there may be use for prolonged ECMO support in children despite severe adenoviral pneumonia.

  5. Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine

    PubMed Central

    O'Laughlin, John P.; Wong, Brian C.

    2016-01-01

    We present a case of a syncopal episode resulting from significant QT interval prolongation in a patient on hydroxychloroquine for the treatment of systemic lupus erythematosus and end stage renal disease. The patient had been treated with hydroxychloroquine for two years prior to presentation. After thorough workup for secondary causes of QT interval prolongation hydroxychloroquine was discontinued and the patient's QT interval shortened. The patient was treated with mexiletine to prevent sudden ventricular arrhythmias, which was unique compared to other documented cases in which lidocaine was used. The patient was noted to have mild prolongation of the QT interval on electrocardiogram prior to initiation of hydroxychloroquine therapy which was exacerbated by its use and may have been caused due to toxicity from underlying renal failure. PMID:27478650

  6. Effect of prolonged hypokinesia on resistance of resistive vessels in rats

    NASA Technical Reports Server (NTRS)

    Saltykova, V. A.

    1982-01-01

    Under the effect of prolonged hypokinesia, the perfusion pressure in resistive vessels, measured under conditions of deep anesthesia and complete denervation, increased by approximately the same degree as arterial pressure in non-anesthetized animals. The increase in arterial, perfusion pressure and the resistance of resistive vessels in animals subjected to prolonged hypokinesia was accompanied by an increase in adrenoreactivity. During prolonged hypokinesia, partial obliteration of the vascular bed of the skeletal muscles plays a significant role in the observed increase in resistance of vessels of the extremities. The increase in adrenoreactivity of the vessels during hypokinesia may be realized as a partial case of an increase in the adrenoreactivity of structures whose innervation is disturbed.

  7. Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined with Circadian Disruption

    PubMed Central

    Buxton, Orfeu M.; Cain, Sean W.; O’Connor, Shawn P.; Porter, James H.; Duffy, Jeanne F.; Wang, Wei; Czeisler, Charles A.; Shea, Steven A.

    2013-01-01

    Epidemiological studies link short sleep and circadian disruption with risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur with shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks in controlled laboratory conditions including: sleep extension (baseline), 3-week sleep restriction (5.6 h sleep/24 h) combined with circadian disruption (recurring 28-h ‘days’), and 9-day recovery sleep with circadian re-entrainment. Prolonged sleep restriction with concurrent circadian disruption significantly decreased resting metabolic rate, and increased postprandial plasma via inadequate pancreatic beta cell responsivity; these normalized with 9 days of recovery sleep and stable circadian reentrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase risk of obesity and diabetes. PMID:22496545

  8. Prolonged cold storage of red blood cells by oxygen removal and additive usage

    DOEpatents

    Bitensky, Mark W.; Yoshida, Tatsuro

    1998-01-01

    Prolonged cold storage of red blood cells by oxygen removal and additive usage. A cost-effective, 4.degree. C. storage procedure that preserves red cell quality and prolongs post-transfusion in vivo survival is described. The improved in vivo survival and the preservation of adenosine triphosphate levels, along with reduction in hemolysis and membrane vesicle production of red blood cells stored at 4.degree. C. for prolonged periods of time, is achieved by reducing the oxygen level therein at the time of storage; in particular, by flushing the cells with an inert gas, and storing them in an aqueous solution which includes adenine, dextrose, mannitol, citrate ion, and dihydrogen phosphate ion, but no sodium chloride, in an oxygen-permeable container which is located in an oxygen-free environment containing oxygen-scavenging materials.

  9. Prolonged cold storage of red blood cells by oxygen removal and additive usage

    DOEpatents

    Bitensky, M.W.; Yoshida, Tatsuro

    1998-08-04

    Prolonged cold storage of red blood cells by oxygen removal and additive usage. A cost-effective, 4 C storage procedure that preserves red cell quality and prolongs post-transfusion in vivo survival is described. The improved in vivo survival and the preservation of adenosine triphosphate levels, along with reduction in hemolysis and membrane vesicle production of red blood cells stored at 4 C for prolonged periods of time, is achieved by reducing the oxygen level therein at the time of storage; in particular, by flushing the cells with an inert gas, and storing them in an aqueous solution which includes adenine, dextrose, mannitol, citrate ion, and dihydrogen phosphate ion, but no sodium chloride, in an oxygen-permeable container which is located in an oxygen-free environment containing oxygen-scavenging materials. 8 figs.

  10. Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures.

    PubMed

    Lagae, Lieven

    2014-10-01

    An historical overview is provided regarding the use of benzodiazepines for the treatment of acute prolonged convulsive seizures. It is clear that intravenous benzodiazepines remain a first step for the in-hospital treatment of prolonged seizures or status epilepticus. However, in the community, in a pre-hospital situation, intravenous administration is not possible. In recent years, it was shown that rectal, buccal, intranasal, and intramuscular administration of benzodiazepines is very effective as a first and safe treatment step. In many cases, rectal diazepam is not socially acceptable anymore, and therefore more emphasis is now put on buccal, intranasal, and intramuscular administration. At present, based on the available data, midazolam is the product of choice for the acute treatment of prolonged convulsive seizures.

  11. Circadian, endocrine, and metabolic effects of prolonged bedrest: Two 56-day bedrest studies

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.; Winget, C. M.; Leach, C. S.; Rambaut, P. C.

    1974-01-01

    Two bedrest studies of 56 days each have been conducted to evaluate the effects of prolonged bedrest on circadian synchrony and endocrine and metabolic function. Measurements included the pituitary-adrenal, thyroid, parathyroid, insulin-glucose-growth hormones, catecholamine excretion, body temperature, and heart rate. The results indicated that a rigorous regimen of exercise did not prevent the endocrine and metabolic effects of prolonged bedrest. Changes in circadian, endocrine, and metabolic functions in bedrest appear to be due to changes in hydrostatic pressure and lack of postural cues rather than to inactivity, confinement, or the bleeding schedule. Prolonged bedrest, particularly beyond 24 days, resulted in rhythm desynchronization in spite of well regulated light/dark cycles, temperature, humidity, activity, and meal times and meal composition and in increased lability of all endocrine parameter measured. It also resulted in an apparent insensitivity of the glucose response to insulin, of cortisol secretion to ACTH, and of growth hormone secretion to hypoglycemia.

  12. The personal and financial impact of repetitive or prolonged seizures on the patient and family.

    PubMed

    O'Dell, Christine; Wheless, James W; Cloyd, James

    2007-05-01

    Individuals with epilepsy consistently report diminished quality of life. The clinical characteristics of seizures and the unpredictable nature of seizure occurrences are some factors that affect quality of life. Prolonged or repetitive seizures can impose psychologic comorbidities, social issues, and lifestyle restrictions that can affect quality of life of patients and their caregivers and family members, who also bear the considerable indirect costs of seizures, including time away from work or school, and even loss of employment. The availability and use of an at-home medication to terminate prolonged or repetitive seizures or in seizure emergencies improves quality of life for patients and their families. Fewer visits to the emergency department are associated with a reduction in the financial burden to families and the health care system. This article discusses factors that contribute to the personal and financial impact of prolonged seizures on adult and pediatric patients, their families, and caregivers.

  13. Drugs and the Brain.

    ERIC Educational Resources Information Center

    National Institutes of Health (DHHS), Bethesda, MD.

    This booklet explores various aspects of drug addiction, with a special focus on drugs' effects on the brain. A brief introduction presents information on the rampant use of drugs in society and elaborates the distinction between drug abuse and drug addiction. Next, a detailed analysis of the brain and its functions is given. Drugs target the more…

  14. Prolonged fasting activates Nrf2 in post-weaned elephant seals.

    PubMed

    Vázquez-Medina, José Pablo; Soñanez-Organis, José G; Rodriguez, Ruben; Viscarra, Jose A; Nishiyama, Akira; Crocker, Daniel E; Ortiz, Rudy M

    2013-08-01

    Elephant seals naturally experience prolonged periods of absolute food and water deprivation (fasting). In humans, rats and mice, prolonged food deprivation activates the renin-angiotensin system (RAS) and increases oxidative damage. In elephant seals, prolonged fasting activates RAS without increasing oxidative damage likely due to an increase in antioxidant defenses. The mechanism leading to the upregulation of antioxidant defenses during prolonged fasting remains elusive. Therefore, we investigated whether prolonged fasting activates the redox-sensitive transcription factor Nrf2, which controls the expression of antioxidant genes, and if such activation is potentially mediated by systemic increases in RAS. Blood and skeletal muscle samples were collected from seals fasting for 1, 3, 5 and 7 weeks. Nrf2 activity and nuclear content increased by 76% and 167% at week 7. Plasma angiotensin II (Ang II) and transforming growth factor β (TGF-β) were 5000% and 250% higher at week 7 than at week 1. Phosphorylation of Smad2, an effector of Ang II and TGF signaling, increased by 120% at week 7 and by 84% in response to intravenously infused Ang II. NADPH oxidase 4 (Nox4) mRNA expression, which is controlled by smad proteins, increased 430% at week 7, while Nox4 protein expression, which can activate Nrf2, was 170% higher at week 7 than at week 1. These results demonstrate that prolonged fasting activates Nrf2 in elephant seals and that RAS stimulation can potentially result in increased Nox4 through Smad phosphorylation. The results also suggest that Nox4 is essential to sustain the hormetic adaptive response to oxidative stress in fasting seals.

  15. Determinants of Prolonged Length of Stay in the Emergency Department; a Cross-sectional Study

    PubMed Central

    Hosseininejad, Seyed Mohammad; Aminiahidashti, Hamed; Pashaei, Seyede Masoume; Goli Khatir, Iraj; Montazer, Seyed Hosein; Bozorgi, Farzad; Mahmoudi, Fahime

    2017-01-01

    Introduction: Timeliness has been considered as a key domain in quality of emergency department (ED) care and delay in care providing is influential determinants of patient’s outcomes. The present study, aimed to evaluate the determinants of prolonged ED length of stay (LOS). Methods: In this cross-sectional study, using adopted version of the latest form for external evaluation and accreditation of EDs introduced by Iranian Ministry of Health, determinants of prolonged LOS were evaluated in the ED of an educational Hospital. Using SPSS 11, multivariate binary logistic regression was applied to estimate adjusted odds ratios (OR) for determining factors associated with prolonged LOS. Results: 162 (10.2%) cases with prolonged LOS were detected. Based on univariate analysis, female gender (OR: 1.42, 95% CI: 1.14-1.75, p = 0.001), older age (OR: 1.05, 95% CI: 1.02-1.08, p < 0.0001), admission on evening shifts (OR: 4.0; 95% CI: 1.84-8.68, p < 0.001), triage level I (OR: 1.76, 95% CI: 1.21-2.57, p = 0.003), lack of insurance support (OR: 1.56, 95% CI: 1.12-2.19, p = 0.010), higher number of ordered para-clinical tests (OR: 1.23, 95% CI: 1.11-1.37, p = 0.016), and disposition time > 6 hours (OR, 0.13, p < 0.0001), were significant risk factors of prolonged LOS. Conclusion Older age, lack of insurance support, disposition time > 6 hours due to complexity of patients’ complaint, and the necessity of repeated para-clinical measures were the most important reasons for failed provision of timely services. From the view point of ED personnel, a small part of prolonged LOS in ED was concerned with defective ED workflow, while, the most important cause of such delays was the delayed response of the consultancy services. PMID:28286860

  16. DrugCentral: online drug compendium

    PubMed Central

    Ursu, Oleg; Holmes, Jayme; Knockel, Jeffrey; Bologa, Cristian G.; Yang, Jeremy J.; Mathias, Stephen L.; Nelson, Stuart J.; Oprea, Tudor I.

    2017-01-01

    DrugCentral (http://drugcentral.org) is an open-access online drug compendium. DrugCentral integrates structure, bioactivity, regulatory, pharmacologic actions and indications for active pharmaceutical ingredients approved by FDA and other regulatory agencies. Monitoring of regulatory agencies for new drugs approvals ensures the resource is up-to-date. DrugCentral integrates content for active ingredients with pharmaceutical formulations, indexing drugs and drug label annotations, complementing similar resources available online. Its complementarity with other online resources is facilitated by cross referencing to external resources. At the molecular level, DrugCentral bridges drug-target interactions with pharmacological action and indications. The integration with FDA drug labels enables text mining applications for drug adverse events and clinical trial information. Chemical structure overlap between DrugCentral and five online drug resources, and the overlap between DrugCentral FDA-approved drugs and their presence in four different chemical collections, are discussed. DrugCentral can be accessed via the web application or downloaded in relational database format. PMID:27789690

  17. Drug Preferences of Multiple Drug Abusers.

    ERIC Educational Resources Information Center

    Harford, Robert J.

    1978-01-01

    Examined drug preferences of a group of active multiple drug abusers referred for treatment. Nearly half the respondents preferred drugs other than type they most frequently used. Preferences were related to method of administration. Results suggest preference is one among several determinants of drug use. (Author/BEF)

  18. Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium.

    PubMed

    Heller, Simon; Darpö, Börje; Mitchell, Malcolm I; Linnebjerg, Helle; Leishman, Derek J; Mehrotra, Nitin; Zhu, Hao; Koerner, John; Fiszman, Mónica L; Balakrishnan, Suchitra; Xiao, Shen; Todaro, Thomas G; Hensley, Ingrid; Guth, Brian D; Michelson, Eric L; Sager, Philip

    2015-07-01

    Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy.

  19. The Impact of Prolonged Economic Downturns and Economic Crises on the Nursing Profession.

    PubMed

    Phua, Kai-Lit; Hue, Jia-Wern

    2015-01-01

    Prolonged economic downturns and economic crises are affecting nations around the world, including developed countries such as Portugal, Spain, and Greece. In the United States, recovery from the latest economic crisis has been accompanied by a persistently high rate of unemployment. To a large extent, the impacts on the nursing profession may depend on the severity of economic downturns and their duration in the country of employment of nurses. Nurses in certain areas of patient care (such as mental health) may also be more strongly affected because of the impact of economic crises and high unemployment on morbidity patterns. Emigration of nurses may also increase as a result of prolonged economic crisis.

  20. Kerato-lenticular ocular deposits and visual impairment with prolonged chlorpromazine use: A case series.

    PubMed

    Gowda, Guru S; Hegde, Aditya; Shanbhag, Vandita; Narayanaswamy, Janardhanan C; Jaisoorya, T S

    2017-02-01

    Chlorpromazine is a low potency "typical" antipsychotic agent used to treat schizophrenia. It continues to be prescribed frequently in India owing to its lower cost. There have been previous reports of ocular adverse effects with prolonged use of chlorpromazine. We report three patients who developed corneal and lenticular opacities secondary to prolonged chlorpromazine use leading to visual impairment. Early detection of ocular deposits and switching over to risperidone from chlorpromazine helped in the reversal of chlorpromazine- induced ocular side effects in one of them. The case series further adds evidence to the causative relationship between chlorpromazine and ocular side effects.

  1. Prolonged duodenal paralysis after PEG placement in a patient with traumatic brain injury: a case report.

    PubMed

    Mammi, P; Zaccaria, B; Dazzi, F; Saccavini, M

    2011-03-01

    Percutaneous endoscopic gastrostomy (PEG) has recently become a usual procedure for patients with prolonged disorders of consciousness after brain injuries. Despite a high rate of success and a very low procedure-related mortality, morbidity associated to PEG placement reaches 9.4% in a recent large meta-analysis. This case report describes an uncommon complication of PEG placement in a patient with vegetative state after traumatic brain injury: the development of prolonged duodenal paralysis. This patient was treated by placement of a transient jejunostomy until recovery of duodenal functional activity, to permit adequate nutrition. This procedure-related complication is previously unreported in scientific literature.

  2. The effect of neutrophil migration and prolonged neutrophil contact on epithelial permeability.

    PubMed Central

    Parsons, P. E.; Sugahara, K.; Cott, G. R.; Mason, R. J.; Henson, P. M.

    1987-01-01

    The effect of neutrophil migration and prolonged neutrophil contact on epithelial permeability was examined. Although neutrophil migration was not associated with a change in epithelial permeability, prolonged neutrophil-epithelial contact following migration resulted in an increase in epithelial permeability. These results were not altered by catalase, a specific neutrophil elastase inhibitor, methoxysuccinyl-Ala-Ala-Pro-Val-chloromethyl ketone or cyclohexamide. This suggests that neutrophil migration does not occur via an H2O2-induced reversible mechanism of junctional opening, which we describe herein. PMID:3314530

  3. [Therapeutic effects of prolonged normovolemic hemodilution in patients with Raynaud's disease].

    PubMed

    Mamurov, V A

    1998-01-01

    51 patients with Raynaud's disease has undergone prolonged normovolemic hemodilution (PNH) with a good effect. Disappearance of painful syndrome in 78.43% of cases, and a significant decrease of pains in 21.37% of cases was demonstrated. Complete healing of ulcero-necrotic defects of end phalanges of the hands was observed in 7 patients of 10 and partial--in 3. A significant remission of the disease in follow-up period was obtained. Thus, prolonged normovolemic hemodilution has resulted in significant improvement of short- and long-term results of treatment in patients with Raynaud's disease.

  4. Green teeth are a late complication of prolonged conjugated hyperbilirubinemia in extremely low birth weight infants.

    PubMed

    Battineni, Sireesha; Clarke, Paul

    2012-01-01

    Eruption of green, discolored teeth affecting the primary dentition has been described in association with congenital viral infection, sepsis, hemolytic jaundice, and cholestasis. The purpose of this paper was to present the cases of 3 extremely low birth weight preterm infants who were noted to have green teeth at the corrected ages of 10 to 12 months. All had a history of prolonged conjugated hyperbilirubinemia during their time in neonatal intensive care. For infants with prolonged conjugated hyperbilirubinemia, extreme preterm birth and/or extremely low birth weight may be additional risk factors predisposing to the eruption of green teeth in later infancy.

  5. Effect of prolonged bed rest on lung volume in normal individuals

    NASA Technical Reports Server (NTRS)

    Beckett, W. S.; Vroman, N. B.; Nigro, D.; Thompson-Gorman, S.; Wilkerson, J. E.

    1986-01-01

    The effect of prolonged bed rest on the lung function was studied by measuring forced vital capacity (FVC) and total lung capacity (TLC) in normal subjects before, during, and after 11- to 12-day rest periods. It was found that both FVC and TLC increased during bed rest (compared with the ambulatory controls), while residual volume and functional residual capacity of the respiratory system did not change. It is concluded that the increase in TLC by prolonged bed rest is not dependent on alterations in plasma volume.

  6. The experimental type 2 diabetes therapy glycogen phosphorylase inhibition can impair aerobic muscle function during prolonged contraction.

    PubMed

    Baker, David J; Greenhaff, Paul L; MacInnes, Alan; Timmons, James A

    2006-06-01

    Glycogen phosphorylase inhibition represents a promising strategy to suppress inappropriate hepatic glucose output, while muscle glycogen is a major source of fuel during contraction. Glycogen phosphorylase inhibitors (GPi) currently being investigated for the treatment of type 2 diabetes do not demonstrate hepatic versus muscle glycogen phosphorylase isoform selectivity and may therefore impair patient aerobic exercise capabilities. Skeletal muscle energy metabolism and function are not impaired by GPi during high-intensity contraction in rat skeletal muscle; however, it is unknown whether glycogen phosphorylase inhibitors would impair function during prolonged lower-intensity contraction. Utilizing a novel red cell-perfused rodent gastrocnemius-plantaris-soleus system, muscle was pretreated for 60 min with either 3 micromol/l free drug GPi (n=8) or vehicle control (n=7). During 60 min of aerobic contraction, GPi treatment resulted in approximately 35% greater fatigue. Muscle glycogen phosphorylase a form (P<0.01) and maximal activity (P<0.01) were reduced in the GPi group, and postcontraction glycogen (121.8 +/- 16.1 vs. 168.3 +/- 8.5 mmol/kg dry muscle, P<0.05) was greater. Furthermore, lower muscle lactate efflux and glucose uptake (P<0.01), yet higher muscle Vo(2), support the conclusion that carbohydrate utilization was impaired during contraction. Our data provide new confirmation that muscle glycogen plays an essential role during submaximal contraction. Given the critical role of exercise prescription in the treatment of type 2 diabetes, it will be important to monitor endurance capacity during the clinical evaluation of nonselective GPi. Alternatively, greater effort should be devoted toward the discovery of hepatic-selective GPi, hepatic-specific drug delivery strategies, and/or alternative strategies for controlling excess hepatic glucose production in type 2 diabetes.

  7. Drug-coated balloons in interventional cardiology.

    PubMed

    Giannini, Francesco; Naim, Charbel; Costopoulos, Charis; Latib, Azeem; Colombo, Antonio

    2013-10-01

    Over the last few years, drug-coated balloon (DCB) therapy has emerged as a promising therapeutic intervention for the management of obstructive cardiovascular disease. The dictum of this novel technology is that effective prevention of restenosis can be achieved by the short-term transfer of antiproliferative drug to local arterial tissue by means of a single prolonged balloon angioplasty dilatation. Its main attraction is that no foreign body is implanted eliminating thus the risk of late inflammatory response to device components without preventing positive remodeling. Here, we discuss the evidence regarding the effectiveness of DCB in different lesion types and clinical settings as well as the types of DCB commercially available or under development.

  8. Understanding performance-enhancing drug use.

    PubMed

    Wang, David

    2012-09-01

    Performance-enhancing drug use is a prevalent problem in sports. It is a problem that has captured the world's attention as the media highlights story after story of athletes who have transformed their bodies over a short period of time, those who have simply defied the aging process in an attempt to prolong a career and those whose careers have been tarnished because of drug use. The baseball investigations and the Mitchell Report of 2007 opened our eyes and gave us a glimpse of a secretive underground world. This "world" is much more intelligent and sophisticated than it is given credit for. It is the goal of this article to increase the awareness of the medical provider about the types of steroids and other medications used, the influence these substances have on the athletes, and how and why they use them.

  9. Personality, Drug Preference, Drug Use, and Drug Availability

    ERIC Educational Resources Information Center

    Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice

    2011-01-01

    This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…

  10. A comprehensive analysis of the influence of drug binding kinetics on drug action at molecular and systems levels.

    PubMed

    Yin, Ning; Pei, Jianfeng; Lai, Luhua

    2013-06-01

    Binding kinetics is closely related to the efficacy of drugs. Several aspects of binding kinetics, such as long residence or frequent dissociation, have been proposed to affect drug properties such as efficacy, selectivity, and multi-target potency. However, a comprehensive and balanced study of binding kinetics in various scenarios is still needed. We performed a comprehensive computational analysis of the role of drug binding kinetics in various situations such as enzyme inhibition, receptor binding, multi-target drug targeting, signal transduction pathways, and metabolic networks. Molecular studies of enzyme inhibition, receptor binding, and multi-target drugs have shown that at constant binding affinity, fast associating drugs show better enzyme inhibitory effects, earlier and higher receptor occupancy peaks, and better multi-target performances, while slow dissociating drugs show prolonged receptor occupancy, as suggested by others. Different situations exemplify slightly different kinetic-efficacy relationships, and each must be considered separately. At the systems level, binding kinetics can not only change the overall effect of drugs, but can also affect signaling dynamics. For example, in the tumor necrosis factor α-induced nuclear factor-κB pathway, inhibitor addition can delay the onset of oscillations and decrease their frequencies, with these changes varying with the binding kinetics of the inhibitor. The effects of drug binding kinetics also depend on network topology and where the target is located in the network. For successful drug discovery, both molecular binding kinetics and systems level requirements need to be considered.

  11. In silico assessment of kinetics and state dependent binding properties of drugs causing acquired LQTS.

    PubMed

    Lee, William; Mann, Stefan A; Windley, Monique J; Imtiaz, Mohammad S; Vandenberg, Jamie I; Hill, Adam P

    2016-01-01

    The Kv11.1 or hERG potassium channel is responsible for one of the major repolarising currents (IKr) in cardiac myocytes. Drug binding to hERG can result in reduction in IKr, action potential prolongation, acquired long QT syndrome and fatal cardiac arrhythmias. The current guidelines for pre-clinical assessment of drugs in development is based on the measurement of the drug concentration that causes 50% current block, i.e., IC50. However, drugs with the same apparent IC50 may have very different kinetics of binding and unbinding, as well as different affinities for the open and inactivated states of Kv11.1. Therefore, IC50 measurements may not reflect the true risk of drug induced arrhythmias. Here we have used an in silico approach to test the hypothesis that drug binding kinetics and differences in state-dependent affinity will influence the extent of cardiac action potential prolongation independent of apparent IC50 values. We found, in general that drugs with faster overall kinetics and drugs with higher affinity for the open state relative to the inactivated state cause more action potential prolongation. These characteristics of drug-hERG interaction are likely to be more arrhythmogenic but cannot be predicted by IC50 measurement alone. Our results suggest that the pre-clinical assessment of Kv11.1-drug interactions should include descriptions of the kinetics and state dependence of drug binding. Further, incorporation of this information into sophisticated in silico models should be able to better predict arrhythmia risk and therefore more accurately assess safety of new drugs in development.

  12. Linguistic and Psychological Perspectives on Prolonged Periods of Silence in Dual-Language Learners

    ERIC Educational Resources Information Center

    Le Pichon, Emmanuelle; de Jonge, Maretha

    2016-01-01

    In this paper, we present an examination of the literature on prolonged periods of silence in children from the perspective of two different scientific fields. The aim is to call attention to the inherent complexity of the factors that may be involved in the etiology of mutistic behavior during child development. Medical and linguistic literature…

  13. Prolonged survival of a cat diagnosed with feline infectious peritonitis by immunohistochemistry.

    PubMed

    Hugo, Timothy B; Heading, Kathryn L

    2015-01-01

    A 4-year-old, neutered male, British shorthair cat was presented with inappetence, vomiting, hyperproteinemia, and hyperglobulinemia. An exploratory celiotomy identified enlarged mesenteric lymph nodes. Immunohistochemistry of lymph node biopsies confirmed feline infectious peritonitis. This patient had a prolonged survival of 787 d after initial presentation.

  14. Prolonged leucine infusion differentially affects tissue protein synthesis in neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leucine (Leu) acutely stimulates protein synthesis by activating the mammalian target of rapamycin complex 1 (mTORC1) pathway. To determine whether Leu can stimulate protein synthesis in muscles of different fiber types and visceral tissues of the neonate for a prolonged period and to determine the ...

  15. Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients.

    PubMed

    Tang, Wei-Hua; Wang, Chao-Ping; Chung, Fu-Mei; Huang, Lynn L H; Yu, Teng-Hung; Hung, Wei-Chin; Lu, Li-Fen; Chen, Po-Yuan; Luo, Ching-Hsing; Lee, Kun-Tai; Lee, Yau-Jiunn; Lai, Wen-Ter

    2015-01-01

    Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.

  16. Sudden Gains in Prolonged Exposure for Children and Adolescents with Posttraumatic Stress Disorder

    ERIC Educational Resources Information Center

    Aderka, Idan M.; Appelbaum-Namdar, Edna; Shafran, Naama; Gilboa-Schechtman, Eva

    2011-01-01

    Objective: Our objective was to examine sudden gains during developmentally adjusted prolonged exposure for posttraumatic stress disorder (PTSD) among children and adolescents. We hypothesized that sudden gains would be detected and would be predictive of treatment outcome and follow-up. Method: Sixty-three youngsters (ages 8-17) completed a…

  17. As time goes by: reasons and characteristics of prolonged episodes of mechanical restraint in forensic psychiatry.

    PubMed

    Gildberg, Frederik A; Fristed, Peter; Makransky, Guido; Moeller, Elsebeth H; Nielsen, Lea D; Bradley, Stephen K

    2015-01-01

    Evidence suggests the prevalence and duration of mechanical restraint are particularly high among forensic psychiatric inpatients. However, only sparse knowledge exists regarding the reasons for, and characteristics of, prolonged use of mechanical restraint in forensic psychiatry. This study therefore aimed to investigate prolonged episodes of mechanical restraint on forensic psychiatric inpatients. Documentary data from medical records were thematically analyzed. Results show that the reasons for prolonged episodes of mechanical restraint on forensic psychiatric inpatients can be characterized by multiple factors: "confounding" (behaviors associated with psychiatric conditions, substance abuse, medical noncompliance, etc.), "risk" (behaviors posing a risk for violence), and "alliance parameters" (qualities of the staff-patient alliance and the patients' openness to alliance with staff), altogether woven into a mechanical restraint spiral that in itself becomes a reason for prolonged mechanical restraint. The study also shows lack of consistent clinical assessment during periods of restraint. Further investigation is indicated to develop an assessment tool with the capability to reduce time spent in mechanical restraint.

  18. Prolonged Exposure versus Dynamic Therapy for Adolescent PTSD: A Pilot Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Gilboa-Schechtman, Eva; Foa, Edna B.; Shafran, Naama; Aderka, Idan M.; Powers, Mark B.; Rachamim, Lilach; Rosenbach, Lea; Yadin, Elna; Apter, Alan

    2010-01-01

    Objective: To examine the efficacy and maintenance of developmentally adapted prolonged exposure therapy for adolescents (PE-A) compared with active control time-limited dynamic therapy (TLDP-A) for decreasing posttraumatic and depressive symptoms in adolescent victims of single-event traumas. Method: Thirty-eight adolescents (12 to 18 years old)…

  19. Artifactual prolongation of activated partial thromboplastin time with PEGylated compounds in silica-based assays.

    PubMed

    Murphy, Bethanne; Parrula, Maria C M; Perigard, Christopher J; Li, Jinze

    2014-12-01

    Conjugation of polyethylene glycol (PEG) to another molecule prolongs its half-life in the body, but has a potential to artifactually increase the activated partial thromboplastin time (aPTT) as measured with certain assays. Studies conducted in-house at Bristol-Myers Squibb using the STA-PTT Automate 5 assay, the routine assay used to measure aPTT, demonstrated prolongation of aPTT in plasma samples spiked in vitro with 40-kDa branched PEG (PEG40) conjugated compounds or PEG40 alone, but not in samples spiked with vehicle or non-PEGylated compound, suggesting that the interference is because of the PEG40 moiety. To investigate the cause of this phenomenon, cynomolgus monkey and rat plasma samples were spiked with different concentrations of PEG40 and the aPTT was measured using different proprietary assays. With one exception, prolongation of aPTT was observed with all assays containing silica as the contact activator. No changes in aPTT were noted in assays using kaolin as a contact activator. The findings indicated that the observed prolongation of aPTT is largely because of interference of PEG40 with the silica, but other features of the reagent mixture may also influence aPTT times.

  20. Does Prolonged Therapy with a Long-Acting Stimulant Suppress Growth in Children with ADHD?

    ERIC Educational Resources Information Center

    Spencer, Thomas J.; Faraone, Stephen V.; Biederman, Joseph; Lerner, Marc; Cooper, Kimberly M.; Zimmerman, Brenda

    2006-01-01

    Objective: To investigate whether prolonged therapy with a long-acting stimulant affects growth in children with attention-deficit/hyperactivity disorder (ADHD). Method: One hundred seventy-eight children ages 6 to 13 years received OROS methylphenidate (OROS MPH, CONCERTA) for at least 21 months. Height and weight were measured monthly during the…