Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.

BACKGROUND: Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure. CASE PRESENTATION: The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased. CONCLUSIONS: Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.

Factors influencing the effectiveness of recombinant human soluble thrombomodulin on disseminated intravascular coagulation: a retrospective study.

BACKGROUND: Although recombinant human soluble thrombomodulin (rTM) has been widely used to treat disseminated intravascular coagulation (DIC) in Japan, there is no consensus regarding rTM efficacy. Therefore, if the factors influencing rTM efficacy is revealed, it may be possible to demonstrate the effectiveness of rTM by limiting the patients who use rTM. This study investigated the factors of rTM treatment which influence DIC status. METHODS: This retrospective case-control study enrolled hospitalized adult patients treated with rTM from October 2010 to May 2020. Among these patients, 227 who were diagnosed with DIC according to the Japanese Association for Acute Medicine DIC scoring system were assessed. The primary endpoint was the 28-day mortality after rTM treatment. For Cox-proportional hazards model, explanatory factors determined using univariate analysis with p <  0.1 were used. In addition, some factors considered to affect DIC-related mortality such as age ≥ 75 years, rTM dose ≥380 U/kg, antithrombin III treatment, and diseases with a poor prognosis (sepsis, solid tumors, and trauma) were added as covariates. RESULTS: Univariate analyses suggested that male sex (p = 0.029), treatment in intensive care unit (p = 0.061), and prothrombin time-international normalized ratio (PT-INR) (p <  0.001) were the factors influencing DIC-related 28-day mortality after rTM treatment. According to Cox-proportional hazard analysis, the adjusted odds ratio for DIC-related 28-day mortality in patients with PT-INR ≥ 1.67 was 2.23 (95% confidence interval: 1.451-3.433, p <  0.001), age ≥ 75 years was 1.57 (95% confidence interval: 1.009-2.439, p = 0.046), and male sex was 1.66 (95% confidence interval: 1.065-2.573, p = 0.025), respectively. As life-threatening bleeding events were not observed, prolonged PT-INR might directly or indirectly affect DIC-related mortality caused by rTM treatment. CONCLUSION: rTM treatment for DIC was less effective in male patients with PT-INR ≥ 1.67 and age ≥ 75 years.

Gene silencing in a mouse lung metastasis model by an inhalable dry small interfering RNA powder prepared using the supercritical carbon dioxide technique.

In this study, a novel dry small interfering RNA (siRNA) powder for inhalation, containing chitosan and mannitol, was prepared using the supercritical carbon dioxide (CO2) technique. Although the siRNA/chitosan powder was difficult to disperse because of a long needle-like structure, it could be reduced to fragments of 10-20 µm by manual grinding, which allowed for administration into mice. Electrophoresis revealed that the supercritical CO2 technique and manual grinding didn't greatly affect the integrity of the siRNA. Furthermore, the siRNA was more stable in the lungs than in blood, suggesting the utility of pulmonary delivery. Biodistribution experiments using Cy5.5-labeled siRNA demonstrated that pulmonary administration of the powder achieved a prolonged exposure of the siRNA/chitosan complex on the lung epithelial surface at a higher concentration. For the evaluation of the in-vivo gene silencing effect of the siRNA/chitosan powder, mice bearing colon26/Luc cells were used. The powder significantly inhibited the increase in luminescence intensity in the lungs, but the siRNA/chitosan solution and a non-specific dry siRNA/chitosan powder didn't, indicating the effective and specific gene silencing against the tumor cells metastasized in the lungs of mice by the siRNA/chitosan powder. These results strongly indicate that inhalable dry siRNA powders have the possibility of effective pulmonary gene silencing and that the supercritical CO2 technique can be applied to the production.

Inhalation performance of physically mixed dry powders evaluated with a simple simulator for human inspiratory flow patterns.

PURPOSE: To construct a simple simulator reproducing human inspiratory flow patterns and use it to evaluate the inhalation performance of active ingredient particle-carrier particle systems (physically mixed dry powders). METHODS: Inspiratory flow patterns were collected and analyzed using a flow recorder. The simulator was constructed using an airtight container, a valve, and a connecting tube. Several of the patterns reproduced by the simulator were compared with those recorded. In addition, the influence of inspiratory flow on the inhalation performance of physically mixed dry powders composed of salbutamol sulfate (SS) and coarse lactose monohydrate was investigated using a twin-stage liquid impinger (TSLI) equipped with the simulator. RESULTS: Human inspiratory flow patterns could be characterized by three parameters: inspiratory flow volume (area under the flow rate-time curve (AUC)), flow increase rate (FIR), and peak flow rate (PFR). The patterns could be reproduced using the simulator. Testing with the simulator in vitro revealed that PFR, but not FIR or AUC, greatly affected the inhalation performance of physically mixed dry powders. CONCLUSIONS: The simulator is simple to construct and can schematically reproduce human inspiratory flow patterns. Testing with a TSLI and the simulator is useful to evaluate dry powder formulations for clinical application.