The Application of Nitric Oxide for Ocular Hypertension Treatment.

Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using 'nitric oxide' and 'glaucoma' as key words.

Nitric Oxide Releasing Delivery Platforms: Design, Detection, Biomedical Applications, and Future Possibilities.

Gasotransmitters belong to the subfamily of endogenous gaseous signaling molecules, which find a wide range of biomedical applications. Among the various gasotransmitters, nitric oxide (NO) has an enormous effect on the cardiovascular system. Apart from this, NO showed a pivotal role in neurological, respiratory, and immunological systems. Moreover, the paradoxical concentration-dependent activities make this gaseous signaling molecule more interesting. The gaseous NO has negligible stability in physiological conditions (37 °C, pH 7.4), which restricts their potential therapeutic applications. To overcome this issue, various NO delivering carriers were reported so far. Unfortunately, most of these NO donors have low stability, short half-life, or low NO payload. Herein, we review the synthesis of NO delivering motifs, development of macromolecular NO donors, their advantages/disadvantages, and biological applications. Various NO detection analytical techniques are discussed briefly, and finally, a viewpoint about the design of polymeric NO donors with improved physicochemical characteristics is predicted.

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.

Development of nitric oxide releasing visible light crosslinked gelatin methacrylate hydrogel for rapid closure of diabetic wounds.

Management of non-healing and slow to heal diabetic wounds is a major concern in healthcare across the world. Numerous techniques have been investigated to solve the issue of delayed wound healing, though, mostly unable to promote complete healing of diabetic wounds due to the lack of proper cell proliferation, poor cell-cell communication, and higher chances of wound infections. These challenges can be minimized by using hydrogel based wound healing patches loaded with bioactive agents. Gelatin methacrylate (GelMA) has been proven to be a highly cell friendly, cell adhesive, and inexpensive biopolymer for various tissue engineering and wound healing applications. In this study, S-Nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, was incorporated in a highly porous GelMA hydrogel patch to improve cell proliferation, facilitate rapid cell migration, and enhance diabetic wound healing. We adopted a visible light crosslinking method to fabricate this highly porous biodegradable but relatively stable patch. Developed patches were characterized for morphology, NO release, cell proliferation and migration, and diabetic wound healing in a rat model. The obtained results indicate that SNAP loaded visible light crosslinked GelMA hydrogel patches can be highly effective in promoting diabetic wound healing.

Pharmaceuticals agents for preventing NSAID-induced gastric ulcers: a patent review.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs widely used due to their pharmacological potential, demonstrating anti-inflammatory, analgesic, or antipyretic activity. However, prolonged use of these medications can lead to the development of gastric ulcers in patients. This review aimed to find patents for drugs with an anti-inflammatory and gastroprotective character to treat NSAID-induced gastric ulcers. AREAS COVERED: For the treatment of NSAID-induced gastric ulcers, formulations with different action mechanisms were found, including donors of nitric oxide, heterocyclic compounds, and natural products. EXPERT OPINION: Many of the structures found have already been used in clinic settings and others, and according to the results found, they are promising for the treatment of gastric ulcers.

Development of Novel Amphotericin B-Immobilized Nitric Oxide-Releasing Platform for the Prevention of Broad-Spectrum Infections and Thrombosis.

Indwelling medical devices currently used to diagnose, monitor, and treat patients invariably suffer from two common clinical complications: broad-spectrum infections and device-induced thrombosis. Currently, infections are managed through antibiotic or antifungal treatment, but the emergence of antibiotic resistance, the formation of recalcitrant biofilms, and difficulty identifying culprit pathogens have made treatment increasingly challenging. Additionally, systemic anticoagulation has been used to manage device-induced thrombosis, but subsequent life-threatening bleeding events associated with all available therapies necessitates alternative solutions. In this study, a broad-spectrum antimicrobial, antithrombotic surface combining the incorporation of the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) with the immobilization of the antifungal Amphotericin B (AmB) on polydimethylsiloxane (PDMS) was developed in a two-step process. This novel strategy combines the key advantages of NO, a bactericidal agent and platelet inhibitor, with AmB, a potent antifungal agent. We demonstrated that SNAP-AmB surfaces significantly reduced the viability of adhered Staphylococcus aureus (99.0 ± 0.2%), Escherichia coli (89.7 ± 1.0%), and Candida albicans (93.5 ± 4.2%) compared to controls after 24 h of in vitro exposure. Moreover, SNAP-AmB surfaces reduced the number of platelets adhered by 74.6 ± 3.9% compared to controls after 2 h of in vitro porcine plasma exposure. Finally, a cytotoxicity assay validated that the materials did not present any cytotoxic side effects toward human fibroblast cells. This novel approach is the first to combine antifungal surface functionalization with NO-releasing technology, providing a promising step toward reducing the rate of broad-spectrum infection and thrombosis associated with indwelling medical devices.

Prolonged use of nitric oxide donor sodium nitroprusside induces ocular hypertension in mice.

Nitric oxide (NO) donors are promising therapeutic candidates for treating intraocular hypertension (IOP) and glaucoma. This study aims to investigate the effect of prolonged use of NO donor sodium nitroprusside (SNP) on IOP. Since SNP has a short biological half-life, a nanoparticle drug delivery system (mesoporous silica nanoparticles) has been used to deliver SNP to the target tissues (trabecular meshwork and Schlemm's canal). We find that the sustained use of NO donor initially reduced IOP followed, surprisingly, by IOP elevation, which could not recover by drug withdraw but could be reversed by the antioxidant MnTMPyP application. The IOP elevation and normalization coincide with increased and reduced protein nitration in the mouse conventional outflow tissue. These findings suggest that the prolonged use of NO donor SNP may be problematic as it can cause outflow tissue damage by protein nitration. MnTMPyP is protective of the nitrative damage which could be considered to be co-applied with NO donors.

Evaluating the efficacy of outpatient use of isosorbide mononitrate on cervical ripening in pregnant women with unfavourable cervix.

The aim of the present study was to evaluate the efficacy of outpatient administration of nitric oxide donor isosorbide mononitrate for cervical ripening. A randomised clinical trial was performed on term pregnant women with Bishop Score < 6. In the case group, Isosorbide-5-mononitrate capsule and in the control group, placebo was inserted in the posterior vaginal fornix for two consecutive days. The main outcomes were increases in Bishop Score after 48 hours of intervention, number of vaginal deliveries and interval from intervention to delivery.There was a significant increase of the mean Bishop score in the isosorbide group [3.57 ± 1.12 VS 1.54 ± 1.42 respectively (p = .001)]. The other outcome variables did not show a significant difference between the two groups except for headache which was significantly more in the case group. No cases of tachysystole were observed in the two groups. Additionally, haemoglobin levels after delivery did not show a significant difference between the two groups.Impact statement:What is already known on this subject? Cervical ripening in women with an unfavourable cervix and having an indication for induction of labour is an important issue in modern obstetrics. Different methods have been used for cervical ripening and induction of labour including mechanical (i.e. laminaria tents, Dilapan-S, foley catheter), medical (i.e. PGs) and supportive methods. There is no consensus on the best option for cervical ripeningWhat will the results of this study add to the current knowledge of this subject? Outpatient administration of nitric oxide could affect cervical ripening without a significant improvement in the duration of different stages of labour, intervention to delivery interval and number of vaginal deliveries.What are the implications of these findings for clinical practice and/or further research? Due to the contradictory results of various studies, more studies should be performed with greater sample size to evaluate nitric oxide donor isosorbide mononitrate effect on labour duration and reducing caesarean deliveries. Additional data is needed to assess the real impact of NO donors on different stages of labour and its implications.

Hypertension is associated with blunted NO-mediated leg vasodilator responsiveness that is reversed by high-intensity training in postmenopausal women.

The menopausal transition is associated with increased prevalence of hypertension, and in time, postmenopausal women (PMW) will exhibit a cardiovascular disease risk score similar to male counterparts. Hypertension is associated with vascular dysfunction, but whether hypertensive (HYP) PMW have blunted nitric oxide (NO)-mediated leg vasodilator responsiveness and whether this is reversible by high-intensity training (HIT) is unknown. To address these questions, we examined the leg vascular conductance (LVC) in response to femoral infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) and skeletal muscle markers of oxidative stress and NO bioavailability before and after HIT in PMW [12.9 ± 6.0 (means ± SD) years since last menstrual cycle]. We hypothesized that ACh- and SNP-induced LVC responsiveness was reduced in hypertensive compared with normotensive (NORM) PMW and that 10 wk of HIT would reverse the blunted LVC response and decrease blood pressure (BP). Nine hypertensive (HYP (clinical systolic/diastolic BP, 149 ± 11/91 ± 83 mmHg) and eight normotensive (NORM (122 ± 13/75 ± 8 mmHg) PMW completed 10 wk of biweekly small-sided floorball training (4-5 × 3-5 min interspersed by 1-3-min rest periods). Before training, the SNP-induced change in LVC was lower (P < 0.05) in HYP compared with in NORM. With training, the ACh- and SNP-induced change in LVC at maximal infusion rates, i.e., 100 and 6 µg·min-1·kg leg mass-1, respectively, improved (P < 0.05) in HYP only. Furthermore, training decreased (P < 0.05) clinical systolic/diastolic BP (-15 ± 11/-9 ± 7 mmHg) in HYP and systolic BP (-10 ± 9 mmHg) in NORM. Thus, the SNP-mediated LVC responsiveness was blunted in HYP PMW and reversed by a period of HIT that was associated with a marked decrease in clinical BP.

Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study.

BACKGROUND: There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent studies of SNP in patients with psychosis have mixed results, and the drug has to be administered intravenously. Glyceryl trinitrate (GTN) is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. AIMS: We explored the safety and potential effects of GTN in unmedicated patients with a first episode of psychosis. METHODS: This was a single-centre, randomised, double-blind, placebo-controlled trial from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients received 3 × sprays of GTN or placebo for three consecutive days, and were re-assessed on Days 1, 2, 3 and 7. The primary outcome was cognition (Jumping to Conclusions task), secondary outcomes were symptoms (Positive and Negative Syndrome Scale (PANSS)), verbal memory (Hopkins Verbal Learning task), and mood (Bond-Lader Visual Analogue Scales). RESULTS: Nineteen patients were randomised, and 13 participants were included in the analyses. Compared with placebo, GTN was well tolerated, but was not associated with significant effects on cognition, symptoms, or mood. Bayesian statistics indicate that our results were 2× more likely under the null hypothesis than the alternative hypothesis, providing anecdotal evidence that GTN does not improve psychotic symptoms. CONCLUSIONS: We found no indication of an effect of GTN on symptoms of psychosis or cognition.

In vitro vascular toxicity assessment of NitDOX, a novel NO-releasing doxorubicin.

The conjugation of doxorubicin (DOX) with nitric oxide (NO)-releasing groups gave rise to novel anthracyclines, such as nitrooxy-DOX (NitDOX), capable to overcome multidrug resistance. The widely described anthracycline cardiovascular toxicity, however, might limit their clinical use. This study aimed to investigate NitDOX-induced effects, as potential hazard, on vascular smooth muscle A7r5 and endothelial EA.hy926 cell viability, on the mechanical activity of freshly and cultured rat aorta rings, as well as on Cav1.2 channels of A7r5 cells. DOX was used as a reference compound. Although an increase in intracellular radicals and a reduction in mitochondrial potential occurred upon treatment with both drugs, A7r5 and EA.hy926 cells proved to be more sensitive to DOX than to NitDOX. Both compounds promoted comparable effects in A7r5 cells, whereas NitDOX was less active than DOX in inducing DNA damage and in eliciting apoptotic-mediated cell death revealed as an increase in sub-diploid-, DAPI- and annexin V-positive- EA.hy926 cell percentage. Moreover, in EA.hy926 cells, NitDOX doubled basal NO content, while preincubation with the NO-scavenger PTIO increased NitDOX-induced cytotoxicity. DOX exhibited a negligible contracturing effect in endothelium-intact rings, while NitDOX induced a significant ODQ-sensible, vasodilation in endothelium-denuded rings. In arteries cultured with both drugs for 7 days, NitDOX prevented either phenylephrine- or KCl-induced contraction at a concentration 10-fold higher than that of DOX. These results demonstrate that NitDOX displays a more favourable vascular toxicity profile than DOX. Taking into account its greater efficacy against drug-resistant cells, NitDOX is worth of further investigations in preclinical and clinical settings.

Modification of nitric oxide donors onto a monoclonal antibody boosts accumulation in solid tumors.

Although monoclonal antibodies (mAbs) have revolutionized cancer treatment, their accumulation in solid tumors is limited and requires improvement to enhance therapeutic efficacy. Here we developed a strategy to modify mAb with a donor of nitric oxide (NO) because NO functions to vasodilate as well as to enhance the permeability of vascular endothelium, which will contribute to enhancing the tumor accumulation of mAb. We selected S-nitrosothiol as a NO donor and established the procedure to modify S-nitrosothiol group on mAb under ambient conditions. The modified mAb (Ab-SNO) thus obtained released NO in a preferable speed and maintained its original properties such as binding affinity to a target antigen and efficacy to induce antibody-dependent cellular cytotoxicity. We demonstrated that Ab-SNO enhanced the tumor accumulation of co-administered proteins such as antibody and serum albumin.

S-Nitroso-N-Pivaloyl-D-Penicillamine, a novel non-neuronal ACh system activator, modulates cardiac diastolic function to increase cardiac performance under pathophysiological conditions.

We have previously reported the development of a novel chemical compound, S-Nitroso-N-Pivaloyl-D-Penicillamine (SNPiP), for the upregulation of the non-neuronal cardiac cholinergic system (NNCCS), a cardiac acetylcholine (ACh) synthesis system, which is different from the vagus nerve releasing of ACh as a neurotransmitter. However, it remains unclear how SNPiP could influence cardiac function positively, and whether SNPiP could improve cardiac function under various pathological conditions. SNPiP-injected control mice demonstrated a gradual upregulation in diastolic function without changes in heart rate. In contrast to some parameters in cardiac function that were influenced by SNPiP 24 h or 48 h after a single intraperitoneal (IP) injection, 72 h later, end-systolic pressure, cardiac output, end-diastolic volume, stroke volume, and ejection fraction increased. IP SNPiP injection also improved impaired cardiac function, which is a characteristic feature of the db/db heart, in a delayed fashion, including diastolic and systolic function, following either several consecutive injections or a single injection. SNPiP, a novel NNCCS activator, could be applied as a therapeutic agent for the upregulation of NNCCS and as a unique tool for modulating cardiac function via improvement in diastolic function.

S-Nitroso-N-acetylpenicillamine impregnated endotracheal tubes for prevention of ventilator-associated pneumonia.

The chances of ventilator-associated pneumonia (VAP) increases 6-20 folds when an endotracheal tube (ETT) is placed in a patient. VAP is one of the most common hospital-acquired infections and comprises 86% of the nosocomial pneumonia cases. This study introduces the idea of nitric oxide-releasing ETTs (NORel-ETTs) fabricated by the incorporation of the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) into commercially available ETTs via solvent swelling. The impregnation of SNAP provides NO release over a 7-day period without altering the mechanical properties of the ETT. The NORel-ETTs successfully reduced the bacterial infection from a commonly found pathogen in VAP, Pseudomonas aeruginosa, by 92.72 ± 0.97% when compared with the control ETTs. Overall, this study presents the incorporation of the active release of a bactericidal agent in ETTs as an efficient strategy to prevent the risk of VAP.

Repeated but not acute exposure with a low dose range of the nitric oxide (NO) donor sodium nitroprusside (SNP) induces anxiolytic-like behaviour in a dose-independent manner in two different rat models of anxiety.

Sodium nitroprusside (SNP) is a nitric oxide (NO) donor which actually is under assessment as a potential candidate for the treatment of schizophrenia. It is well documented that anxiety symptoms are a prominent future in various psychiatric diseases comprising schizophrenia. Prior research has shown that acute challenge with SNP (1-3 mg/kg) induced anti-anxiety effects in rats but these effects at high doses were confounded by sedation and were disappeared after repeated application of it. It is still unknown if administration of a lower SNP dose range, either acutely or sub-chronically, could induce anxiolytic-like behaviour. The present study was designed to investigate this issue in rats. For this aim, the light/dark and the open field tests were used. Acute challenge with SNP (0.1 and 0.3 mg/kg, 30 min before testing) did not affect rodents' performance in the above mentioned behavioural paradigms. Conversely, rats treated sub-chronically with SNP (0.1 and 0.3 mg/kg, once per day, for 5 consecutive days), displayed longer time spent in the light chamber of the light/dark box and in the central area of the open field with respect to their vehicle-treated counterparts. Interestingly, SNP did not influence the first latency to enter the dark chamber and the number of transitions between the light and dark compartments of the apparatus in the light/dark test and did not modify the number of squares crossed, grooming episodes and rearings in the open field test. Finally, acute administration of SNP (0.1, 0.3 and 1 mg/kg, 10 min before testing) also did not influence rats' performance in the light/dark test. The present results indicate that short-term repeated but not acute application of a range of low doses of the NO donor SNP in a dose-independent manner induced an anti-anxiety behaviour in the rat which was not accompanied by undesired effects.

Sensitizing activities of nitric oxide donors for cancer resistance to anticancer therapeutic drugs.

Cancer is not a single disease but it constitutes a large variety of different types that are also different from each other phenotypically and molecularly. Although the standard treatments have resulted in clinical responses in a subset of patients, though, many patients relapse and no longer respond to further treatments. Hence, both the innate and adaptive resistance to treatments are the main challenges in today's treatment strategies. Noteworthy, several novel treatment strategies, particularly immunotherapies, used alone or in combination, have been developed and that have significantly improved the therapeutic response of many unresponsive cancer patients. Nevertheless, even with the latest new developments of therapeutics that were effective in a larger subset of patients, there is still an urgent need to treat the remaining unresponsive subset of patients. This requires the development of new targeting agents of superior antitumor activities that will lead to overcoming the unaffected resistance by current treatments. There has been accumulating evidence suggesting nitric oxide donors as such targeting agents and considering their pleiotropic antitumor activities, including both the reversal of chemo and immuno-resistance of various unresponsive resistant cancers. The in vitro and in vivo preclinical findings corroborate the sensitizing antitumor activities of nitric oxide donors. In addition, a few clinical findings with NO donors that have been applied in patients have corroborated their antitumor and sensitizing activities in combination with standard therapies. In this review, the role and underlying mechanisms by which nitric oxide donors sensitize cancer resistant cells to both chemotherapy and immunotherapy are briefly described.

A Comparative Study of Inhaled Nitric Oxide and an Intravenously Administered Nitric Oxide Donor in Acute Pulmonary Hypertension.

PURPOSE: Inhaled nitric oxide (iNO) selectively vasodilates the pulmonary circulation but the effects are sometimes insufficient. Available intravenous (iv) substances are non-selective and cause systemic side effects. The pulmonary and systemic effects of iNO and an iv mono-organic nitrite (PDNO) were compared in porcine models of acute pulmonary hypertension. METHODS: In anesthetized piglets, dose-response experiments of iv PDNO at normal pulmonary arterial pressure (n=10) were executed. Dose-response experiments of iv PDNO (n=6) and iNO (n=7) were performed during pharmacologically induced pulmonary hypertension (U46619 iv). The effects of iv PDNO and iNO were also explored in 5 mins of hypoxia-induced increase in pulmonary pressure (n=2-4). RESULTS: PDNO (15, 30, 45 and 60 nmol NO kg-1 min-1 iv) and iNO (5, 10, 20 and 40 ppm which corresponded to 56, 112, 227, 449 nmol NO kg-1 min-1, respectively) significantly decreased the U46619-increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) to a similar degree without significant decreases in mean arterial pressure (MAP) or systemic vascular resistance (SVR). iNO caused increased levels of methemoglobin. At an equivalent delivered NO quantity (iNO 5 ppm and PDNO 45 nmol kg-1 min-1 iv), PDNO decreased PVR and SVR significantly more than iNO. Both drugs counteracted hypoxia-induced pulmonary vasoconstriction and they decreased the ratio of PVR and SVR in both settings. CONCLUSION: Intravenous PDNO was a more potent pulmonary vasodilator than iNO in pulmonary hypertension, with no severe side effects. Hence, this study supports the potential of iv PDNO in the treatment of acute pulmonary hypertension.

Protein kinase inhibitor-based cancer therapies: Considering the potential of nitric oxide (NO) to improve cancer treatment.

The deregulation of a wide variety of protein kinases is associated with cancer cell initiation and tumor progression. Owing to their indispensable function in signaling pathways driving malignant cell features, protein kinases constitute major therapeutic targets in cancer. Over the past two decades, intense efforts in drug development have been dedicated to this field. The development of protein kinase inhibitors (PKIs) have been a real breakthrough in targeted cancer therapy. Despite obvious successes across patients with different types of cancer, the development of PKI resistance still prevails. Combination therapies are part of a comprehensive approach to address the problem of drug resistance. The therapeutic use of nitric oxide (NO) donors to bypass PKI resistance in cancer has never been tested in clinic yet but several arguments suggest that the combination of PKIs and NO donors may exert a potential anticancer effect. The present review summarized the current state of knowledge on common targets to both PKIs and NO. Herein, we attempt to provide the rationale underlying a potential combination of PKIs and NO donors for future directions and design of new combination therapies in cancer.

Transdermal delivery of glyceryl trinitrate: clinical applications in acute stroke.

Introduction: Glyceryl trinitrate (GTN), a nitric oxide donor, is a candidate treatment for the management of acute stroke with hemodynamic and potential reperfusion and neuroprotective effects.Areas covered: Here we discuss the evidence to date from clinical trials and present and future possibilities for the clinical application of transdermal GTN in acute stroke. When administered as a transdermal patch during the acute and subacute phases after stroke, GTN was safe, lowered blood pressure, maintained cerebral blood flow, and did not induce cerebral steal or alter functional outcome. However, when given within the hyperacute phase (<6 h of stroke onset), GTN reduced death and dependency, death, disability, cognitive impairment, and mood disturbance, and improved quality of life. However, in a large prehospital trial with treatment within 4 h, GTN did not influence clinical outcomes.Expert opinion: Transdermal GTN is an easy to administer BP-lowering therapy, which is safe when given after 2 h of stroke onset, may improve outcome when initiated within 2-6 h, but should be avoided (outside of a clinical trial) in the ultra-acute period within 2 h of stroke onset. Further research needs to investigate the mechanisms of benefit or harm in ultra/hyperacute stroke patients.

A turn-on and lysosome-targeted fluorescent NO releaser in water media and its application in living cells and zebrafishes.

Due to the high activity and difficult to transport of nitric oxide, the controlled release of nitric oxide has been a new trend in the research on the biological effect of nitric oxide. In this paper, a water-soluble and turn-on fluorescent NO donor Rh-NO was synthesized. Upon 525 nm irradiation, the fluorescence of the Rh-NO at 568 nm enhanced with the quantum yield (ΦF) of Rh-NO changing from 5.08% to 35.96%. The mechanism of NO releasing was proved by HRMS and the Dan. The releasing time of 6 min and the releasing yield of 0.61 proved the superiority of Rh-NO. Excellent cell activity above 80% of Rh-NO and Rh guaranteed that nitric oxide was released from Rh-NO in lysosome and zebrafishes successfully, which provided a good platform to understand the biological effects of nitric oxide in lysosomes.