Therapeutic improvements of nifedipine controlled-release tablets combined with sacubitril valsartan on patients with diabetic nephropathy complicated with hypertension.

This study aimed to evaluate the efficacy of nifedipine controlled-release tablets combined with sacubitril valsartan in diabetic nephropathy (DN) patients with hypertension. One hundred and twelve DN patients with hypertension were enrolled. They were randomly divided into the control group (treated with nifedipine controlled-release tablets combined with valsartan) and the observation group (treated with nifedipine controlled-release tablets combined with sacubitril valsartan). Renal function, endothelial function and inflammatory response were examined. After three-months treatment, the levels of clinical indexes (glycosylated hemoglobin, fasting blood glucose, systolic and diastolic blood pressure), renal function indicators (urinary albumin excretion rate, blood urea nitrogen, serum creatinine and cystatin C), endothelial function indicators (microalbumin, angiotensin II, thrombomodulin and cartilage oligomeric matrix protein) and inflammatory response factors (interleukin-6 and tumor necrosis factor-α) in the observation group were significantly lower than those in the control group. Nifedipine controlled-release tablets combined with sacubitril valsartan could effectively alleviate the progression of DN combined with hypertension.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients. DISCLOSURES: Dr Huang had stock ownership in Gilead and Pfizer. Dr Liang received support for article processing and medical writing.

Novel antihypertensive agents for resistant hypertension: what does the future hold?

Finding complementary compelling novel therapeutic agents for better control of blood pressure in people with resistant hypertension is moving into unchartered territory. The latest therapeutic developments explore approaches in the clinical arena that were either not examined or could only be examined in animal models two decades ago. Four main mechanisms have now been explored and operationalized in drug development: (a) mineralocorticoid receptor blockade using a nonsteroidal structure with many fewer side effects, (b) an aminopeptidase A inhibitor that has central effects on vasopressin, (c) a combined endothelin A and B receptor blocker and (d) an aldosterone synthase inhibitor devoid of glucocorticoid activity. All these agents are either completing Phase II development and starting Phase III or are involved in the ongoing recruitment of Phase III trials. Additionally, novel agents use antisense inhibition to block angiotensinogen development in the liver. These agents are discussed only for completeness, as they are still in Phase II trial development. Last, another agent that was initially being developed as an antihypertensive and once the data were reviewed by the company clearly showed efficacy as a heart failure agent was sacubitril/valsartan, which was ultimately approved. However, there are some discussions about reinvigorating the quest for an indication for hypertension, although no such steps have been formally initiated.

Clinical Effect of Qili Qiangxin Capsule Combined with Sacubitril-Valsartan in Patients with Chronic Heart Failure.

The clinical effect of Qili Qiangxin capsule combined with sacubitril-valsartan on patients with chronic heart failure was studied. We selected 108 patients with chronic heart failure in our hospital from March 2016 to January 2020 and divided them into a control group and a study group according to the random table method, with 54 cases in each. The control group took sacubitril and valsartan orally, and the study group took Qili Qiangxin pill on the basis of sacubitril and valsartan. The course of the treatment for 2 groups is 4 weeks. We compared the total effective rate of the treatment of the 2 groups for 4 weeks, cardiac function (left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF)) before and after 4 weeks of treatment, 6 min walking distance (6MWT), changes in cTnI and NT-proBNP levels, and adverse reactions. The total effective rate in the study group (90.74%) is higher than that in the control group (72.22%) (P＜0.05). After 4 weeks of treatment, the study group LVESV (45.23 ± 2.98 mm) and LVEDV (43.38 ± 4.01 mm) are lower than those of the control group ((49.98 ± 2.56 mm) and (50.75 ± 3.49 mm), respectively), while LVEF (47.38 ± 2.78%) is higher than that in the control group (42.08 ± 3.24%) (P ＜ 0.05). After 4 weeks of treatment, the study group 6MWT (476.58 ± 31.25 m) of patients with chronic heart failure is higher than that of the control group (396.52 ± 24.52 m) (P ＜0.05). After 4 weeks of treatment, the study group serum cTnI (0.36 ± 0.12 µg/L) and NT-proBNP (276.91 ± 30.12 pg/ml) of patients with chronic heart failure are lower than those in the control group (0.87 ± 0.25 µg/L) and (367.48 ± 48.57 pg/ml) (P＜0.05). There is no significant difference between the adverse reactions in the two groups (P ＞ 0.05). Conclusion: Xinbao pills combined with sacubitril and valsartan have a good effect on patients with chronic heart failure, which can improve the heart function and exercise endurance and reduce serum cTnI and NT-proBNP levels.

Design, synthesis and biological evaluation of 1,5-disubstituted α-amino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders.

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.

Sacubitril/Valsartan: A New Dawn has Begun! A Revisited Review.

Heart Failure (HF) is among the major causes of global morbidity as well as mortality. Increased prevalence, frequent and prolonged hospitalization, rehospitalization, long-term consumption of healthcare resources, absenteeism, and death upsurge the economic burden linked to HF. For decades, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Blockers (ARBs), Beta-Blockers (BBs), and mineralocorticoid receptor antagonists (MRA), have remained the mainstay of the standard of care for HF management. Despite their proven efficacy and cost-effectiveness, HF remains a global pandemic and is still increasing in prevalence. Sacubitril/ Valsartan (SAC/VAL) is an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) that proved out to be a game-changer drug in HF treatment. Recent data indicated that SAC/VAL is more efficient and can improve the overall quality of life of HF patients with reduced ejection fraction (HFrEF) with fewer side effects. It is now incorporated in the guidelines as an alternative to ACEIs or ARBs to lower morbidity in addition to mortality in HFrEF patients. This review article will discuss the current guidelines-approved indications and highlight the potential emerging indications, in addition to the currently ongoing clinical trials that will expand the use of SAC/VAL.

Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats.

Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus. Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits (p < 0.001) than the treatment with Eucalyptus or Candesartan alone (p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.

Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker.

Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis.

Aspergillus spp. infections remain a global concern, with ∼30% attributable mortality of invasive aspergillosis (IA). VT-1598 is a novel fungal CYP51 inhibitor designed for exquisite selectivity versus human CYP enzymes to achieve a maximal therapeutic index and therefore maximal antifungal efficacy. Previously, its broad-spectrum in vitro antifungal activity was reported. We report here the pharmacokinetics (PK) and pharmacodynamics (PD) of VT-1598 in neutropenic mouse models of IA. The plasma area-under-the-curve (AUC) of VT-1598 increased nearly linearly between 5 and 40 mg/kg after 5 days of QD administration (155 and 1033 µg*h/ml, respectively), with a further increase with 40 mg/kg BID dosing (1354 µg*h/ml). When A. fumigatus isolates with in vitro susceptibilities of 0.25 and 1.0 µg/ml were used in a disseminated IA model, VT-1598 treatment produced no decrease in kidney fungal burden at QD 10 mg/kg, intermediate decreases at QD 20 mg/kg and maximum or near maximum decreases at 40 mg/kg QD and BID. The PK/PD relationships of AUCfree/MIC for 1-log killing for the two strains were 5.1 and 1.6 h, respectively, similar to values reported for approved CYP51 inhibitors. In a survival study where animals were observed for 12 days after the last treatment, survival was 100% at the doses tested (20 and 40 mg/kg QD), and fungal burden remained suppressed even though drug wash-out was complete. Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection.

Tedizolid as Step-Down Therapy following Daptomycin versus Continuation of Daptomycin against Enterococci and Methicillin- and Vancomycin-Resistant Staphylococcus aureus in a Rat Endocarditis Model.

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

Effects of sacubutril/valsartan on nutritional status in heart failure with reduced ejection fraction.

BACKGROUND: Malnutrition commonly occurs in patients with heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan, which is an AT1 neprilysin inhibitor, has been shown to reduce mortality and hospitalization in patients with HFrEF. However, its effects on nutritional status remain unclear. METHODS: Sacubitril/valsartan was initiated in 164 symptomatic patients with HFrEF receiving an optimal medical treatment with angiotensin inhibition (mean age: 63 ±â€Š20 years; 120 males, 60% ischemic cause). The New York Heart Association (NYHA) functional class and nutritional statuses of the patients were evaluated at the switching to AT1 neprilysin inhibitor and at the 6th-month follow-up of the maximum sacubitril/valsartan dose using the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and prealbumin. RESULTS: After the sacubutril/valsartan treatment, a significant reduction in the number (%) of malnourished patients was observed according to CONUT (before 47% vs. after 7%, P < 0.001), GNRI (before 39% vs. after 19%, P < 0.001), PNI scores (before 36% vs. after 12%, P = 0.002), and prealbumin (before 41% vs. after 12%, P < 0.001). Also significant changes were observed at the baseline and follow-up in the mean scores of the three different nutritional indexes and prealbumin levels [CONUT: 2.68 ±â€Š2.5, 1.02 ±â€Š1.0 (P < 0.001); GNRI: 97.1 ±â€Š9.7, 101.2 ±â€Š5.9 (P < 0.001); PNI: 38.8 ±â€Š4.8, 41.6 ±â€Š3.7 (P < 0.001); prealbumin: 14.6 ±â€Š6.9 mg/dl, 17.1 ±â€Š5.2 mg/dl (P < 0.001)]. Overall, the patients exhibited a significant functional improvement following the initiation of sacubitril/valsartan: 23% of the patients improved by two NYHA classes, 48% improved by one NYHA class, and 39% remained stable. CONCLUSION: In patients with HFrEF, the switch from angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to sacubitril/valsartan resulted in a significant improvement in both nutritional and functional statuses.

Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients.

BACKGROUND: Tedizolid is a protein synthesis inhibitor in clinical use for the treatment of Gram-positive infections. Pulmonary MRSA infections are a growing problem in patients with cystic fibrosis (CF) and the efficacy of tedizolid-based therapy in CF pulmonary infections is unknown. OBJECTIVES: To evaluate the in vitro and in vivo activity of tedizolid and predict the likelihood of tedizolid resistance selection in CF-background Staphylococcus aureus strains. METHODS: A collection of 330 S. aureus strains (from adult and paediatric patients), either of normal or small colony variant (SCV) phenotypes, gathered at three CF centres in the USA was used. Tedizolid activity was assessed by broth microdilution, Etest and time-kill analysis. In vivo tedizolid efficacy was tested in a murine pneumonia model. Tedizolid in vitro mutants were obtained by 40 days of exposure and progressive passages. Whole genome sequencing of clinical S. aureus strains with reduced susceptibility to tedizolid was performed. RESULTS: MRSA strain MIC90s were tedizolid 0.12-0.25 mg/L and linezolid 1-2 mg/L; for MSSA strains, MIC90s were tedizolid 0.12 mg/L and linezolid 1-2 mg/L. Two strains, WIS 441 and Seattle 106, with tedizolid MICs of 2 mg/L and 1 mg/L, respectively, had MICs above the FDA tedizolid breakpoint (0.5 mg/L). Tedizolid at free serum concentrations exhibited a bacteriostatic effect. Mean bacterial burdens in lungs (log10 cfu/g) for WIS 423-infected mice were: control, 11.2±0.5; tedizolid-treated (10 mg/kg), 3.40±1.87; linezolid-treated (40 mg/kg), 4.51±2.1; and vancomycin-treated (30 mg/kg), 5.21±1.93. For WIS 441-infected mice the (log10 cfu/g) values were: control, 9.66±0.8; tedizolid-treated, 3.18±1.35; linezolid-treated 5.94±2.19; and vancomycin-treated, 4.35±1.7. CONCLUSIONS: These results suggest that tedizolid represents a promising therapeutic option for the treatment of CF-associated MRSA/MSSA infections, having potent in vivo activity and low resistance potential.

Efficacy of sacubitril valsartan sodium tablet for the treatment of chronic heart failure: A systematic review protocol of randomized controlled trials.

BACKGROUND: This study aims to systematically explore the efficacy of sacubitril valsartan sodium tablet (SVST) for the treatment of chronic heart failure (CHF). METHODS: Nine electronic databases, including PUBMED, Cochrane Library, EMBASE, PsycINFO, Web of Science, Allied and Complementary Medicine Database, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be searched. Randomized controlled trials on SVST in the treatment of CHF will be collected. The search time limit will be from the establishment of each electronic database until June 1, 2019. Two authors will independently select the literature, carry out the data, and assess the methodological quality. RESULTS: This study will systematically investigate the efficacy and safety of SVST for CHF. The outcomes consist of all-cause mortality, change in body weight, urine output, change in serum sodium; and incidence of any expected and unexpected adverse events. CONCLUSION: The findings of this study will summarize from evidence-based medicine and a scientific basis for the efficacy and safety of SVST in the clinical treatment of CHF. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019138882.

Photochemical property of two Ru(II) compounds based on 5-(2-pyrazinyl)tetrazole for cancer phototherapy by changing auxiliary ligand.

Ru(II) compounds are potential candidates for photodynamic therapy (PDT) and auxiliary ligands may have an impact on the property of the resulting coordination compounds. In the present study, two Ru(II) compounds based on 5-(2-pyrazinyl)tetrazole (Hpztz) and two classic auxiliary ligands, 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen) have been prepared and characterized, namely [Ru(pztz)(bipy)2][PF6] (1) and [Ru(pztz)(phen)2][PF6] (2). The nanoparticles (NPs) of the two compounds have been prepared by self-assembly in aqueous solution. In vitro MTT assay on HeLa cells show that [Ru(pztz)(phen)2][PF6] with a lower IC50 (half-maximal inhibitory concentration) of only 7.4 µg/mL is superior to that of [Ru(pztz)(bipy)2][PF6] (17.8 µg/mL) under irradiation. Meanwhile, negligible dark toxicity have been also observed for the two compounds. In addition, in vivo fluorescence imaging suggests that [Ru(pztz)(phen)2][PF6] NPs are able to target to the tumor by enhanced permeability and retention effect (EPR). Furthermore, in vivo phototherapy on nude mice demonstrate that such NPs can effectively inhibit the growth of the tumor. After treatment for 10 cycles, an obvious decrease in the tumor volume can be observed while the normal tissues, including heart, liver, spleen, lung and kidney, suffer from no damage, indicating the high phototoxicity, low dark toxicity and excellent biocompatibility of [Ru(pztz)(phen)2][PF6] NPs.

In Vitro Activity of Tedizolid in Comparison with Other Oral and Intravenous Agents Against a Collection of Community-Acquired Methicillin-Resistant Staphylococcus aureus (2014-2015) in the United States.

Tedizolid activity was compared with other agents with oral and intravenous formulations against community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Tedizolid (MIC50/90, 0.12/0.12 mg/L; 100.0% susceptible) was the most potent agent tested against CA-MRSA and subsets from adult and pediatric patients. Tedizolid minimum inhibitory concentrations (MICs) were twofold to fourfold lower than daptomycin (MIC50/90, 0.25/0.5 mg/L; 99.9-100% susceptible) and fourfold to eightfold lower than linezolid (MIC50/90, 1/1 mg/L; 100.0% susceptible), ceftaroline (MIC50/90, 0.5-1/1 mg/L; 96.6-98.8% susceptible), and vancomycin (MIC50/90, 0.5-1/1 mg/L; 100.0% susceptible) against CA-MRSA and subsets. Clindamycin resistance rates among CA-MRSA from pediatric and adult patients were 18.3-19.1% (13.4-14.2% constitutive, 4.9-6.4% inducible) and 36.2-37.6% (29.8-30.1% constitutive, 6.4-7.5% inducible), respectively. Tetracycline (90.4-96.4% susceptible) and trimethoprim-sulfamethoxazole (96.2-100.0% susceptible) were active against CA-MRSA or subsets, whereas erythromycin (83.8-89.4% nonsusceptible) and levofloxacin (50.2-70.8% nonsusceptible) had limited activities. Tedizolid had MIC50/90 values of 0.12/0.12 mg/L against CA-MRSA showing clindamycin constitutive-resistance and recovered from adult or pediatric patients. Tedizolid had potent activities against CA-MRSA, regardless of clindamycin phenotype or patient population. Tedizolid may be considered for the treatment of ABSSSI in adults. Further studies are warranted for the clinical development in the pediatric population.

Sacubitril/valsartan for heart failure with reduced left ventricular ejection fraction : A retrospective cohort study.

BACKGROUND: The combination drug sacubitril/valsartan was reported to be superior to enalapril in reducing all-cause death, cardiovascular mortality, and heart failure (HF) hospitalizations in patients with cardiac insufficiency and reduced left ventricular ejection fraction (HFREF) with NYHA class II-IV. METHODS: Our retrospective cohort study aimed to assess the effects of sacubitril/valsartan in addition to a beta-blocker and mineral receptor antagonist (MRA) in a group of HFREF patients with NYHA class II-III HF vs. conventional therapy (ACE inhibitor or angiotensin II receptor blocker added to a beta-blocker plus an MRA) administered to a control group of HFREF patients with comparable clinical features. In both groups, treatment was supplemented by a loop diuretic, usually furosemide, at variable doses. The primary outcomes were all-cause death and HF hospitalizations. Safety outcomes were symptomatic hypotension, angioedema, hyperkalemia, and worsening renal function. RESULTS: Mortality at 6 months was 6.8% in patients taking sacubitril/valsartan vs. 34% in those on conventional therapy (odds ratio [OR] = 0.14; 95% CI: 0.04-0.49). Moreover, there was a 4.5% rate of HF hospitalizations in the sacubitril/valsartan group vs. 59% in the control group (OR = 0.03; 95% CI: 0.01-0.14). Safety outcomes were comparable in the two groups, although hypotension (systolic blood pressure < 100 mm Hg) was found in 15.9% of patients in the sacubitril/valsartan group vs. 5.7% in the control group (OR = 3.14; 95% CI: 0.94-10.55). CONCLUSION: Sacubitril/valsartan offered strong protection against all-cause death and HF hospitalizations at 6 months without any significant side effects. To validate this efficacious molecule, further postmarketing observational studies, focusing mainly on hypotension and angioedema are warranted.

The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris.

Candida auris is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 µg/ml and MICs ranging from 0.03 to 8 µg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10 CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.