The current study aimed to improve the dissolution rate and physical stability of two antihypertensive drugs, hydrochlorothiazide, and valsartan, through the development of a co-amorphous system. A co-amorphous system was successfully prepared at molar ratios of 1:1, 1:2, and 1:6 employing rotary evaporation technique. Characterization of the formulations was performed using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis. Powder X-ray diffraction confirmed the amorphous nature of all samples, which remained physically stable under ambient dry conditions for at least 8 months. Differential scanning calorimetry confirmed the formation of a single-phase system. The experimental glass transition temperature values revealed a negative deviation from those calculated by the Gordon-Taylor equation, indicating nonideal mixing and intermolecular interactions. Fourier transform infrared spectroscopy spectra supported these findings, showing peak broadening in regions corresponding to the functional groups of the parent drugs. The thermogravimetric analysis demonstrated that the samples were thermally stable, with no degradation observed up to 100°C. Dissolution studies performed in phosphate buffer (pH 6.8, 25°C) revealed significant enhancements in the dissolution rates of both hydrochlorothiazide and valsartan from the co-amorphous formulations compared to their unprocessed forms and corresponding physical mixtures. A validated high-performance liquid chromatography method was developed for the simultaneous analysis of hydrochlorothiazide and valsartan using a Shimadzu LC-2030C 3D Plus system with a photodiode array detector. Separation was achieved on a Waters C18 column (250 × 4.6 mm, 5 μm) using a mobile phase of acetonitrile, methanol, and ammonium acetate buffer (20:50:30, v/v) at a flow rate of 0.70 mL/min. Detection wavelengths were set at 271 nm for hydrochlorothiazide and 249 nm for valsartan. The method showed good linearity in the range from 0.0033 to 0.0670 mM (3.3-67.0 μM), precision (RSD < 2%), and reproducibility, with hydrochlorothiazide and valsartan eluting at 3.5 and 7.2 min, respectively. At the first minute, hydrochlorothiazide release increased by approximately 8.5-, 8.7-, and 7.1-fold from the 1:1, 1:2, and 1:6 co-amorphous systems relative to the unprocessed drug, and by 4.5-, 4.8-, and 2.4-fold, respectively, compared to the corresponding physical mixtures. For valsartan, the co-amorphous systems showed 2.9-, 2.6-, and 1.9-fold improvements over the unprocessed drug, and 1.5-, 1.8-, and 1.5-fold improvements over the matching physical mixtures at the same molar ratios. Calcium carbonate was physically mixed with all samples to minimize gelation upon aqueous exposure. These results suggest that co-amorphous formulation is a promising strategy for enhancing the dissolution rate and physical stability of hydrochlorothiazide and valsartan.

We evaluate the consequences of medicine supply disruptions for healthcare utilization, care fragmentation, and costs. To provide causal evidence on such systemic effects, we examine the global recall of valsartan in July 2018, a widely used antihypertensive medicine. Drawing on German healthcare claims data covering 30,976 affected patients, we employ a difference-in-differences design with matched patients unaffected by supply disruptions. We find that nearly 70% of valsartan users discontinued medication but switched to other treatments, keeping the overall provision of antihypertensive care stable. Pharmaceutical costs rose, driven primarily by a 5.3% increase in costs for antihypertensives, imposing a significant financial burden on insurers. The recall temporarily increased general practitioner service utilization and care fragmentation, while pharmacy fragmentation persisted for up to a year, affecting one in five patients. Our quantification of hidden adjustment costs and burden-shifting effects in outpatient care underscores the need for pharmaceutical shortage management policies that recognize the temporary inefficiencies specifically introduced into medicine dispensing. Our findings generalize to other sudden supply disruptions and likely represent a benchmark of the consequences of medicine shortages.

Minimally invasive lumbar spinal surgery can precipitate rare perioperative Takotsubo syndrome (stress-induced cardiomyopathy, SIC), a condition frequently misdiagnosed as acute myocardial infarction. Cardiac magnetic resonance (CMR) serves as a valuable diagnostic tool for the multimodal evaluation of Takotsubo syndrome, helping exclude alternative etiologies such as myocarditis. Diagnosis of Takotsubo syndrome relies on comprehensive integration of clinical manifestations, ventricular imaging, coronary angiography, electrocardiography, and cardiac biomarkers, rather than depending on CMR alone. We herein report the case of a 66-year-old postmenopausal woman without conventional cardiovascular risk factors who developed Takotsubo syndrome shortly after elective lumbar discectomy. Obstructive coronary artery lesions were ruled out by coronary angiography. Owing to the patient's claustrophobia, we implemented a combined imaging protocol of two-dimensional speckle-tracking echocardiography (2D-STE) and dynamic single‑photon emission computed tomography (D-SPECT), which verified reversible myocardial dysfunction. The patient received guideline-directed medical therapy consisting of sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and a sodium‑glucose cotransporter 2 (SGLT2) inhibitor. Cardiac biomarkers returned to normal levels on postoperative day 11, and myocardial strain parameters showed substantial improvement at the eight-week outpatient follow-up. This case underscores the need for clinical vigilance for Takotsubo syndrome after spinal surgery. In this individual patient with CMR contraindications, combined 2D‑STE and D‑SPECT provided complementary supportive diagnostic information. Further studies are required to validate the general utility of this multimodal imaging approach.

Background and Clinical Significance: Heart failure with reduced ejection fraction (HFrEF) is highly prevalent among patients with end-stage kidney disease (ESKD) undergoing maintenance hemodialysis (MHD) and is associated with poor clinical outcomes. Sacubitril/valsartan (SV) is a cornerstone therapy for HFrEF; however, its use in dialysis patients remains limited due to safety concerns and lack of robust evidence. This case series describes the clinical response and safety of SV in patients with HFrEF receiving MHD; Case Presentation: Four male patients with HFrEF undergoing MHD were treated with SV and followed for 12 months. Baseline evaluation showed a left ventricular ejection fraction (LVEF) of 35.5%, left ventricular end-systolic volume (LVESV) of 118.5 mL, left ventricular end-diastolic volume (LVEDV) of 185.7 mL, pulmonary artery systolic pressure (PASP) of 52.7 mmHg, and NT-proBNP levels above 35,000 pg/mL in all patients. After 12 months of SV therapy, LVEF improved to 53.7%, corresponding to a 51.4% relative increase from baseline. Reverse cardiac remodeling was observed, with LVESV decreasing to 58.2 mL and LVEDV to 110 mL, together with reductions in left ventricular dimensions. PASP decreased to 32 mmHg, and NT-proBNP levels declined to 7261.7 pg/mL. Blood pressure improved, serum potassium remained stable at 4.95 mmol/L, and no severe hyperkalemia, intradialytic hypotension, post-dialysis hypotension, or heart failure-related hospitalization occurred; Conclusions: In this case series, SV was associated with improved cardiac function, reverse remodeling, pulmonary pressure reduction, and an acceptable safety profile in patients with HFrEF undergoing MHD. These findings suggest a potential therapeutic role for SV in selected dialysis patients and support further investigation.

Sacubitril/valsartan is increasingly used in pediatric cardiac patients, though its acute physiologic effects in critically ill children remain incompletely characterized. We sought to define the early hemodynamic and tissue-level response to sacubitril/valsartan using high-fidelity physiologic data. This was a retrospective study of children in a cardiac intensive care unit with continuous physiologic monitoring. High-resolution data were temporally aligned to the time of sacubitril/valsartan initiation. Locally weighted regression was used to characterize percent change in physiologic variables relative to baseline. Linear mixed effects models were used to estimate post-initiation trends in absolute units from 2 to 24 h, accounting for repeated measures within patients and adjusting for age, ventricular assist device status, milrinone exposure, and circulatory physiology. Unsupervised clustering using Ward linkage was performed on percent change features to assess heterogeneity in response. Fifty-nine patients were included in the final analyses. Following sacubitril/valsartan initiation, heart rate and systolic blood pressure decreased while diastolic and mean arterial pressure increased. Central venous pressure rose over time. Measures of systemic oxygen delivery improved, including pulse oximetry and renal near-infrared spectroscopy (NIRS), with the largest effect observed in renal NIRS. These changes were consistent across models and remained significant after adjustment. Clustering identified two response patterns, reflecting differences in magnitude rather than distinct physiologic phenotypes. Sacubitril/valsartan initiation in critically ill children is associated with coordinated changes in arterial, venous, and tissue-level physiology consistent with improved systemic oxygen delivery. The response appears continuous, with variability in magnitude across patients rather than discrete phenotypes.

Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor (ARNIs), has antihypertensive and organ-protective effects. However, previous meta-analyses have mainly compared it with angiotensin receptor blockers (ARBs) and neglected other commonly used antihypertensive agents, while its effect on ambulatory blood pressure remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of sacubitril/valsartan in patients with hypertension. We searched CNKI, Wanfang, VIP, PubMed, Embase, and the Cochrane Library from inception to June 2025 for randomized controlled trials comparing sacubitril/valsartan with ARBs or calcium channel blockers (CCBs). Fifteen studies involving 4,824 hypertensive patients were included. Compared with ARBs or CCBs, sacubitril/valsartan significantly reduced 24-hour systolic variability (24hSBPV) and 24-hour diastolic blood pressure variability (24hDBPV), as well as 24-hour, daytime, and nighttime ambulatory blood pressure. It also improved the dipper blood pressure proportion and blood pressure control rate. Subgroup analysis showed that both 200 mg/d and 400 mg/d dosages achieved superior antihypertensive efficacy. In terms of safety, sacubitril/valsartan had a similar adverse event profile to CCBs. Compared with ARBs, sacubitril/valsartan at 200 mg/d was associated with a lower incidence of serious adverse events (SAE), and the overall rate of liver function abnormalities was also reduced. Sensitivity analyses confirmed robust results with no significant publication bias. In conclusion, sacubitril/valsartan effectively improves multiple ambulatory blood pressure parameters with a favorable safety profile, supporting its rational use in hypertensive patients.

To determine the effects of the comprehensive disease-modifying pharmacological approach among patients with heart failure with reduced ejection fraction, a cross-trial, aggregate-data analysis was performed to estimate the expected combined effect of quintuple therapy by multiplying trial-level HRs, assuming independent and multiplicative treatment effects from Phase III randomised clinical trials: EMPHASIS-HF, PARADIGM-HF, pooled DAPA-HF and EMPEROR-Reduced, and pooled VICTORIA and VICTOR. The imputed aggregate treatment effects on the primary endpoint of cardiovascular death or first heart failure hospitalisation were favourable to the quintuple compared with conventional therapy (HR 0.34; 95% CI [0.27-0.42]). This also occurred for cardiovascular death alone (HR 0.47; 95% CI [0.35-0.63]), first heart failure hospitalisation (HR 0.31; 95% CI [0.23-0.40]) and all-cause mortality (HR 0.51; 95% CI [0.39-0.67]). The numbers needed to treat per year for the primary outcome, cardiovascular death and first heart failure hospitalisation were 10, 23 and 15, respectively. Our findings support the potential benefit of comprehensive therapy, with the incremental role of vericiguat likely greatest in higher-risk patients or those with recent worsening heart failure.

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) widely used in human heart failure and has demonstrated potential cardiorenal and neurohormonal effects in experimental canine studies. Hydrochlorothiazide is a thiazide diuretic that acts at a more distal segment of the nephron than furosemide. Its addition to loop diuretic therapy may enhance sodium and fluid excretion through sequential nephron blockade and thereby improve the diuretic response in cases of refractory congestion. However, information regarding the combination of these two drugs in cats with congestive heart failure is lacking. This report describes the long-term clinical outcome of a cat with recurrent cardiogenic pleural effusion treated with sacubitril/valsartan and hydrochlorothiazide. A 14-year-old spayed female Persian-cross cat was referred for severe respiratory distress caused by recurrent pleural effusion. Echocardiography identified advanced cardiomyopathy with a nonspecific phenotype and overlapping hypertrophic and restrictive features, including focal basal septal hypertrophy, biatrial enlargement, atrial fibrillation and spontaneous echocardiographic contrast. Despite conventional treatment, which included pimobendan, torasemide, and antithrombotic medications, the cat experienced multiple episodes of pleural effusion over the following months, requiring repeated thoracocentesis. Consequently, the treatment regimen was expanded to include sacubitril/valsartan and hydrochlorothiazide. According to the owner, all other cardiac medications were discontinued approximately one week later without veterinary consultation. At long-term follow-up approximately two years after sacubitril/valsartan and hydrochlorothiazide therapy initiation, the cat remained clinically stable, with no further episodes of respiratory distress. Echocardiography revealed persistent severe structural heart disease, although improved left ventricular systolic indices were observed. This case report describes prolonged clinical stabilization in a cat with advanced cardiomyopathy and recurrent congestive heart failure following the administration of sacubitril/valsartan and hydrochlorothiazide over a two-year period. Whether this outcome reflects a specific effect of sacubitril/valsartan, the addition of hydrochlorothiazide, or a combination of both cannot be determined from a single observation. Nonetheless, the duration and completeness of the response observed here warrant prospective evaluation of combination of ARNI therapy and hydrochlorothiazide in cats with refractory congestive heart failure. Further studies are needed to assess the safety and effectiveness of this approach in feline cardiomyopathy.