Delivery Of Nitric Oxide Donor Research Articles

Local Delivery and Sustained-Release of Nitric Oxide Donor Loaded in Mesoporous Silica Particles for Efficient Treatment of Primary Open-Angle Glaucoma.

Nitric oxide (NO) donors are ideal drug candidates for reducing intraocular pressure in the treatment of glaucoma. However, poor cornea penetration, short duration of efficacy, and narrow therapeutic index of most NO donors obstruct their clinical applications in glaucoma treatment. This study reports a novel NO donor delivery system based on mesoporous silica nanoparticles that can readily overcome the above difficulties and deliver the NO-donating drug sodium nitroprusside to the target tissues (trabecular meshwork and Schlemm's canal). Mesoporous silica nanoparticles loaded with sodium nitroprusside can produce more exogenous NO and sustain higher NO concentration in animal eye models, which significantly extend the duration of intraocular pressure reduction from 3 to 48 h with only 1/40 of the dose of sodium nitroprusside solution. These findings open up the possibility of mesoporous silica nanoparticles loading sodium nitroprusside for effective management of ocular hypertension.

Nitric oxide-mediated pain processing in the spinal cord.

A large body of evidence indicates that nitric oxide (NO) plays an important role in the processing of persistent inflammatory and neuropathic pain in the spinal cord. Several animal studies revealed that inhibition or knockout of NO synthesis ameliorates persistent pain. However, spinal delivery of NO donors caused dual pronociceptive and antinociceptive effects, pointing to multiple downstream signaling mechanisms of NO. This review summarizes the localization and function of NO-dependent signaling mechanisms in the spinal cord, taking account of the recent progress made in this field.

Inhalable Microparticles Containing Nitric Oxide Donors: Saying NO to Intracellular Mycobacterium tuberculosis

Although nitric oxide (NO) is a bactericidal component of the macrophage's innate response to intracellular infections such as tuberculosis (TB), prolonged inhalation of NO gas has little benefit in chemotherapy of TB. The impact of controlled release of NO through intracellular delivery of NO donors to macrophages infected in vitro with Mycobacterium tuberculosis (Mtb) was investigated. Inhalable microparticles (MP) were prepared by spray-drying. Isosorbide mononitrate (ISMN), sodium nitroprusside (SNP), and diethylenetriamine nitric oxide adduct (DETA/NO) were incorporated in poly(lactic-co-glycolic acid) (PLGA) with encapsulation efficiencies of >90% to obtain MP yields of ∼70%. The mass median aerodynamic diameter (MMAD) of the MP was 2.2-2.4 μm within geometric standard deviations (GSD) of ≤0.1 μm. MP were phagocytosed by THP-1 derived macrophages in culture and significantly (P < 0.05) sustained NO secretion into culture supernatant from 6 to 72 h in comparison to equivalent amounts of drugs in solution. Significantly (P < 0.05) higher dose-dependent killing of intracellular Mtb by MP compared to equivalent amounts of drugs in solution was observed on estimation of colony forming units (CFU) surviving 24 h after exposure to drugs or MP. The cytotoxicity of MP toward macrophages was lower than that of dissolved drugs. It was concluded that inhalable MP can target NO donors to the macrophage, control NO release in the macrophage cytosol, and reduce Mtb CFU by up to 3-log in 24 h, at doses that are much lower than those required for cardiovascular effects.

Iontophoretic delivery of nitric oxide donor improves local skin flap viability

The dimensions of local flaps are often limited by the vascular supply to the distal aspect of the flap. Distal flap necrosis occurs if the vascular supply is inadequate. The purpose of this study was to investigate the use of iontophoretic delivery of nitric oxide (NO) donors to a local skin flap model to improve the survival area of the flap. Thirty-two male Sprague-Dawley rats (300 g) were divided into seven experimental groups to determine the effect of iontophoretic delivery of NO on surface perfusion and flap survival area. A caudally based 3 x 11 cm dorsal skin flap was used to measure the effect of iontophoretic delivery of NO donors to a local skin flap to improve survival area of the flap. Iontophoretic delivery of the NO donors sodium nitroprusside (SNP) and diethylenetriamine NONOate (DETA-NO) resulted in a significant increase in survival area and surface perfusion when compared with sham controls. Iontophoretic delivery of saline was associated with a 13% improvement in flap survival when compared with nontreated controls. Iontophoretic delivery and subcutaneous injection of NO donors (SNP and DETA-NO) increased skin flap viability by demonstrating improved flap survival areas. The results of this study suggest that NO may serve as a postoperative treatment of skin flaps to encourage skin flap survival and prevent distal necrosis.

Differential Expression of Glut 1 mRNA and Protein Levels Correlates with Increased Sensitivity to the Glyco-Conjugated Nitric Oxide Donor (2-glu-SNAP) in Different Tumor Cell Types

Nitric Oxide (NO) releasing agents can serve as potent cytotoxic agents. However at present there are no effective ways to target delivery of NO donors like S-nitroso-N-acetyl-penicillamine (SNAP). SNAP conjugated to glucose (2-gluSNAP) can be readily transported across the membrane by GLUT 1 transporters. Therefore, sensitivity of cells to 2-gluSNAP may depend on glucose-transporter GLUT 1. We evaluated the cytotoxicity of SNAP and 2-gluSNAP on a GLUT 1 rich glioblastoma cell line T98G and GLUT 1 deficient osteoblastoma cell line 143B andits mitochondria-deficient variant ρ° (cell line 206). The cytotoxity of SNAP and 2-gluSNAP was assessed by clonogenic assay performed in the above cell lines in vitro. Immunoblotting and semi-quantitative real-time PCR assays were used to evaluate the expression of GLUT 1 transporter at protein and mRNA levels. The glioblastoma cell line T98G was more sensitive to 2-gluSNAP than unconjugated SNAP. SNAP and 2-gluSNAP affected the osteosarcoma cell lines 143B and ρ° poorly. Immunoblot analysis detected GLUT 1 protein in T98G cells and not in 143B or ρ°. There was about a 10-fold difference in GLUT 1 mRNA level in T98G cells compared to 143B and ρ° cell lines. This is consistent with our cytotoxicity studies and immunoblot analysis. Our results give credence to our hypothesis that the sensitivity to NO donors can be increased by glyco-conjugation and the cytotoxicity of the glyco-conjugated NO donors depends on the expression of GLUT 1 mRNA and protein.

Coronary artery restenosis: vascular biology and emerging therapeutic strategies

Percutaneous coronary intervention with drug-eluting stents is currently the preferred approach to the treatment of obstructive coronary stenoses. Large, randomized trials have demonstrated a significant reduction in the incidence of restenosis after drug-eluting stent placement compared with balloon angioplasty or bare metal stents across a wide range of lesions. Furthermore, these stents have appeared to be effective in maintaining the luminal patency at follow up for up to 2–4 years. Concerns regarding the potential adverse effects of drug-eluting stents, such as aneurysm formation in arteries secondary to drug toxicity or hypersensitivity, as well as the overdependence on antiplatelet therapy for a protracted period to prevent subacute thrombosis, have been raised. However, evidence from large studies has not demonstrated any significant increase in the incidence of such adverse events. Future approaches to treating coronary stenoses involve technical modifications, such as direct stenting, accelerating endothelialization with gene delivery of nitric oxide donors, smooth muscle cell growth inhibitors after stent placement, biodegradable stents and concurrent use of local molecule delivery and oral chemotherapy. Ongoing large-scale postmarketing surveillance studies are expected to provide credible answers to the concerns regarding the safety of these stents.

Nitric oxide in subarachnoid haemorrhage and its therapeutics implications

After the discovery that nitric oxide (NO) plays a major role in the regulation of vascular tone, this substance moved into the focus of interest with regard to vasospasm after subarachnoid haemorrhage (SAH). A multitude of interactions were discovered and some concepts of therapeutic intervention were developed. The present review is based on a Medline search with the terms "nitric oxide" and "subarachnoid haemorrhage". SAH and particularly liberated oxyhaemoglobin sequestrate the physiologically produced NO. Reactivity to NO appears to be principally preserved. As other types of injury, SAH leads to induction of inducible NO synthase (iNOS). The NO produced by this pathway cannot compensate for the lack of the physiological NO and may even lead to tissue damage by oxidative stress. Experimental therapeutic attempts use stimulation of NO production and delivery of NO donors. NO donors were also used in some small clinical trials. A final assessment of efficacy and safety is not yet possible. NO physiology and pathophysiology are important in the genesis of vasospasm after subarachnoid haemorrhage. NO directed therapeutic strategies enlarge the spectrum of available instruments, but complete elimination of the problem of vasospasm cannot be expected.

Augmentation of intrapericardial nitric oxide level by a prolonged-release nitric oxide donor reduces luminal narrowing after porcine coronary angioplasty.

Nitric oxide (NO) is a potent vasodilator and antiplatelet agent that suppresses vascular smooth muscle cell proliferation. Hypothesizing that generating NO in the pericardial space would reduce luminal narrowing after coronary angioplasty without affecting systemic hemodynamics, we have determined the effect of a novel NO donor on vascular healing after balloon overstretch. Diazeniumdiolated bovine serum albumin (D-BSA; molecular weight 74 kDa, half-life for NO release 20 days) was radioiodinated and found by intravital gamma-imaging to have a longer residence time in pig pericardium than a low-molecular-weight (0.5 kDa) analogue (22 versus 4.6 hours, respectively). Intrapericardial injection of D-BSA immediately before 30% overstretch of normal left anterior descending and left circumflex coronary arteries dose dependently reduced the intimal/medial area ratio by up to 50% relative to controls treated with underivatized albumin when measured 2 weeks after intervention. Positive remodeling was also noted, which increased luminal area relative to control. Perivascular exposure of coronary arteries to NO via intrapericardial D-BSA administration reduced flow-restricting lesion development after angioplasty in pigs without causing significant systemic effects. The data suggest that intrapericardial delivery of NO donors for which NO release rates and pericardial residence times are matched and optimized might be a beneficial adjunct to coronary angioplasty.

Double-blind evaluation of transdermal nitroglycerine as adjuvant to oral morphine for cancer pain management

Study Objectives: To examine analgesia and adverse effects following transdermal application of nitroglycerine (a nitric oxide generator) combined with oral morphine, in cancer pain patients. Design: Randomized, double-blind study. Setting: Teaching hospital. Patients: 36 patients suffering from cancer pain. Interventions: Patients were divided into two groups (n = 18). All patients were regularly taking oral amitriptyline 50 mg at bedtime. Pain was evaluated using a 10-cm visual analog scale (VAS). The morphine regimen was individually adjusted to a maximal oral dose of 80 to 90 mg/day, to maintain the VAS score less than 4/10 cm. When patients complained of pain (VAS equal or greater than 4/10), despite taking 80 to 90 mg of oral morphine daily, the transdermal test drug was supplemented as follows: the control group received a placebo patch daily, and the nitroglycerine group received a 5-mg/24-hour nitroglycerine patch daily. Patients were free to manipulate their daily morphine consumption at the time the test drug was administered, to keep VAS less than 4/10 cm. After the introduction of the transdermal test drug, patients were evaluated by the staff on a weekly basis as outpatients, over four consecutive weeks. Measurements and Main Results: The groups were similar in respect to demographic data and VAS pain scores before the treatment. The daily consumption of oral morphine was smaller in the nitroglycerine group compared with the control group after the 14th day of evaluation (p < 0.002). Patients from the control group in general complained of somnolence, compared with the nitroglycerine group. Conclusion: Transdermal nitroglycerine was an effective coadjuvant analgesic. In conjunction with its opioid tolerance sparing function, delivery of nitric oxide donors together with opioids may be of significant benefit in cancer pain management in delaying morphine tolerance and decreasing the incidence of adverse effects related to high doses of opioids.

Successful Coronary Stent Implantation Using Local Nitric Oxide Donor Delivery

With the introduction of high pressure balloon inflations and antiplatelet therapy, the incidence of stent thrombosis has been markedly reduced, but the incidence of late stent restenosis has not. A new strategy may be local drug delivery, which maintains sustained local concentration and limits systemic complications. To evaluate the efficacy of local nitric oxide (NO) donor delivery on stent thrombosis and complications, local NO donor delivery was performed in stented patients. NO donor (2.0-mg molsidomine) was delivered (1.0 mL/min > 10 min) using the Dispatch Catheter after predilation of target lesions in 13 patients (6 angina, 7 myocardial infarction, age 53.1 ± 11.4 years). After local NO donor delivery, Palmaz-Schutz stents were placed using standard methods. Follow-up coronary angiograms were performed 48 hours and 6 months after stenting. None of the patients had hypotensive effects, ischemic symptoms, or ECG changes during and after local NO donor delivery. APTT and CK values were unchanged at 3 and 24 hours after local NO donor delivery and stenting. Follow-up coronary angiograms at 48 hours and 6 months showed all stents patent with TIMI III flow and without intrastent thrombus. No target lesion revascularization and 100% event-free survival were observed during the 6-month clinical follow-up period. Intracoronary stenting may be performed safely and effectively by local NO donor delivery prior to stent implantation.

Perivascular Delivery Of A Nitric Oxide Donor Inhibits Neointimal Hyperplasia In Vein Grafts Implanted In The Arterial Circulation

Objective: Nitric oxide has been reported to reduce intimal hyperplasia as a response to arterial injury. This study was designed to assess the possible effect of perivascular application of a nitric oxide donor on neointimal proliferation occurring in veins exposed to the dynamics of the arterial circulation in a hypercholesterolemic rabbit model. Methods: Autologous jugular vein grafts were implanted in the carotid circulation of 20 hypercholesterolemic rabbits. A mixture of a biodegradable polymer and the nitric oxide donor, spermine/nitric oxide, which releases nitric oxide with a half-life of 39 minutes, was applied periadventitially at the time of implantation. Controls were veins bathed in saline solution, polymer alone, and polymer plus the carrier vehicle spermine without nitric oxide. Animals ( n = 5 in each group) were put to death on day 28 for morphometric analysis, cell count, and immunohistochemical staining. Results: Treatment with perivascular nitric oxide donor significantly decreased wall thickness (126 ± 24 μm vs 208 ± 45 μm, p = 0.0017) and area (124 ± 22 μm 2/μm vs 211 ± 37 μm 2/μm, p = 0.005). With the carrier vehicle spermine alone, there was a trend toward reduced intimal thickness, but the change was not statistically significant. In the grafts treated with nitric oxide donor, expression of insulin-like growth factor, fibroblast growth factor, thrombospondins, fibronectin, and tenascin was reduced. Conclusion: The periadventitial delivery of nitric oxide donor produces a reduction of neointimal hyperplasia in veins implanted in the arterial circulation. The mechanism of action is not entirely clear, but the reduction cannot be explained on the basis of decreased cell proliferation alone. Other possibilities are modulation of protein synthesis of vascular smooth muscle cells and production of extracellular matrix components. (J Thorac Cardiovasc Surg 1998;115:604-14)

Local Delivery of Nitric Oxide Donor

Local Delivery of Nitric Oxide Donor