Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review

Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses such as allergic and non-allergic rhinitis and sinusitis. The nose is also considered an attractive route for needle-free vaccination and for systemic drug delivery, especially when rapid absorption and effect are desired. In addition, nasal delivery may help address issues related to poor bioavailability, slow absorption, drug degradation, and adverse events in the gastrointestinal tract and avoids the first-pass metabolism in the liver. However, when considering nasal delivery devices and mechanisms, it is important to keep in mind that the prime purpose of the nasal airway is to protect the delicate lungs from hazardous exposures, not to serve as a delivery route for drugs and vaccines. The narrow nasal valve and the complex convoluted nasal geometry with its dynamic cyclic physiological changes provide efficient filtration and conditioning of the inspired air, enhance olfaction, and optimize gas exchange and fluid retention during exhalation. However, the potential hurdles these functional features impose on efficient nasal drug delivery are often ignored. With this background, the advantages and limitations of existing and emerging nasal delivery devices and dispersion technologies are reviewed with focus on their clinical performance. The role and limitations of the in vitro testing in the FDA guidance for nasal spray pumps and pressurized aerosols (pressurized metered-dose inhalers) with local action are discussed. Moreover, the predictive value and clinical utility of nasal cast studies and computer simulations of nasal airflow and deposition with computer fluid dynamics software are briefly discussed. New and emerging delivery technologies and devices with emphasis on Bi-Directional™ delivery, a novel concept for nasal delivery that can be adapted to a variety of dispersion technologies, are described in more depth

Pre and post functional endoscopic sinus surgery nasal cavity volume assessment by acoustic rhinometry

Acoustic rhinometry is an objective method to determine nasal cavity geometry. The technique is based on sound wave reflexion analysis in the nasal cavity, and determines crossectional areas as a function of distance as well as volume. AIM: The purpose of this study is to analyse nasal cavity volume changes caused by functional endoscopic sinus surgery (FESS) in adults with chronic rhinosinusitis by acoustic rhinometry, and to correlate these changes with improvements in the sensation of nasal obstruction. MATERIAL AND METHOD: Forty patients aged from 18 to 73 years were prospectively evaluated between August and October 1999 at the Graz University Hospital, Austria. All patients were diagnosed with chronic rhinosinusitis, and undertook acoustic rhinometry before and after FESS. SCIENTIFIC DESIGN: A clinical prospective study. RESULTS: The nasal cavity total volume increased significantly after surgery. Nasal obstruction was improved in 88% of the patients, 20% with partial improvement and 68% with total improvement. There was no correlation between volume increase and improvement of the sensation of nasal obstruction. CONCLUSION: Total nasal cavity volume significantly increased after surgery; however, there was no correlation between volume increase and improvements of nasal obstruction. No significant pre or postoperative increase in total nasal cavity volume after decongestion were observed.A rinometria acústica é um método objetivo de determinar a geometria da cavidade nasal, pela análise da reflexão de ondas sonoras. Determina a área de secção transversal da cavidade em função da distância da narina e seu volume. OBJETIVO: Analisar a alteração do volume da cavidade nasal causada pela cirurgia endoscópica funcional dos seios paranasais, em adultos com rinossinusite crônica, e correlacionar esta alteração com a melhora da obstrução nasal. MATERIAL E MÉTODO: Foram avaliados 40 pacientes de 18 a 73 anos, entre agosto e outubro de 1999, na Universidade de Graz - Áustria, com rinossinusite crônica, antes e depois de serem submetidos à CEFSP. FORMA DE ESTUDO: Clínico prospectivo. RESULTADOS: O volume total da cavidade nasal aumentou significativamente no pós-operatório. 88% dos pacientes referiram melhora da obstrução nasal, 20% de forma parcial e 68% total. Nenhum paciente piorou deste sintoma. Não houve relação linear entre o aumento do volume da cavidade nasal e melhora subjetiva da obstrução nasal. CONCLUSÃO: O volume total da cavidade nasal aumentou no pós-operatório, mas não houve relação entre aumento do volume e melhora da obstrução nasal. Não houve aumento do volume da cavidade nasal após o uso do vasoconstritor, seja no pré ou no pós-operatório.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina setor de RinologiaUniversidade de Graz Depto. de OtorrinolaringologiaUNIFESP, EPM, setor de RinologiaSciEL

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain

Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals. The naïve macrophage (Mϕ) exosomes can utilize, 1) on the one hand, the integrin lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), and, 2) on the other hand, the carbohydrate-binding C-type lectin receptors, to interact with brain microvessel endothelial cells comprising the BBB. Notably, upregulation of ICAM-1, a common process in inflammation, promotes Mϕ exosomes uptake in the BBB cells. We further demonstrate in vivo that naïve Mϕ exosomes, after intravenous (IV) administration, cross the BBB and deliver a cargo protein, the brain derived neurotrophic factor (BDNF), to the brain. This delivery is enhanced in the presence of brain inflammation, a condition often present in CNS diseases. Taken together, the findings are of interest to basic science and possible use of Mϕ-derived exosomes as nanocarriers for brain delivery of therapeutic proteins to treat CNS diseases

Mesenchymal Stromal Cell derived Extracellular Vesicles reduce Hypoxia-Ischaemia Induced Perinatal Brain Injury

Background: Neonatal hypoxic ischemic (HI) insult is a leading cause of disability and death in newborns, with therapeutic hypothermia being the only currently available clinical intervention. Thus there is a great need for adjunct and novel treatments for enhanced or alternative post-HI neuroprotection. Extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) have recently been shown to exhibit regenerative effects in various injury models. Here we present findings showing neuroprotective effects of MSC-derived EVs in the Rice-Vannucci model of severe HI-induced neonatal brain insult. Method: MSC-derived EVs were applied intranasally immediately post HI-insult and behavioural outcomes were observed 48 h following MSC-EV treatment, as assessed by negative geotaxis. Brains were thereafter excised and assessed for changes in glial responses, cell death and neuronal loss as markers of damage at 48 h post HI-insult. Results: Brains of the MSC-EV treated group showed a significant decrease in microglial activation, cell death and percentage tissue volume loss in multiple brain regions, compared to the control-treated groups. Furthermore, negative geotaxis test showed improved behavioural outcomes at 48 h following MSC-EV treatment. Conclusion: Our findings highlight the clinical potential of using MSC-derived EVs following neonatal hypoxia-ischaemia

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Numerical study of unsteady flow in slits and investigation of methods to reduce pressure pulsations in pipes

Noe av vannet som strømmer gjennom en Francis turbin lekker opp over løpehjulet mot øvre lokk. Dette vannet evakueres gjennom små spalter i lokket, og ledes videre gjennom et rørsystem til et kjølevannsbasseng. Virvelavløsninger i disse spaltene skaper trykkpulsasjoner når høyhastighets vann passerer gjennom åpningen. Det ble gjort en vibrasjonsmåling av Norconsult på Torpa kraftverk i Januar 2014 som ble sammensatt til en rapport. Disse målingene viste høye trykkvibrasjoner på et målepunkt som er gjort i volumet nedstrøms spalten. Som følge av dette utviklet Rainpower en hypotese som foreslo at virvelavløsningene i spalten kan være årsaken til de høye trykkvibrasjonene. Hvis disse trykkpulsasjonene ikke dempes eller fjernes kan det redusere levetiden til rørene. Strømningen gjennom spalten ble undersøkt ved bruk av CFD beregninger i denne rapporten. Dette gjøres for å validere hypotesen og også opprette en numerisk modell som fungerer til å løse dette problemet. Rainpower har ønsket å undersøke om designet på spalteåpningen kan gjøres om slik at trykkpulsasjonene fra virvelavløsningene reduseres. Siden dette er en transient case med et avansert strømningsfelt krever det mye tid og datakraft å løse. Dermed har ikke optimalisering av designet blitt vurdert i denne oppgaven på grunn av begrensninger relatert til CFD. Geometrien fra Torpa brukes i CFD simuleringene. Dette gjør det mulig å validere simuleringene mot målingene som allerede er gjort på Torpa. I tillegg ble det gjort arbeid for å finne andre måter å løse problemet på Torpa. Dette inkluderer en undersøkelse av rådataen fra målingene presentert i FFT plot og beregninger på resonans. Rådataen ble brukt til å identifisere hvilke frekvenser som det oppsto høye trykkvibrasjoner på. Resonansberegningene gikk ut på å sammenligne rørlengder og bølgehastigheter med en stående bølgeform som indikerer resonans. Dette ble gjort for å se om resonans kan være en årsak til de høye trykkverdiene eller om det kan bli det i fremtiden. De høyeste trykkverdiene ble målt på $36.5$ Hz på begge målepunktene som er analysert. Denne frekvensen ble brukt sammen med en målt trykkamplitude som grensebetingelse i CFD beregningene. Von Karman avløsninger, som er et nærliggende fenomen, skjer når Strouhal tallet er omtrent 0.21. Hvis man bruker spaltehøyden på $93$ mm som karakteristisk lengde og omtrent $40$ m/s som hastighet, får man en avløsningsfrekvens på $90$ Hz. Det ble også produsert en frekvens på $90$ Hz i spalten i CFD simuleringen. Resultatene fra CFD simuleringen indikerte ikke at virvelavløsninger i spalten er en sannsynlig årsak til trykkvibrasjonene på $36.5$ Hz. Det var ingen forsterkning av $36.5$ Hz frekvensene i spalten, og ingen av virvelavløsningsfrekvensene i spalten forplantet seg videre nedstrøms. Likevel er det mange feilkilder i CFD beregningene som ble gjort. Derfor er det foreslått spesifikke forbedringer som kan gjøres på CFDen som en del av det videre arbeidet. Resonansberegningene indikerte ikke at resonans var kilden til noen av de høye målingene i vibrasjonsrapporten. Disse beregningene er basert på bølgehastighetsberegninger som antar null luftinnhold i vannet. Bølgeforplantningshastighetene er veldig sensitive til luftbobler i vannet, og det er sannsynligvis en liten andel luft i vannet naturlig. Dette kunne det ikke tas høyde for i disse beregningene. Bedre antakelser kan gjøres hvis denne hastigheten måles i rørene på anlegget. Det er en akkumulator som er installert i rørsystemet. Målingene viser en betydelig demping av trykkverdiene nedstrøms dette punktet. Dersom luftinnholdet i akkumulatoren økes kan denne effekten forsterkes og gi bedre beskyttelse til rørene nedstrøms. Siden det er rør oppstrøms akkumulatoren også er disse utsatt for de høye trykkverdiene i volumet over spalten. Det kan settes akkumulatorer på alle tre innløpene til disse rørsystemene, for å isolere trykkpulsasjonene i volumet over spalten, og dermed øke levetiden på hele rørsystemet

Alternative methods for reduction of operational downtime related to dis-/reconnection of the marine drilling riser

The global energy demand is increasing. The oil companies are going into harsher climates and deeper waters to replace their reserves. Much of the undiscovered hydrocarbon reservoirs are believed to be located in the Arctic region. The seasonable ice free waters surrounding the Arctic can be drilled utilizing conventional drilling vessels designed for open water conditions. The region introduces several new operational challenges leading to an increased possibility of the drilling vessel moving off location. This Master Thesis looks at the challenges related to operating a conventional drilling vessel in the seasonable open waters in the Arctic, using today’s methods for disconnecting and reconnecting the marine drilling riser from the BOP. The need for a reduction in the operational downtime related to planned and unplanned disconnections is identified and several alternative methods for reducing the dis-/reconnect time are presented and rated. A concept is chosen based on a wide range of design requirements thus leading to an 89-97 % reduction in costs related to planned and unplanned disconnections, depending on water depth and well type. The operational subsea control system needs are mapped and several possible control options are presented and evaluated. Based on a Preliminary Hazard Analysis, cost and system complexity, a control system is chosen