الفهرس 
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Abstract
Background:
Direct Delivery Of Aerosolized Therapy To The Target Site Is Greatly Beneficial. It Elevates The Drug Concentration At The Target Site And Minimizes Systemic Exposure, Maximizing The Drug’s Efficacy And Safety. Salbutamol As A Short-Acting Bronchodilator Is Recommended To Be Used As Needed During Acute Attacks Of Asthma Or COPD. Inhaled Medications Were Reported To Achieve A Faster And Better Therapeutic Response During Mechanical Ventilation Than During Spontaneous Breathing. In Egypt, Jns Were Previously Employed To Administer Aerosolized Therapy In Clinical Settings, But A New Type Of Nebulizer Called Vmns Was Produced. It Has Been Proven That They Have Better Delivery Efficiency Over Jns.
The Main Challenge For COPD Subjects Is To Maximize FEV1 By Improving Airway Narrowing, Which In Turn Reduces Lung End-Expiratory Volume And Pressure, And Thereby Optimizes The Aerosol Delivery During Inspiration. Hence, A Novel Double Cone-Shaped Spacer ’’Combihaler’’, Designed To Simultaneously Employ Pmdis And Vmns Within A Ventilation Circuit, Could Be Utilized To Deliver An Introductory Bronchodilator Dose Via A Pmdi In An Attempt To Elevate FEV1 Before Nebulization And So Aerosol Delivery.
Aims Of The Study:
To Determine The Total Emitted Dose, Aerodynamic characteristics Of Inhaled Mass, And Relative Pulmonary And Systemic Bioavailability Of Salbutamol Released from A VMN Aeroneb Solo, Attached To Three Variable Connections In Five Scenarios, Or A Pmdi, Attached To Three Connections In Four Scenarios, In order To Evaluate Their Effectiveness In Delivering Aerosols.
To Assess The Bronchodilator Impact Of A Pre-Nebulized Dose On Dose Emission In An Attempt To Improve Delivery Efficacy.
Methodology:
The Study Was Divided Into Three Principal Sections:
1. In-Vitro Study:
A. Determination Of The Fate Of Salbutamol Dose Emission (Drug Remaining In The VMN Reservoir, Deposited Within The Connections And Inhalation Filter ) Via A VMN Attached To Three Connections In Five Scenarios (VMN+ T-Piece, VMN+ Old Combihaler, VMN+ New Combihaler, Pmdi+ VMN+ Old Combihaler, And Pmdi+ VMN+ New Combihaler) And A Pmdi Attached To Three Connections In Four Scenarios ( Pmdi+ Old Combihaler, Pmdi+ New Combihaler, Pmdi+ T-Piece (2 Puffs), And Pmdi+ T-Piece (5 Puffs) Using A Double Limb IMV Circuit.
B. characterizing The Aerodynamic Particle Size Of The Inhaled Mass Via Only Four Scenarios ( Pmdi+ VMN+ New Combihaler, VMN+ New Combihaler, VMN+ T-Piece, And Pmdi+ T-Piece (5 Puffs) Using ACI, A Close Representative Of Human Airway Geometry, Composed Of A Throat And Nine Stages With Variable Cut-Off Diameters. ACI Was Inserted Into IMV Circuit Besides The Incorporation Of A Breathing Simulator Via A Mixing Inlet (Modified ACI). The Drug Particles Were Passed Through The Impactor At A 15 L Min-1 Flow Rate. The Drug Collected from Every Stage Besides The Drug Remaining Inside The Nebulizer, The Connections, And On The Inhalation Filters Was Washed By 25% Acetonitrile.
C. Quantifying The Salbutamol In Aqueous Samples Using HPLC Analysis Method By Injecting The Sample Through An Auto-Sampler. The Analysis Method Was Done Through C18- Column At 25°C. The Mobile Phase Composed Of 90:10 Acetonitrile: Water With 0.1% Ortho-Phosphoric Acid Added To Water Was Pumped At A Flow Rate Of 1 Ml Min-1. UV Detection Was Predetermined At 225 Nm. The Salbutamol Samples Concentration Was Calculated Using A Pre-Developed Calibration Curve Based On Prepared Standard Solutions.
D. To Provide APSD (MMAD And FPF ≤ 5 µm) Of Emitted Dose Through Four Scenarios, Copley Software Was selected For Data Entry.
2. In-Vivo Study:
A. A Urinary PK Method Was Adopted To Estimate The Relative Pulmonary Bioavailability, Based On The Urine Sample Taken 30 Min Post-Dosing (USAL0.5), And The Systemic Bioavailability, Based On The Urine Sample Taken After Pooling The Urine Over The Upcoming 24hr Post-Dosing (USAL24). COPD Intubated Subjects Prescribed An Inhaled Salbutamol During Their Attacks Were Nominated For The Research After Consenting Their Trustees. The Research Continued For 8 Days For Each Subject. The Four Scenarios selected For Determining APSD Were Utilized For Completing The In-Vivo Research. The Salbutamol Dose, 1 Ml Nebulized Or 5 Puffs Of A Pmdi, Was Administered On Days 1, 3, 5, And 7 Using A Different Scenario Each Day. Stopping The Study Dosing For 48 Hr Prevented Any Interference Between Doses Of Different Scenarios By The Complete Clearance Of Salbutamol. The Urine Samples Were Taken Based On The Above Protocol. The Sample Volumes Were Recorded To Calculate The Excreted Amounts from Measured Concentrations.
B. Urine Sample Underwent SPE (High Recovery Method) Using Cation Exchange Cartridges Through A Manifold Instrument To Obtain A Highly Clean Extract With No Endogenous Interferents.
C. Quantifying The Salbutamol In Urine Samples By HPLC Analysis Method. The Same Method For Aqueous Sample Was Provided, But A C18 ODS Guard Column Was Used At UV Detection Predetermined At 220 Nm.
3. Ex-Vivo Study:
The Ex-Vivo Research Was Done On Days 2, 4, 6, And 8 Of The Study During Which The Washout-Period Of Salbutamol Was Provided. An Absolute Filter Was Placed Between Y-Tube And ETT To Collect The Total Emitted Dose That Would Be Inhaled By The Subject. The Samples Were Sonicated And Rinsed With 25% Acetonitrile. The Aqueous Samples Were Treated By The Same HPLC Analysis Method Performed With In-Vitro Aqueous Samples.
Statistical Analysis:
All Data Were Presented As Mean ± SD The Absolute Mass Of Salbutamol Delivered. For The In-Vitro Part, One-Way ANOVA With LSD Correction Were Used To Compare The Different Scenarios In Which A VMN And Pmdi Were Used Via Variable Connections. For In-Vivo And Ex-Vivo Parts, Kruskal-Wasllis Test Followed By Mann-Whitney Test Were Applied To Compare Urinary Salbutamol Amounts Excreted And Ex-Vivo TED. Data Didn’t Follow The Normal Distribution. For Significance, P ˂0.05 Was Chosen.
Results:
1. In-Vitro
No Significant Differences Were Observed Among All VMN/Connections At The Levels Of In-Vitro TED, The Remaining Mass Inside The Connection And VMN. However, Pmdi+ VMN+ New Combihaler And VMN+ New Combihaler Produced Significantly Higher FPF And Less MMAD Than VMN+ T-Piece (P˂0.01 For FPF And P≤ 0.01 For MMAD). No Significant Difference Was Noticed When Preliminary Pmdi Puffs Were Actuated Before Nebulization Based The Fate Of Dose Nebulized. The Pmdi+ T-Piece Produced Higher TED And Less Deposited Mass Into The Connection Compared To The Old And New Combihalers (P˂0.05). However, Pmdi+ T-Piece Delivered Significantly Greater MMAD And Less FPF Than Pmdi+ VMN+ New Combihaler And VMN+ New Combihaler (P˂0.01). When Increased The Actuated Doses Via The Pmdi+ T-Piece, A Non-Linear Rise In TED And The Deposition Mass Was Investigated.
2. In-Vivo And Ex-Vivo
The Subjects Who Completed The Study Were 24, Half Of Them Were Females. The Pmdi+ VMN+ New Combihaler Produced USAL0.5 And Ex-Vivo TED Significantly Higher Than VMN+T-Piece (P˂0.05 For USAL0.05 And P≤ 0.01 For TED). No Significant Differences Were Found Between VMN+ New Combihaler And Either Pmdi+ VMN+ New Combihaler Or VMN+T-Piece In Terms Of USAL0.5, USAL24, And Ex-Vivo TED Values. Likewise, There Were No Significant Difference Between Pmdi+ VMN+ New Combihaler And VMN+T-Piece In Terms Of USAL24 Values. The USAL 0.5, USAL24, And Ex-Vivo TED Produced By The Pmdi+ T-Piece Were The Significantly Least, Compared To Other VMN/Connections (P < 0.001).
Conclusion:
1. In-Vitro
The Old And New Combihalers Had An Equal Efficacy To VMN Standard T-Piece In Delivering Salbutamol Aerosols Via A VMN To COPD Subjects Through IMV. However The Combihaler Achieved Better Aerodynamic characteristics Than VMN+ T-Piece. Pmdi Puffs Hadn’t A Significant Impact On The Aerosol Delivered By A VMN Through Combihalers. Therefore, Clinical Studies For More Evaluation Were Needed. Pmdi+ T-Piece Delivered Higher Aerosols Than Combihalers, But The Aerodynamic characteristics Of The Delivered Mass Was Suboptimal.
2. In-Vivo And Ex-Vivo
The Pulmonary Aerosol Delivery By The Combihaler Was Better Than That Of VMN Standard T-Piece, When A Bronchodilator Pmdi Dosing Was Provided Before Nebulization. The Impact Of Pmdi Puffs Needs Further Clinical Trials With Non-Bronchodilator Nebulized Medications. Pmdi Dosing (More Than 500µg) Through Pmdi+ T-Piece Needs To Be Evaluated To Give Pulmonary Aerosol Deposition Comparable To That Produced By The VMN Attached To Its Standard T-Piece Or Combihaler.