Temperature Variations around Medication Cassette and Carry Bag in Routine Use of Epoprostenol Administration in Healthy Volunteers

<div><h3>Background</h3><p>According to several treatment guidelines, epoprostenol is an important treatment option for pulmonary arterial hypertension. However, the pharmacokinetic characteristics and poor stability of epoprostenol at room temperature make its administration challenging. We therefore studied temperature fluctuations between the drug administration cassette and atmosphere to promote the safe use of epoprostenol.</p> <h3>Methods and Findings</h3><p>Five healthy volunteers carried a portable intravenous infusion pump attached to a medication cassette containing saline in a bag during their ordinary activities over 16 days during which the mean atmospheric temperature was 29.6±1.5°C. The temperature around the medication cassette was not less than 25°C on any occasion, and the mean period over 24 h during which the temperature around the cassette exceeded 35°C and 40°C was 96.9±156.4 min and 24.4±77.3 min, respectively. Significant correlations were observed between the temperatures outside the bag and around the cassette, as well as between temperatures around the cassette and of the saline solution in the cassette (r = 0.9258 and 0.8276, respectively). There were no differences in the temperatures outside the bag or around the cassette with respect to the bag material.</p> <h3>Conclusions</h3><p>Temperatures around a medication cassette and outside the bag containing the medication increase with sunlight exposure. The temperature around cassettes used for administering epoprostenol must therefore be kept low for as long as possible during hot summer conditions to maintain the drug stability.</p> </div

Temperature changes around the medication cassette.

<p>Temperature changes around the medication cassette.</p

Stereospecific Synthesis of Tris-heteroleptic Tris-cyclometalated Iridium(III) Complexes via Different Heteroleptic Halogen-Bridged Iridium(III) Dimers and Their Photophysical Properties

Herein, we report on the stereospecific synthesis of two single isomers of tris-heteroleptic tris-cyclometalated iridium­(III) (Ir­(III)) complexes composed of three different nonsymmetric cyclometalating ligands via heteroleptic halogen-bridged Ir dimers [Ir­(tpy)­(F₂ppy)­(μ-Br)]₂ <b>17b</b> and [Ir­(mpiq)­(F₂ppy)­(μ-Br)]₂ <b>27b</b> (tpyH: (2-(4′-tolyl)­pyri­dine) and F₂ppyH: (2-(4′,6′-di­fluoro­phenyl)­pyridine), and mpiqH: (1-(4′-methyl­phenyl)­iso­quinoline)) prepared by Zn²⁺-promoted degradation of Ir­(tpy)₂­(F₂ppy) <b>21</b> and Ir­(mpiq)₂­(F₂ppy) <b>26</b>, as reported by us. Subsequently, <b>17b</b> and <b>27b</b> were converted to the tris-heteroleptic tris-cyclometalated Ir complexes Ir­(tpy)­(F₂ppy)­(mpiq) <b>25</b> consisting of tpy, F₂ppy, and mpiq, as confirmed by spectroscopic data and X-ray crystal structure analysis. The first important point in this work is the selective synthesis of specific isomers among eight possible stereoisomers of Ir complexes having the same combination of three cyclometalating ligands. Namely, two meridional forms of <b>25</b> were synthesized and isolated. The second finding is that the different stereoisomers of <b>25</b> have different stability. Finally, different stereoisomers exhibit different emission spectra. Namely, one of its stereoisomers <b>25a</b> exhibits a single broad emission from <i>ca</i>. 550 nm to <i>ca</i>. 650 nm (orange emission), while stereoisomer <b>25c</b> emits dual emission at <i>ca</i>. 509 nm and <i>ca</i>. 600 nm (pale pink emission), as supported by time-dependent density functional theory calculation. To the best of our knowledge, this is the first report of the selective and efficient synthesis of different stereoisomers of tris-heteroleptic tris-cyclometalated Ir­(III) complexes that have different stabilities and different photophysical properties

Difference in temperature correlation by material of the bag.

<p>Correlations between temperature outside the bag and temperature around the cassette in (A) cloth bags and (B) leather/synthetic leather bags in daytime (×) and nighttime (○). The relativity of temperatures within groups was analyzed using the CORR procedure. Regression curves from plotted graphs were calculated using the GLM procedure.</p

Efficient Synthesis of Tris-Heteroleptic Iridium(III) Complexes Based on the Zn²⁺-Promoted Degradation of Tris-Cyclometalated Iridium(III) Complexes and Their Photophysical Properties

We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the degradation of tris-cyclometalated Ir complexes (IrL₃, L: cyclometalating ligand) in the presence of Brønsted and Lewis acids such as HCl (in 1,4-dioxane), AlCl₃, TMSCl, and ZnX₂ (X = Br or Cl), which affords the corresponding halogen-bridged Ir dimers (μ-complexes). Tris-cyclometalated Ir complexes containing electron-withdrawing groups such as fluorine, nitro, or CF₃ moieties on the ligands were less reactive. This different reactivity was applied to the selective degradation of heteroleptic Ir complexes such as <i>fac</i>-Ir­(tpy)₂(F₂ppy) (<i><b>fac</b></i><b>-12</b>) (tpy: 2-(4′-tolyl)­pyridine and F₂ppy: 2-(4′,6′-difluorophenyl)­pyridine), <i>mer</i>-Ir­(tpy)₂(F₂ppy) (<i><b>mer</b></i><b>-12</b>), and <i>mer</i>-Ir­(mpiq)₂(F₂ppy) (<i><b>mer</b></i><b>-15</b>) (mpiq: 1-(4′-methylphenyl)­isoquinoline). For example, the reaction of <i><b>mer</b></i><b>-12</b> with ZnBr₂ gave the heteroleptic μ-complex [{Ir­(tpy)­(F₂ppy)­(μ-Br)}₂] <b>27b</b> as a major product, resulting from the selective elimination of the tpy ligand of <i><b>mer</b></i><b>-12</b>, and treatment of <b>27b</b> with acetylacetone (acacH) afforded the corresponding tris-heteroleptic Ir complex Ir­(tpy)­(F₂ppy)­(acac)<b>18</b>. In addition, another tris-heteroleptic Ir complex <b>35a</b> having 8-benzene­sulfonyl­amido­quinoline (8BSQ) ligand was synthesized. Mechanistic studies of this degradation reaction and the photochemical properties, especially a dual emission, of these newly synthesized tris-heteroleptic Ir complexes are also reported

Atmospheric temperature and time durations when the temperature around the cassette exceeded 25°C, 35°C, and 40°C.

<p>Atmospheric temperature and time durations when the temperature around the cassette exceeded 25°C, 35°C, and 40°C.</p

Patient inclusion.

<p>Flow chart describing patient inclusion protocol. Within the study period (2001–1013) 58 patients with PAH received IVI epoprostenol in Keio University hospital. Among the group, 16 patients were excluded from this study because they were lost to follow up, had missing protocols, died, or underwent a lung transplantation soon after the initiation of IVI epoprostenol.</p

Typical protocols for rapid and slow initiation of therapy.

<p>The blue and red lines indicate the standard dosing schedules for the slow- and rapid-initiation IVI epoprostenol therapy, respectively.</p

Improvements in hemodynamic data following IVI epoprostenol therapy.

<p>At follow up, the rapid-initiation group achieved significant improvements in mPAP, PVR and CI compared with the slow-initiation group, while there were no significant differences at baseline. mPAP: mean pulmonary artery pressure, PVR: pulmonary vascular resistance, CI: cardiac index, NS: not significant</p

Cumulative epoprostenol dose for each patient.

<p>Bars show the cumulative dose of epoprostenol per body weight within the initial 180 days. The blue and red bars describe each patient’s cumulative dose in the slow- and rapid-initiation groups, respectively.</p