الفهرس 
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Abstract
Salbutamol is a short acting B2 agonist, recommended for first line management of asthma and COPD acute exacerbations. Also, inhaled drugs administered during mechanical ventilation provide greater and faster clinical outcome than when delivered during spontaneous unassisted breathing. Several studies revealed that VMNs provide a dose emission that is 2-4 folds greater than traditional JNs which are used in majority of Egyptian hospitals.
Also it was previously proven that for COPD patients, the depth of aerosol deposition is directly related to FEV1. For that a new double cone shaped inhalation chamber ”combihaler”, designed to connect both pMDIs and nebulizers to NIV circuit, could be used to give the patient a preliminary bronchodilator dose in an attempt to increase FEV1 before nebulization.
Aims of the work:
- To determine the respective dose emission properties and relative pulmonary deposition of salbutamol generated from SOLO with two volume different spacers connected within NIV circuit in order to compare their effectiveness in aerosol delivery.
- To study the effect of a preliminary bronchodilator dose in order to optimize aerosol delivery to the lungs.
Methodology:
To achieve the aims of this study, the work has been divided into three main parts:
1. In-vitro study that include:
A. Determination of the fate of TED of salbutamol within single limb NIV circuit (drug retained on nebulizer chamber, connections, inhalation and expiration filters). Comparing the three different connections to SOLO; I: t-piece II: combihaler III: combihaler with a pMDI preliminary bronchodilator dose.
B. characterization of the emitted dose through ACI, which simulates human lung geometry; consisting of throat and nine stages with a descending pore size. ACI was connected into NIV circuit, at flow rate of 15 l.min-1, and then drug was collected and washed from every stage and throat in definite volumes of 30% acetonitrile.
C. Determination of salbutamol in aqueous samples by HPLC method by sample injection through auto-sampler. Separation was performed through C18 Column at 25oC. Mobile phase was 90:10 acetonitrile: water [0.1% ortho-phosphoric acid] at flow rate 1 ml.min-1. UV detector was set at 225 nm. The concentrations were retrieved from a pre-constructed calibration curve of prepared standard solutions.
D. Data entry into Copley software to obtain main aerodynamic characteristics of generated aerosol with the three different connections to SOLO that provides a powerful tool for comparison; the fine particle doses (FPD ≤ 5μm and FPD ≤ 3μm), fine particle fractions (FPF ≤ 5μm and FPF ≤ 3μm ), MMAD and GSD.
2. In-vivo study that include:
A. Urinary pharmacokinetic study based on absorption lag time, for six days including twelve NIV COPD patients prescribed to inhale salbutamol for their acute exacerbations. Three study doses were given randomly at day 1, 3 and 5 of the study by SOLO using the three different connections. Urine samples were collected to determine the relative lung and systemic bioavailability of salbutamol. Two urine samples were collected for each dose; the first was 30 min post-dose which reveals the effective lung dose. However, the second that was collected for the next 24 hr post-dose reveals the systemic absorption. Volumes were recorded to interpret the total excreted amount from measured concentrations.
B. SPE of urine samples through cation exchange cartridges to obtain a primary ”clean” extract, free from any endogenous interfering compounds.
C. Determination of salbutamol in urine samples by HPLC method. Using the same HPLC method for aqueous samples, changing the mobile phase to be 90:10 acetonitrile: water [0.1% glacial acetic acid + 0.1% triethanolamine], at UV detection at 220 nm.
3. Ex-vivo study:
It was performed at washout periods of the study; days 2, 4 and 6 by placing a filter between patient mask and aerosol generator to collect the inhalable fraction that is assumed to reach to the patient. That is followed by filters sonication and rinsing in 30% acetonitrile, then determination of salbutamol in aqueous samples by HPLC method similar to that of in-vitro aqueous samples.
Statistical Analysis:
All data was compared as percentages of nominal dose to minimize bias toward connection III for its higher nominal dose. For the in-vitro part of the study, one-way ANOVA with the application of LSD correction was used to compare the three different connections to SOLO. However, two-ways ANOVA with the application of LSD correction was used to compare between the salbutamol urinary excretions from in-vivo results as well as salbutamol on ex-vivo filters, for the three connections to SOLO (p < 0.05 was considered significant).
Results:
1. In-Vitro study:
No significant difference was found in the fate of nebulized dose for the three connections. However, TID percentages of both combihaler connections (II and III) were slightly greater than that of t-piece. However, percentage of loss within connections was slightly higher with t-piece than both combihaler connections (II and III).
However, combihaler with pMDI (connection III) had significantly greater FPD ≤ 5μm percentage and MMAD than both t-piece and combihaler without pMDI. However, t-piece had significantly higher FPF ≤ 3μm than both combihaler connections (II and III).
2. In-vivo study:
No significant difference was found between the three connections for in-vivo results. However, combihaler with pMDI showed the highest percentage of USAL0.5 followed by t-piece and combihaler without pMDI that was nearly equal. On the other hand, t-piece had the lowest percentage of USAL24. However, both combihaler connections (II and III) were nearly equal.
3. Ex-vivo study:
No significant difference was found between the three connections for ex-vivo results. However, combihaler with pMDI showed the highest percentage of SALF followed by combihaler without pMDI then t-piece which delivered the lowest dose.
Conclusion:
1. In-Vitro study:
The main finding of in-vitro study was that t-piece and combihaler were found to be equally efficient for salbutamol delivery to COPD patients from SOLO in single limb NIV. However, when two puffs of salbutamol pMDI was given as a preliminary dose pre-nebulization through combihaler; they produce significant aerodynamic particle size alteration to a statistically significant level by saving some fine particles (3-5 μm) from condensation on the t-piece or from deposition by electrostatics.
2. In-vivo study:
In-vivo results emphasized that t-piece and combihaler were equally efficient concerning the effective lung dose of salbutamol. However, adding a preliminary bronchodilator dose pre nebulization was found to optimize the salbutamol fraction delivered to lungs only to a statistically non-significant level. Also, a fraction lost by condensation within t-piece, leads to the lowest overall systemic absorption with it.
3. Ex-vivo study:
Ex-vivo results was matching with in-vitro fate of the dose and in-vivo results; the total inhalable fraction of salbutamol was not significantly different for the three connections, with the slightly higher fraction observed with the addition of a preliminary bronchodilator dose pre nebulization.
Finally, it was recommended to use combihaler with a preliminary bronchodilator dose for better salbutamol delivery to the lungs; to increase the percentage of FPD ≤ 5µm, reduce the fraction of aerosol lost by condensation or deposition and enhance aerosol peripheral penetration to the lung as much as possible. However, the choice between these connections for other medications could be simply based on the target site of drug deposition inside the lungs.