Vasodilator Drugs Research Articles

Release of vascular agonists from liposome-microbubble conjugate by ultrasound-mediated microbubble destruction: effect on vascular function.

The endothelium is a single cell layer of the vessel wall and a key regulator of blood flow in vascular beds. Local and systemic pathologies have been associated with alterations in endothelial function. However, targeting the endothelium with vasoconstrictor or vasodilator drugs is often accompanied by systemic effects. Here, we evaluated a liposome-microbubble delivery system as a vascular hydrophilic agonist carrier. Phenylephrine (Phe) or acetylcholine (Ach)-loaded liposomes were conjugated to microbubbles. The drug release was triggered by ultrasound (US), and the vascular response was assessed in rat aortic rings using an isolated organ chamber. Aortic rings incubated with Phe-liposome-microbubble conjugate, exposed to US showed a marked contractile response (0.79±0.04g) compared to empty liposomes conjugated to microbubbles, aortic rings exposed only to US, and Phe-liposome-microbubble conjugate without US exposure that elicited a minimal or no response. Expressed as %, contractile responses were 85.24±4.31% and 12.62±3.23% for Phe-Chol-liposome-microbubble conjugate and empty Chol-liposome-microbubble conjugate exposed to US, respectively. Addition of 1×10-5M Ach to pre-contracted aortic rings decreased the contraction response from 1 to 0.21g. The addition of Ach-liposome conjugate and exposure to US decreased the contraction response to 0.32g. Additionally, the ED50 values for Phe and Ach released by US from liposome-microbubble conjugates were 3.6×10-8M±2.8×10-9M for Phe and 2.0×10-8M±1.8×10-9M. In conclusion, we evaluated a hybrid delivery system that consisted of loaded liposomes conjugated to microbubbles to deliver and release vascular agonists using UMMD.

Safety and efficacy of ultrafiltration on heart failure patients with reduced ejection fraction and diuretic resistance: results from a single-center randomized controlled trial

Objective: To investigate the safety and efficacy of ultrafiltration on diuretic sensitivity in heart failure patients with reduced ejection fraction and diuretic resistance. Methods: This was a single-center randomized controlled trial. A total of 148 heart failure patients with reduced ejection fraction admitted to the Hospital of Traditional Chinese Medicine of Xinjiang Uygur Autonomous Region from June 2010 to June 2020 were enrolled in this study, and these patients were randomly divided (ratio 1:1) into the ultrafiltration group (n=74) and the control group (n=74). All patients were treated with diuretics, cardiotonic, vasodilator and other comprehensive drugs according to relevant guidelines. After grouping, the patients in the control group were treated with standard treatment plan, while patients in the ultrafiltration group were treated with ultrafiltration on top of standard therapy. Diuretic drugs were discontinued during ultrafiltration, and intravenously furosemide (40 mg) was given immediately and 24 hours after the end of ultrafiltration. Clinical data including gender, age, complicated diseases, New York Heart Association (NYHA) function classification, etc. were collected. Effectiveness indicators include urine volume (the first 12-hour and 24-hour urine volume and the second 24-hour urine volume after using diuretic), body weight and dyspnea severity score. Safety indicators include systolic blood pressure, serum creatinine, serum Na+ concentration, blood K+ concentration and the number of deaths before and after intervention. Results: Two patients in the control group died due to worsening heart failure after randomization and were excluded in this study, 146 patients were finally analyzed (72 patients in the control group and 74 patients in the ultrafiltration group). There were 93 males, and the age was (68.3±11.2) years. There was no significant difference between patients in the ultrafiltration group and the control group in gender, age, body weight, course of disease, dyspnea severity score, NYHA function classification Ⅲ/Ⅳ, the proportion of patients with severe edema of both lower limbs, the proportion of patients with complicated diseases, and basic medication (all P>0.05). After using diuretics, the urine volume of the first 12-hour and 24-hour and the second 24-hour were significantly higher in the ultrafiltration group than in the control group (all P<0.05). Body weight decreased significantly after ultrafiltration treatment as compared with that before intervention in the ultrafiltration group (P<0.05). Compared with the control group, the dyspnea severity score was significantly improved in the ultrafiltration group (P<0.05). There was no significant difference in systolic blood pressure, serum creatinine, serum Na+ concentration, blood K+ concentration of patients between ultrafiltration group and control group before and after intervention (all P>0.05). During the clinical diagnosis and treatment, 2 male patients in the control group died, and the cause of death was aggravation of basic diseases complicated with acute heart failure and cardiogenic shock. There was no death in the ultrafiltration group, and there were no obvious clinical adverse events during and after ultrafiltration. Conclusion: Ultrafiltration therapy is safe and can improve diuretic sensitivity in heart failure patients with reduced ejection fraction and diuretic resistance.

RADIAL-FINGER PULSE WAVE VELOCITY: RESPONSE OF PERIPHERAL SMALLER ARTERIES TO NITROGLYCERIN

Objective: We previously demonstrated a different regional stiffness response of elastic and muscular arteries after the administration of nitroglycerin, leading to an alteration of aortic-brachial stiffness gradient. Peripheral smaller arteries may also respond differently to nitroglycerin. The objectives of this study were 1- to assess the feasibility of measuring arterial stiffness of the hand, i.e. radial-finger pulse wave velocity (RF-PWV) using piezoelectric sensors, and 2- to measure RF-PWV and its response to nitroglycerin. Design and method: This study was conducted in 29 healthy participants (66% were women, mean age was 40.0 ± 15.1 yrs). Piezoelectric sensors (Complior) were place simultaneously on carotid and radial arteries, and tip of the index and/or third finger, to obtain carotid-radial PWV (CR-PWV) and RF-PWV. These measurements were repeated with a subgroup of 11 subjects after 4 minutes of 0.4mg NTG sublingual spray. Raw data were analyzed using Matlab to ensure good quality of signals and adequacy of the foot-to-foot method. Results: Visually, pressure curves at both fingers were obtained with an excellent quality, similar to radial and carotid pressure curves. Identification of the feet of the finger pulse waveforms was optimal with the second derivative algorithm. RF-PWV intra-session coefficient of variation was 7.3%. At baseline, mean CR-PWV and RF-PWV were respectively of 8.21 ± 1.44 m/sec and 4.65 ± 1.42m/sec. After NTG, CR-PWV decreased (7.75 ± 1.32 m/s) and RF-PWV increased (6.75 ± 2.58 m/s), both significantly (p&lt;0.01). However, stiffness of the whole upper limb (carotid-finger PWV) did not change significantly (7.37 ± 0.87 m/s vs 7.29 ± 1.08 m/s, p=0.605). Conclusions: This first attempt to measure regional stiffness of small arteries shows that it is possible to measure hand PWV. Again, we observed opposite changes in regional stiffness of different vascular territories with a vasodilator drug. These results may open up the path to a better understanding of microcirculation consequences of an altered stiffness gradient.

The effects of botulinum toxin A and papaverine on human saphenous vein and internal mammary artery grafts: an in vitro study.

Autologous saphenous vein (SV) and internal mammary artery (IMA) are used as bypass conduits during coronary artery bypass graft surgery. Vasospasm of the arterial and venous grafts may constitute a significant clinical problem. Pretreatment with a vasodilator drug of the graft ex vivo or intraluminal injection before implantation may be used for spasm prophylaxis. This in vitro study was designed to assess the vasoactive effects and time-dependent changes of botulinum toxin A (BTX-A) and papaverine pretreatment on vasospasm of human SV and IMA grafts. Also, histomorphology of the vessels was assessed. SV and IMA segments were suspended in organ baths, and isometric contraction responses to 2 different concentrations of 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) were recorded after incubation with 2 different concentrations of BTX-A and papaverine at 2 time points (0 h and 2 h). The results revealed the following: 1) incubation with BTX-A and papaverine relaxes both SV and IMA rings contracted with 5-HT and ET-1; 2) the duration of the relaxant effect of BTX-A lasts longer than papaverine; and 3) no apparent histomorphological changes were observed in the grafts under light microscopy. This study demonstrates that in human SV and IMA grafts, pretreatment with both BTX-A and papaverine are safe and have a potent inhibitory effect depending on the vessel and vasoconstrictor agent. The long-lasting vasodilatory effect of BTX-A on vascular smooth muscle may provide promising results in the prevention of venous and arterial graft spasm.

Patients with Severe Right Ventricular Dysfunction and Low Arterial Elastance Have Poor Prognosis Even after Heart Transplantation

<h3>Purpose</h3> To study the impact of severe right ventricular (RV) dysfunction on survival after heart transplantation <h3>Methods</h3> Data from 250 patients was analyzed for the effect of severe RV dysfunction , categorized by high right atrial pressure (RAP), low pulmonary artery pulsatility index (PAPi) and the presence of ascites, on 90 day and medium term survival . Systemic afterload was estimated by arterial elastance (<i>E_a</i>) (method given below) and systemic vascular resistance (SVR) . <i>Calculation of E_a: End systolic pressure E_sys) = (2* systolic blood pressure + diastolic pressure) / 3 . (1) Stroke volume (SV) = (CO / HR). (2) Arterial Elastance (E_a ) = E_sys / SV (3)</i> Organ perfusion pressure index (OPPI) ((Mean arterial pressure - RAP) / BSA) and modified MELD score was calculated . <h3>Results</h3> 90 day survival was worse with RAP > 15 (p = 0.014 ) , PAPi < 0.9 (p= 0.104) ,with ascites (p = 0.005) <i>,</i> higher MELD score ( odds ratio 1.07, p = 0.06 ) and lower OPPI (odds ratio 0.92,p = 0.004). The effect of RAP ,PAPi and MELD score on mortality was not seen if afterload was higher (<i>Ea > 2.7,SVR >1600 dynes/cm^-5/sec).</i> 5 years survival was worse for RAP > 15 ( p = 0.0059) , ascites (p = 0.009), PAPi < 0.9 (p= 0.1897) and MELD score > 20 ( p=0.022 ) This effect of RAP , PAPi and MELD score was absent if Ea > 2.7. Survival for OPPI < 40 was worse (p = 0.0124) but only if RAP was more than 15 mm hg. The relationship between RAP,Ea and OPPI and the effect on medium term survival is shown in a cox proportional hazard regression survival curve ( Fig 1). <h3>Conclusion</h3> 90 day and 5 year survival after heart transplantation are worse in patients with severe preoperative RV dysfunction but only <i>if the systemic arterial afterload</i> is low . Organ perfusion pressure index less than 40 appears to be deleterious in the short and medium term. Vasodilator drugs used to treat systolic left heart failure may adversely affect survival if RAP is high . Intra aortic balloon pump might be a more physiological alternative in patients awaiting transplantation.

Low Organ Perfusion Pressure Indexed to Body Surface Area is a Powerful Predictor of Poor Outcomes Even after Heart Transplantation in the Presence of High Right Atrial Pressure

<h3>Purpose</h3> High right atrial pressure (RAP) is associated with deranged renal function and mortality in patients with heart failure. We hypothesised that : 1.This effect may persist after heart transplantation 2. It is essentially mediated through a low organ perfusion pressure indexed to body surface area (OPPI). 3.That OPPI is more sensitive than organ perfusion pressure (OPP) alone in predicting survival. <h3>Methods</h3> The data from 250 patients who had a heart transplant over a 8 period from October 2012 to march 2020 was analyzed for the effect of OPPI and OPP. OPP was calculated as :Mean arterial pressure (MAP) - RAP and OPPI as (MAP-RAP)/body surface area .OPPI value of 40 and OPP of 60 mm hg were chosen for analysis as they were close to the median values. <h3>Results</h3> There was a more significant negative correlation between OPPI and creatinine (r = -0.3551,p =0.000) than OPP and creatinine (r = -0.0688,p = 0.3414).The effect of OPPI on MELD score was more pronounced than OPP.( r = -0.3580, p = 0.000 vs r = -0.1504, p = 0.062). OPPI also had a more significant effect on 90 day mortality than OPP (odds ratio 0.89, p = 0.004 vs odds ratio 1.01 ,p = 0.677). The 90 day mortality for OPPI less than and more than 40 was 23.2 % vs 7.1 %, p = 0.001.This effect of OPPI and OPP on 90 day mortality was absent if RAP was less than 15 mm hg. The effect of OPPI on survival persisted at a follow up of beyond 5 years. (72 % vs 54 % , p = 0.0124).The effect was absent if the RAP was less than 15. The effect was more pronounced for OPPI than OPP. <h3>Conclusion</h3> 90 day and 5 year survival after heart transplantation are worse in patients with low organ perfusion pressure indexed to BSA . OPPI less than 40 appears to be deleterious . Vasodilator drugs used to treat systolic left heart failure may adversely affect survival if RAP is high, to be used with caution.

Pharmacological Interventions for Pulmonary Involvement in Rheumatic Diseases.

Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are two important conditions in patients with rheumatic diseases that are associated with significant morbidity and mortality. The management of ILD and PAH is challenging because the current treatment often provides only limited patient survival benefits. Such challenges derive from their common pathogenic mechanisms, where not only the inflammatory processes of immune cells but also the fibrotic and proliferative processes of nonimmune cells play critical roles in disease progression, making immunosuppressive therapy less effective. Recently, updated treatment strategies adopting targeted agents have been introduced with promising results in clinical trials for ILD ad PAH. This review discusses the epidemiologic features of ILD and PAH among patients with rheumatic diseases (rheumatoid arthritis, myositis, and systemic sclerosis) and the state-of-the-art treatment options, focusing on targeted agents including biologics, antifibrotic agents, and vasodilatory drugs.

Understanding right ventricular myocardial infarction in prehospital care

Right ventricular myocardial infarction (RVMI) most commonly occurs in relation to an inferior myocardial infarction. Patients with this condition where the culprit right coronary artery (RCA) is occluded have a poor prognosis. Early recognition and the specific treatment pathway for RVMI differ from the treatment for general acute coronary syndrome (ACS) which could help the paramedic to treat this condition more appropriately. This article explores current guidelines for the recognition and treatment of RVMI and the possible application of specific guidelines in a prehospital setting with regards to using right-sided precordial ECG, the administration of fluids and potential complications arising from vasodilatory drugs. Furthermore, the purpose of this article is to help educate and develop the understanding of RVMI in this high-risk subgroup who have an increased morbidity and mortality.

Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension.

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

Drug-Nutraceutical Co-Crystal and Salts for Making New and Improved Bi-Functional Analgesics.

The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of chronic pain are multiple non-neuronal processes, among which are tissue hypoxia and oxidative stress. Here we demonstrate the design, synthesis, and activity of new multi-component bi-functional analgesic crystalline solids, co-crystals, and salts, based on pairing of vasodilatory anti-hypoxic drugs pentoxifylline, clonidine and linsidomine with antioxidant nutraceuticals protocatechuic acid, α-lipoic acid, and caffeic acid. After validation, chemical and structural characterization of these novel salts and co-crystals, topical formulations of the products were tested in a rat model of complex regional pain syndrome. Analgesic effects achieved with the salts and co-crystal exceeded the efficacy and/or potency of constituent compounds indicating that more effective, advanced analgesics can readily be developed by careful pairing of compounds that simultaneously target multiple neural and non-neural processes driving chronic pain.

Safety and hemodynamic response of regadenoson stress cardiovascular magnetic resonance imaging in heart transplant recipients

Abstract Background The non-invasive detection of coronary allograft vasculopathy remains a challenge, and there is no consensus about which technique should be used. The hypersensitivity to vasodilator drugs (such as adenosine) of heart transplant recipients may have limited the use of stress cardiovascular magnetic resonance imaging (stress-CMR) in this group of patients. Regadenoson is a more specific agonist of adenosine receptors. There is still little data on its safety profile and the hemodynamic response it causes in these patients. Purpose We aimed to observe safety and hemodynamic response to regadenoson in heart transplant recipients. Methods We studied 505 consecutive patients (22 transplanted and 483 non-transplanted) who underwent stress-CMR between 06/06/2017 and 10/10/2019. We compared the hemodynamic response (blood pressure and heart rate) and the adverse effects and symptoms caused by regadenoson in both groups. Student t test and χ2 were used to compare the continuous and the qualitative variables between both groups, respectively. Results In transplant patients there were no events requiring finalization of the test (e.g. atrioventricular block, symptomatic arterial hypotension or poor tolerance to the symptomatic response to regadenoson). There were no differences in the incidence of symptoms after drug administration in transplanted versus non-transplanted patients (50% vs. 50.4%, p=0.97), and all of those symptoms were transient and well tolerated. Transplant recipients presented an attenuated hemodynamic response compared to non-transplanted patients (Table 1). Conclusions Stress-CMR with regadenoson is a safe and well tolerated technique in heart transplant recipients. In this group of patients, the hemodynamic response is blunted compared to non-transplanted patients. This lower response has been previously described in obese and diabetic patients, and it does not appear to affect the performance of the test. Further studies should confirm these findings. Funding Acknowledgement Type of funding source: None

Dinitrosyl Iron Complexes with Thiol-Containing Ligands Exist in Living Organisms Mainly in the Binuclear Form

The levels of the mononitrosyl iron complex with diethyldithiocarbamate that form in the liver of mice in vivo and in vitro after intraperitoneal injection of binuclear dinitrosyl iron complexes with N-acetyl-L-cysteine or glutathione, S-nitrosoglutathione, sodium nitrite, or the vasodilating drug isosorbide dinitrate (Isoket®) have been assessed by electron paramagnetic resonance (EPR). The levels of the complex in mice that received binuclear dinitrosyl iron complexes with thiol-containing ligands or S-nitrosoglutathione do not change after the treatment of liver preparations with the strong reducing agent dithionite, in contrast to those formed after nitrite or isosorbide dinitrate administration, whose levels sharply increase after the same treatment. It is inferred that in the latter case an EPR-active mononitrosyl iron complex with diethyldithiocarbamate is produced with the absence or presence of dithionite in the reaction of NO formed from nitrite with Fe2+-diethyldithiocarbamate and Fe3+-diethyldithiocarbamate complexes, respectively. In the former case, the mononitrosyl iron complex with diethyldithiocarbamate is produced by transition of iron-mononitrosyl fragments from already present iron-dinitrosyl groups of binuclear dinitrosyl complexes, whose content is three to four times higher than the content of the mononuclear form of these complexes in the tissue. The results we obtained indicate that when dinitrosyl iron complexes with thiol-containing ligands, either introduced into the body or produced with the participation of endogenous NO, appear in animal tissues in vivo, these complexes are presented in these tissues mainly in their diamagnetic, EPR-silent binuclear form.

Étude monocentrique sur les médicaments pris par les patients pour le traitement de la sclérodermie systémique

IntroductionPharmaceutical prescription in systemic sclerosis is guided by national and international recommendations. This study's primary objective was to describe and analyze these prescriptions among patients of our cohort. We also aimed to assess drug compliance among our patients. MethodsThis is a monocentric observational study on two cohorts of patients with systemic sclerosis; a primary cohort comprising ambulatory patients, who were prospectively included, with exhaustive prescription's data collection; and a secondary cohort included patients asked to fill in a self-questionnaire on treatment compliance. ResultsThe main cohort included 157 patients, including 31 cases of diffuse systemic sclerosis. A vasodilator drug for Raynaud's phenomenon was prescribed in 75 patients (47.9%) and a specific treatment for pulmonary arterial hypertension in 10 patients (6.4%). Immuno-modulators/immunosuppressants was prescribed in 62 patients (39.5%), who received prednisone (n=37, 23.6%), mycophenolate mofetil (n=14, 8.9%), hydroxychloroquine (n=12, 7.6%) and colchicine (n=22, 14%). Treatment for “gastro-intestinal tract involvement” was prescribed for 106 patients (67.5%) and treatment of a scleroderma renal crisis with an angiotensin-converting enzyme inhibitor for 6 patients (3.8%). Among the 42 patients in the secondary cohort, 21.4% reported a good compliance, mostly older patients (P=0.045) or those who had not experienced adverse events (P=0.009). ConclusionThis study provides original real-life data illustrating the heterogeneity of prescription habits in systemic sclerosis. As previously reported, treatment compliance was insufficient.

Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine

Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia – an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription.The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.

High-flow nasal cannula oxygen therapy: Alternative respiratory therapy for severe post-transplant hypoxemia in children with hepatopulmonary syndrome.

Severe post-transplant hypoxemia, which is defined as <50mmHg of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F) ratio, is a major post-operative complication with high mortality rates in patients with hepatopulmonary syndrome (HPS). Non-invasive positive pressure ventilation therapy and mechanical ventilation are options for respiratory support of patients with severe post-transplant hypoxemia. However, these therapies are associated with several problems, such as compliance, ventilator-associated pneumonia, and lung injury. We here firstly described two children with HPS who developed severe post-transplant hypoxemia (lowest post-operative P/F ratio, 49.7 and 34.0mmHg, respectively) that was successfully managed with high-flow nasal cannula (HFNC) oxygen therapy and vasodilation drugs without adverse complications or necessity of reintubation. We consider that HFNC oxygen therapy could become a safe alternative respiratory therapy or be added to the other such as inhaled nitric oxide (iNO), methylene blue (MB), inhaled epoprostenol, embolization of abnormal pulmonary vessels, and combination of iNO and MB for severe post-transplant hypoxemia in children with HPS.

Synthesis of Aromatic Diketoximes and their Complexes with Nickel Salts

The diketoximes of 4,4'-diacetyldiphenyl oxide and 4,4'-diacetyldiphenyl sulfide were synthesized, the possibility of their use for the synthesis of simple and complex polyesters and polypyrroles, as well as the ability to complex with nickel salts. Organic chemistry used oximes in the 19th century, afterward, as an analytical reagent in the 20th century. Currently, oximes are superior to carbonyl compounds and alcohols in the variety of reactions and the widespread use in synthetic chemistry. Oximes easily turn into other classes of organic compounds – amines, cyano and nitro compounds, carbonyl compounds, heterocyclic compounds, including pyrroles, imidazoles, pyridines, they can be used as suitable compounds with salts of Cu (II), Ni (II), Zn (II), Cd (II), and Co (II). Oximes with complex heterocyclic and aromatic substituents are used as intermediates in fine organic synthesis. It should be noted that oximes have a wide spectrum of biocidal action and are used as anti-inflammatory, antiviral, antimicrobial agents, insecticides. Their versatile biological activity is considered in the preparation of antidepressant, sedative, vasodilator and other drugs [1].

Hypothesis: The potential therapeutic role of nicorandil in COVID-19.

At present, there is yet no specific antiviral treatment or immunization against the newly identified human severe acute respiratory syndrome virus (SARS‐CoV2) that results in a rapidly progressive pandemic coronavirus disease 2019 (COVID‐19). We believe in a crucial need for a clinical strategy to counteract this viral pandemic based on the known pathogenesis throughout the disease course. Evidence suggests that exaggerated patient's inflammatory response and oxidative stress are likely to aggravate the disease pathology. The resulting endothelial dysfunction further induces fibrosis and coagulopathy. These disturbances can generate severe acute respiratory distress syndrome (ARDS) that can progress into respiratory and circulatory failure. Nicorandil is an anti‐anginal vasodilator drug acts by increasing nitric oxide bioavailability and opening of the KATP channel. Recently, nicorandil has been recognized to possess multiple protective effects against tissue injury. Here, we address a possible modulatory role of nicorandil against COVID‐19 pathogenesis. We hypothesise nicorandil would be an effective form of adjuvant therapy against COVID‐19.

Pentacyanoferrate(II) complex of pyridine-4- and pyrazine-2-hydroxamic acid as source of HNO: investigation of anti-tubercular and vasodilation activities.

A pharmacophore design approach, based on the coordination chemistry of an intimate molecular hybrid of active metabolites of pro-drugs, known to release active species upon enzymatic oxidative activation, is devised. This is exemplified by combining two anti-mycobacterial drugs: pyrazinamide (first line) and delamanid (third line) whose active metabolites are pyrazinoic acid (PyzCOOH) and likely nitroxyl (HNO (or NO.)), respectively. Aiming to generate those active species, a hybrid compound was envisaged by coordination of pyrazine-2-hydroxamic acid (PyzCONHOH) witha Na3[FeII(CN)5]moiety. The corresponding pentacyanoferrate(II) complex Na4[FeII(CN)5(PyzCONHO-)] was synthesized and characterized by several spectroscopic techniques, cyclic voltammetry, and DFT calculations. Chemical oxidation of this complex with H2O2 was shown to induce the release of the metabolite PyzCOOH, without the need of the Mycobacterium tuberculosis (Mtb) pyrazinamidase enzyme (PncA). Control experiments show that both H2O2- and N-coordinated pyrazine FeII species are required, ruling out a direct hydrolysis of the hydroxamic acid or an alternative oxidative route through chelation of ametal center by a hydroxamic group. The release of HNO was observed using EPR spectroscopy in the presence of a spin trapping agent. The devised iron metal complex of pyrazine-2-hydroxamic acid wasfound inactive against an actively growing/non-resistant Mtb strain; however, itshowed a strong dose-dependent and reversible vasodilatory activity with mostly lesser toxic effects than the reference drug sodium nitroprussiate, unveiling thus a potential indication for acute or chronic cardiovascular pathology. This is a priori a further indirect evidence of HNO release from this metal complex, standing as a possible pharmacophore model for an alternative vasodilator drug.

An update on sarcoidosis-associated pulmonary hypertension.

Pulmonary hypertension in sarcoidosis is a well known entity. Sarcoidosis-associated pulmonary hypertension (SAPH) incurs substantial morbidity and mortality. This review examines recent literatures published on epidemiology, prognosis and therapeutic management in SAPH. Several registries have been published between 2017 and 2020. The consensus conclusion - SAPH is a harbinger for poor prognosis. Several factors were noted for predicting adverse outcome in SAPH like reduced 6-min walk distance and diffusing capacity for carbon monoxide. Given its adverse outcome, experts have now focused on methods for early screening of SAPH in sarcoid patients. The exploration of pulmonary vasodilator drugs in SAPH is ongoing. In recent times, trials have been published utilizing Macitentan and parenteral prostacyclin in severe SAPH. Although these trials show encouraging results, the evidence from these studies are limited to approve these agents as preferred drugs for treating SAPH. A large multicentric trial of drugs used for pulmonary arterial hypertension with meaningful, yet feasible, event driven endpoint is still lacking. Lately, interventional treatment by pulmonary artery balloon pulmonary angioplasty and stenting has gained traction for treating pulmonary artery stenosis and chronic thromboembolic pulmonary hypertension. However, the conclusion is still based on small cohorts or case series. Several registries have highlighted SAPH portends an unfavorable consequence. On the contrary, no published guideline exists to treat SAPH. The precise role of immunosuppressive agents is unclear. The limited evidence favoring use of pulmonary vasodilators arise from small retrospective case series and/or single-center nonrandomized observational studies. Further multicenter randomized research is warranted to better define patient population to treat and how best to treat them.

Oxidative/Nitrative Mechanism of Molsidomine Mitotoxicity Assayed by the Cytochrome c Reaction with SIN-1 in Models of Biological Membranes.

Molsidomine is currently used as a vasodilator drug for the treatment of myocardial ischemic syndrome and congestive heart failure, although still presenting some mitochondrial-targeted side effects in many human cells. As a model of molsidomine mitotoxicity, the reaction of cytochrome c with phosphatidylserine (PS)- and cardiolipin (CL)-containing liposomes was investigated in oxidative/nitrosative conditions imposed by SIN-1 decomposition, which renders peroxynitrite (ONOO-) as a main reactive product. In these conditions, the production of thiobarbituric acid-reactive substance (TBARs) and LOOH was affected by the lipid composition and the oxidative/nitrative conditions used. The oxidative/nitrative conditions were the exposure of lipids to SIN-1 decomposition, native cytochrome c after previous exposure to SIN-1, concomitantly to SIN-1 and native cytochrome c, native cytochrome c, and cytochrome c modified by SIN-1 that presents a less-rhombic heme iron (L-R cytc). TBARs and LOOH production by lipids and cytochrome c exposed concomitantly to SIN-1 differed from that obtained using L-R cytc and featured similar effects of SIN-1 alone. This result suggests that lipids rather than cytochrome c are the main targets for oxidation and nitration during SIN-1 decomposition. PS- and CL-containing liposomes challenged by SIN-1 were analyzed by Fourier transform infrared spectroscopy that revealed oxidation, trans-isomerization, and nitration. These products are consistent with reaction routes involving lipids and NOx formed via peroxynitrite or direct reaction of NO• with molecular oxygen that attacks LOOH and leads to the formation of substances that are not reactive with thiobarbituric acid.