The mitochondrial-targeted reactive species scavenger JP4-039 prevents sulfite-induced alterations in antioxidant defenses, energy transfer, and cell death signaling in striatum of rats.

Sulfite oxidase (SO) deficiency is a disorder caused either by isolated deficiency of SO or by defects in the synthesis of its molybdenum cofactor. It is characterized biochemically by tissue sulfite accumulation. Patients present with seizures, progressive neurological damage, and basal ganglia abnormalities, the pathogenesis of which is not fully established. Treatment is supportive and largely ineffective. To address the pathophysiology of sulfite toxicity, we examined the effects of intrastriatal administration of sulfite in rats on antioxidant defenses, energy transfer, and mitogen-activated protein kinases (MAPK) and apoptosis pathways in rat striatum. Sulfite administration decreased glutathione (GSH) concentration and glutathione peroxidase, glucose-6-phosphate dehydrogenase, glutathione S-transferase, and glutathione reductase activities in striatal tissue. Creatine kinase (CK) activity, a crucial enzyme for cell energy transfer, was also decreased by sulfite. Superoxide dismutase-1 (SOD1) and catalase (CAT) proteins were increased, while heme oxygenase-1 (HO-1) was decreased. Additionally, sulfite altered phosphorylation of MAPK by decreasing of p38 and increasing of ERK. Sulfite further augmented the content of GSK-3ß, Bok, and cleaved caspase-3, indicating increased apoptosis. JP4-039 is a mitochondrial-targeted antioxidant that reaches higher intramitochondrial levels than other traditional antioxidants. Intraperitoneal injection of JP4-039 before sulfite administration preserved activity of antioxidant enzymes and CK. It also prevented or attenuated alterations in SOD1, CAT, and HO-1 protein content, as well as changes in p38, ERK, and apoptosis markers. In sum, oxidative stress and apoptosis induced by sulfite injection are prevented by JP4-039, identifying this molecule as a promising candidate for pharmacological treatment of SO-deficient patients.

Delivery of a mitochondria-targeted antioxidant from biocompatible, polymeric nanofibrous scaffolds.

Cardiovascular disease has been associated with increased levels of reactive oxygen species (ROS). Recently, we have shown that a critical balance between cytosolic ROS and mitochondrial ROS is crucial in cardiovascular health and that modulation of mitochondrial ROS helps prevent detrimental effects of cytosolic ROS on endothelial cells (EC) in transgenic animals. Here, we report the development of a controlled delivery system for a mitochondria-targeted antioxidant, JP4-039, from an electrospun scaffold made of FDA-approved biocompatible polymeric nanofibers. We demonstrate that the active antioxidant moiety was preserved in released JP4-039 for over 72 h using electron paramagnetic resonance. We also show that both the initial burst release of the drug within the first 20 min and the ensuing slow and sustained release that occurred over the next 24 h improved tube formation in human coronary artery ECs (HCAEC) in vitro. Taken together, these findings suggest that electrospinning methods can be used to upload mitochondrial antioxidant (JP4-039) onto a biocompatible nanofibrous PLGA scaffold, and the uploaded drug (JP4-039) retains nitroxide antioxidant properties upon release from the scaffold, which in turn can reduce mitochondrial ROS and improve EC function in vitro.

A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS-986231 in Healthy Volunteers.

Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first-in-human study for BMS-986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS-986231 after 24- and 48-hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS-986231 0.1, 0.33, 1, 3, 5, 10, and 15 µg/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 µg/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug-related AE (48%) in those who received BMS-986231, although their severity was reduced by hydration. No other significant drug-related AEs were noted. BMS-986231 was associated with dose-dependent and well-tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS-986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half-life was 0.7-2.5 hours. BMS-986231 was safe and well-tolerated for up to 24 hours (15 µg/kg/min) or 48 hours (10 µg/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS-986231 in patients with acute heart failure.

A randomised controlled trial exploring the effects of different beverages consumed alongside a nitrate-rich meal on systemic blood pressure.

BACKGROUND:: Ingestion of nitrate (NO3-)-containing vegetables, alcohol and polyphenols, separately, can reduce blood pressure (BP). However, the pharmacokinetic response to the combined ingestion of NO3- and polyphenol-rich or low polyphenol alcoholic beverages is unknown. AIM:: The aim of this study was to investigate how the consumption of low and high polyphenolic alcoholic beverages combined with a NO3--rich meal can influence NO3- metabolism and systemic BP. METHODS:: In a randomised, crossover trial, 12 normotensive males (age 25 ± 5 years) ingested an acute dose of NO3- (∼6.05 mmol) in the form of a green leafy salad, in combination with either a polyphenol-rich red wine (NIT-RW), a low polyphenol alcoholic beverage (vodka; NIT-A) or water (NIT-CON). Participants also consumed a low NO3- salad and water as a control (CON; ∼0.69 mmol NO3-). BP and plasma, salivary and urinary [NO3-] and nitrite ([NO2-]) were determined before and up to 5 h post ingestion. RESULTS:: Each NO3--rich condition elevated nitric oxide (NO) biomarkers when compared with CON ( P < 0.05). The peak rise in plasma [NO2-] occurred 1 h after NIT-RW (292 ± 210 nM) and 2 h after NIT-A (318 ± 186 nM) and NIT-CON (367 ± 179 nM). Systolic BP was reduced 2 h post consumption of NIT-RW (-4 mmHg), NIT-A (-3 mmHg) and NIT-CON (-2 mmHg) compared with CON ( P < 0.05). Diastolic BP and mean arterial pressure were also lower in NIT-RW and NIT-A compared with NIT-CON ( P < 0.05). CONCLUSIONS:: A NO3--rich meal, consumed with or without an alcoholic beverage, increases plasma [NO2-] and lowers systemic BP for 2-3 h post ingestion.

Evaluation of Different Formulations and Routes for the Delivery of the Ionizing Radiation Mitigator GS-Nitroxide (JP4-039).

BACKGROUND/AIM: The mitochondrial targeted GS-nitroxide, JP4-039, is an effective total body irradiation (TBI) mitigator when delivered intravenously (IV) up to 72 h after exposure. Effective systemic and localized administration to oral cavity/oropharynx and esophagus has been demonstrated. The objective of the study was to establish alternatives to IV administration suitable for JP4-039 delivery to mass casualties. MATERIALS AND METHODS: JP4-039 was administered to C57BL/6 mice by topically applied carboxy-methyl-cellulose microneedle arrays (MNAs) or by intramuscular (IM) injection. Three different formulations that have passed Food and Drug Administration review, namely Captisol, 2-hydroxypropyl-ß-cyclodextrin (cyclodextrin), and Miglyol-812-N, were used for drug delivery. Intraoral (IO) administration with each formulation was also evaluated. RESULTS: All tested formulations and MNAs successfully delivered JP4-039. However, IM delivery of the Miglyol-812-N displayed very efficient and highly reproducible radiation mitigation. CONCLUSION: Effective IM delivery of JP4-039 in animal models after TBI or partial-body irradiation suggested the use of the Miglyol-812-N formulation in both medical indications and radiation countermeasures.

Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin.

Glutathione-liganded binuclear dinitrosyl iron complex (glut-BDNIC) has been proposed to be a donor of nitric oxide (NO). This study was undertaken to investigate the mechanisms of vasoactivity, systemic hemodynamic effects, and pharmacokinetics of glut-BDNIC. To test the hypothesis that glut-BDNICs vasodilate by releasing NO in its reduced [nitroxyl (HNO)] state, a bioassay method of isolated, preconstricted ovine mesenteric arterial rings was used in the presence of selective scavengers of HNO or NO free radical (NO•); the vasodilatory effects of glut-BDNIC were found to have characteristics similar to those of an HNO donor and markedly different than an NO• donor. In addition, products of the reaction of glut-BDNIC with CPTIO [2-(4-carboxyphenyl)-4,4,5-tetramethyl imidazoline-1-oxyl-3-oxide] were found to have electron paramagnetic characteristics similar to those of an HNO donor compared with an NO• donor. In contrast to S-nitroso-glutathione, which was vasodilative both in vitro and in vivo, the potency of glut-BDNIC-mediated vasodilation was markedly diminished in both rats and sheep. Wire myography showed that plasma albumin contributed to this loss of hypotensive effects, an effect abolished by modification of the cysteine-thiol residue of albumin. High doses of glut-BDNIC caused long-lasting hypotension in rats that can be at least partially attributed to its long circulating half-life of ∼44 minutes. This study suggests that glut-BDNIC is an HNO donor, and that its vasoactive effects are modulated by binding to the cysteine residue of plasma proteins, such as albumin.

Liquid chromatography-tandem mass spectrometric assay for the quantitation of the novel radiation protective agent and radiation mitigator JP4-039 in murine plasma.

JP4-039 radio-protects prior to, and radio-mitigates after ionizing radiation by neutralizing reactive oxygen species. We developed and validated an LC-MS/MS assay for the quantitation of JP4-039 in murine plasma. Methanol protein precipitation of 50µL plasma was followed by isocratic reverse phase chromatography for a 6min run time, and electrospray positive mode ionization mass spectrometric detection. The plasma assay was linear from 1 to 1000ng/mL with appropriate accuracy (97.1-107.6%) and precision (3.7-12.5%CV), and fulfilled FDA guidance criteria. Recovery was 77.2-136.1% with moderate ionization enhancement (10.9-39.5%). Plasma freeze-thaw stability (98.8-104.2%), stability for 13.5 months at -80°C (93.1-105.6%), and stability for 4h at room temperature (94.2-97.6%) were all acceptable. Limited cross-validation to tissue homogenates suggested that these could also be analyzed for JP4-039 accurately. This assay has been directly applied to determine the pharmacokinetics of JP4-039 in C57BL/6 male mice after IV administration of 20mg/kg JP4-039 and will be extended to other studies of this agent.

Hypotensive Effect and Accumulation of Dinitrosyl Iron Complexes in Blood and Tissues after Intravenous and Subcutaneous Injection.

Subcutaneous injection of Oxacom with glutathione-bound dinitrosyl iron complex as the active principle produced a slower drop of mean BP and longer accumulation of protein-bound dinitrosyl iron complexes in whole blood and tissues than intravenous injection of this drug, while durations of hypotensive effect in both cases were practically identical. In contrast to intravenous injection of the drug, its subcutaneous administration was not characterized by a high concentration of protein-bound dinitrosyl iron complexes in the blood at the onset of experiment; in addition, accumulation of these NO forms in the lungs was more pronounced after subcutaneous injection than after intravenous one.

A mathematical model for the role of N2O3 in enhancing nitric oxide bioavailability following nitrite infusion.

Nitrite infusion into the bloodstream has been shown to elicit vasodilation and protect against ischemia-reperfusion injury through nitric oxide (NO) release in hypoxic conditions. However, the mechanism by which nitrite-derived NO escapes scavenging by hemoglobin in the erythrocyte has not been fully elucidated, owing in part to the difficulty in measuring the reactions and transport on NO in vivo. We developed a mathematical model for an arteriole and surrounding tissue to examine the hypothesis that dinitrogen trioxide (N2O3) acts as a stable intermediate for preserving NO. Our simulations predict that with hypoxia and moderate nitrite concentrations, the N2O3 pathway can significantly preserve the NO produced by hemoglobin nitrite reductase in the erythrocyte and elevate NO reaching the smooth muscle cells. Nitrite retains its ability to increase NO bioavailability even at varying flow conditions, but there is minimal effect under normoxia or very low nitrite concentrations. Our model demonstrates a viable pathway for reconciling experimental findings of potentially beneficial effects of nitrite infusions despite previous models showing negligible NO elevation associated with hemoglobin nitrite reductase. Our results suggest that additional mechanisms may be needed to explain the efficacy of nitrite-induced vasodilation at low infusion concentrations.

In vivo evaluation of different alterations of redox status by studying pharmacokinetics of nitroxides using magnetic resonance techniques.

Free radicals, particularly reactive oxygen species (ROS), are involved in various pathologies, injuries related to radiation, ischemia-reperfusion or ageing. Unfortunately, it is virtually impossible to directly detect free radicals in vivo, but the redox status of the whole organism or particular organ can be studied in vivo by using magnetic resonance techniques (EPR and MRI) and paramagnetic stable free radicals - nitroxides. Here we review results obtained in vivo following the pharmacokinetics of nitroxides on experimental animals (and a few in humans) under various conditions. The focus was on conditions where the redox status has been altered by induced diseases or harmful agents, clearly demonstrating that various EPR/MRI/nitroxide combinations can reliably detect metabolically induced changes in the redox status of organs. These findings can improve our understanding of oxidative stress and provide a basis for studying the effectiveness of interventions aimed to modulate oxidative stress. Also, we anticipate that the in vivo EPR/MRI approach in studying the redox status can play a vital role in the clinical management of various pathologies in the years to come providing the development of adequate equipment and probes.

Brain contrasting ability of blood-brain-barrier-permeable nitroxyl contrast agents for magnetic resonance redox imaging.

PURPOSE: The detailed in vivo T1 -weighted contrasting abilities of nitroxyl contrast agents, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, in mouse brain were investigated. METHODS: Distribution and pharmacokinetics of five types of five-membered-ring nitroxyl radical compound were compared using T1 -weighted MRI. RESULTS: The blood-brain barrier (BBB) -impermeable 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP) could not be distributed in the brain. The slightly lipophilic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP) showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl (MCP) had good initial uniform distribution in the brain and showed typical 2-phase signal decay profiles. A brain-seeking nitroxyl probe, acetoxymethyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl-3-carboxylate (CxP-AM), showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 4-(N-methyl piperidine)-2,2,5,5-tetramethylpyrroline-N-oxyl (23c) was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay. CONCLUSION: Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool. Magn Reson Med 76:935-945, 2016. © 2015 Wiley Periodicals, Inc.

Brain imaging in methamphetamine-treated mice using a nitroxide contrast agent for EPR imaging of the redox status and a gadolinium contrast agent for MRI observation of blood-brain barrier function.

Methamphetamine (METH)-induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. The aims of the present study conducted in the mouse brain repetitively treated with METH were to (1) examine the redox status using the redox-sensitive imaging probe 3-methoxycarbonyl-2,2,5,5-tetramethylpiperidine-1-oxyl (MCP) and (2) non-invasively visualize the brain redox status with electron paramagnetic resonance (EPR) imaging. The rate of reduction of MCP was measured from a series of temporal EPR images of mouse heads, and this rate was used to construct a two-dimensional map of rate constants called a "redox map." The obtained redox map clearly illustrated the change in redox balance in the METH-treated mouse brain that is a known result of oxidative damage. Biochemical assays also showed that the level of thiobarbituric acid-reactive substance, an index of lipid peroxidation, was increased in mouse brains by METH. The enhanced reduction in MCP observed in mouse brains was remarkably suppressed by treatment with the dopamine synthase inhibitor, α-methyl-p-tyrosine, suggesting that enhancement of the reduction reaction of MCP resulted from enzymatic reduction in the mitochondrial respiratory chain. Furthermore, magnetic resonance imaging (MRI) of METH-treated mice using a blood-brain barrier (BBB)-impermeable paramagnetic contrast agent revealed BBB dysfunction after treatment with METH for 7 days. MRI also indicated that the impaired BBB recovered after withdrawal of METH. EPR imaging and MRI are useful tools not only for following changes in the redox status and BBB dysfunction in mouse brains repeatedly administered METH, but also for tracing the drug effect after withdrawal of METH.

[Hemodynamic effects of the synthetic analogue of endogenous nitric oxide (II) donors a dinitrosyl iron complex in hypertensive patients with uncomplicated hypertensive crisis].

AIM: To examine the antihypertensive effect of the synthetic analogue of the endogenous nitric oxide donors in patients with grades 2-3 hypertension and uncomplicated hypertensive crisis (HC). SUBJECTS AND METHODS: The study included 30 male patients aged 35 to 73 years (mean age 55.5 ± 10.8 years). All the patients had grades 2-3 essential or secondary hypertension. Thirteen (43.3%) patients were observed to have signs of HC; 17 (56.7%) patients had persistent blood pressure (BP) elevation. A dinitrosyl iron complex was injected in a dose of 1.5 or 3 mg per kg of body weight. The purpose of its administration was to lower BP by at least 20% of its baseline level. RESULTS: No significant side effects associated with the administration of the test drug were recorded when the clinical trial protocol was implemented. All the patients reported fever and facial hyperemia during and 10-20 minutes after injection. They all (100%) showed efficient blood pressure reduction of at least 20% of the baseline level. Blood pressure changes were similar when the agent was administered in doses of 1.5 or 3 mg/kg. At 6-8 minutes after the drug was injected, there was a maximal decrease in blood pressure, then its gradual rise and stabilization at a lower level than the baseline one within the following 8 hours. There were no significant differences in the magnitude of a blood pressure reduction after administration of 1.5 and 3 mg/kg. CONCLUSION: The findings suggest that the dinitrosyl iron complex is highly effective in treating uncomplicated HC. The antihypertensive effect of the drug persists for 8 hours after its injection, which is very important during prehospital therapy. The drug is well tolerated by patients and causes an insignificant number of side effects.

Esophageal radioprotection by swallowed JP4-039/F15 in thoracic-irradiated mice with transgenic lung tumors.

BACKGROUND/AIM: To determine whether Gramicidin S (GS)-nitroxide, JP4-039, esophageal radiation protection protected lung tumors in a transgenic model, LoxP-Stoop-LoxP Kristen Rat Sarcoma Viral oncogene (LSL-K-RAS) mice were administered intra-tracheal- Carbapenem-resistant Enterobacteriaceae (CRE) recombinase, bilateral lung tumors were confirmed at 11 weeks, then thoracic irradiation was delivered. MATERIALS AND METHODS: Mice received single-fraction 15 Gy or 24 Gy to both lungs, in subgroups receiving intraesophageal administration 10 min before irradiation of JP4-039 (in F15 emulsion) tumor size reduction and survival were investigated. Mice were followed for survival, and reduction in tumor size. RESULTS: There was no evidence of tumor radioprotection in mice receiving JP4-039/F15. CONCLUSION: Intraesophageal radioprotective small-molecule antioxidant therapy protects normal tissue but not tumor tissue in mice with transgenic lung tumors.

Tissue redox activity as a hallmark of carcinogenesis: from early to terminal stages of cancer.

PURPOSE: The study aimed to clarify the dynamics of tissue redox activity (TRA) in cancer progression and assess the importance of this parameter for therapeutic strategies. EXPERIMENTAL DESIGN: The experiments were carried out on brain tissues of neuroblastoma-bearing, glioma-bearing, and healthy mice. TRA was visualized in vivo by nitroxide-enhanced MRI on anesthetized animals or in vitro by electron paramagnetic resonance spectroscopy on isolated tissue specimens. Two biochemical parameters were analyzed in parallel: tissue total antioxidant capacity (TTAC) and plasma levels of matrix metalloproteinases (MMP). RESULTS: In the early stage of cancer, the brain tissues were characterized by a shorter-lived MRI signal than that from healthy brains (indicating a higher reducing activity for the nitroxide radical), which was accompanied by an enhancement of TTAC and MMP9 plasma levels. In the terminal stage of cancer, tissues in both hemispheres were characterized by a longer-lived MRI signal than in healthy brains (indicating a high-oxidative activity) that was accompanied by a decrease in TTAC and an increase in the MMP2/MMP9 plasma levels. Cancer progression also affected the redox potential of tissues distant from the primary tumor locus (liver and lung). Their oxidative status increased in both stages of cancer. CONCLUSIONS: The study shows that tissue redox balance is very sensitive to the progression of cancer and can be used as a diagnostic marker of carcinogenesis. The study also suggests that the noncancerous tissues of a cancer-bearing organism are susceptible to oxidative damage and should be considered a therapeutic target.

An orally administered redox nanoparticle that accumulates in the colonic mucosa and reduces colitis in mice.

BACKGROUND & AIMS: Drugs used to treat patients with ulcerative colitis are not always effective because of nonspecific distribution, metabolism in the gastrointestinal tract, and side effects. We designed a nitroxide radical-containing nanoparticle (RNP(O)) that accumulates specifically in the colon to suppress inflammation and reduce the undesirable side effects of nitroxide radicals. METHODS: RNP(O) was synthesized by assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in an ether-linked hydrophobic side chain. Biodistribution of RNP(O) in mice was determined from radioisotope and electron spin resonance measurements. The effects of RNP(O) were determined in mice with dextran sodium sulfate (DSS)-induced colitis and compared with those of low-molecular-weight drugs (4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl [TEMPOL] or mesalamine). RESULTS: RNP(O), with a diameter of 40 nm and a shell of poly(ethylene glycol), had a significantly greater level of accumulation in the colonic mucosa than low-molecular-weight TEMPOL or polystyrene latex particles. RNP(O) was not absorbed into the bloodstream through the intestinal wall, despite its long-term retention in the colon, which prevented its distribution to other parts of the body. Mice with DSS-induced colitis had significantly lower disease activity index and less inflammation following 7 days of oral administration of RNP(O) compared with mice with DSS-induced colitis or mice given low-molecular-weight TEMPOL or mesalamine. CONCLUSIONS: We designed an orally administered RNP(O) that accumulates specifically in the colons of mice with colitis and is more effective in reducing inflammation than low-molecular-weight TEMPOL or mesalamine. RNP(O) might be developed for treatment of patients with ulcerative colitis.

[Study of dinitrosyl-iron complexes pharmacokinetics and accumulation in depot in rat organs].

Protein-bound dinitrosyl-iron complexes (DNIC) in rat whole blood and organs were studied after intravenous injection of this substance with glutathione ligand (DNIC-GH). The effect of DNIC-GH injection on NO level (including NO physiological forms) in hydrophobic areas of rat tissues was also studied in normal physiological blood circulation condition. It has been shown, that after DNIC-GH injection the concentration of protein-bound DNICs in rat whole blood and organs rapidly reached maximum values, and then gradually decreased, that pointed to decomposition of DNIC molecules, coupled with NO release. At the beginning of the experiment the rates of DNIC decay in rat heart and lung were substantially higher, as compared with those in liver and kidney. By spin trappping it has been demonstrated that DNIC-GH, as a source of NO physiological forms (including S-nitrosothiols), in normal physiological blood circulation influence heart more selectively, as compared with the other organs.

Metal-free and MRI visible theranostic lyotropic liquid crystal nitroxide-based nanoparticles.

The development of improved, low toxicity, clinically viable nanomaterials that provide MRI contrast have tremendous potential to form the basis of translatable theranostic agents. Herein we describe a class of MRI visible materials based on lyotropic liquid crystal nanoparticles loaded with a paramagnetic nitroxide lipid. These readily synthesized nanoparticles achieved enhanced proton-relaxivities on the order of clinically used gadolinium complexes such as Omniscan™ without the use of heavy metal coordination complexes. Their low toxicity, high water solubility and colloidal stability in buffer resulted in them being well tolerated in vitro and in vivo. The nanoparticles were initially screened in vitro for cytotoxicity and subsequently a defined concentration range was tested in rats to determine the maximum tolerated dose. Pharmacokinetic profiles of the candidate nanoparticles were established in vivo on IV administration to rats. The lyotropic liquid crystal nanoparticles were proven to be effective liver MRI contrast agents. We have demonstrated the effective in vivo performance of a T1 enhancing, biocompatible, colloidally stable, amphiphilic MRI contrast agent that does not contain a metal.

[The study of hypotensive action of dinitrosyl-iron complex with glutathione containing drug oxacom in healthy volunteers].

On the basis of earlier executed studies of hypotensive effect of dinitrosyl iron complexes (DNIC) with glutathione, the drug has been created in industrial conditions named oxacom. Preliminary pharmacological studies of oxacom have not revealed negative qualities. The drug has been now tested in 14 healthy men in whom at single intravenous introduction it caused typical response - a decrease of diastolic as well as systolic arterial pressure on 24-27 mmHg through 3-4 min with subsequent very slow restoration in 8-10 hours. The heart rate after initial rise was quickly normalized. Echocardiography revealed unaltered cardiac output in spite of reduced cardiac filling by 28%. The multilateral analysis of clinical and biochemical data has revealed an absence of essential alterations which could lead to pathological consequences. The drug is recommended for carrying out of the second phase of clinical trial. The comparative study of the efficiency of hypotensive action of oxacom, S-nitrosoglutathione (GS-NO) and sodium nitrite (NO2) in rats has shown that the duration of effect was the greatest at oxacom action.