Chemical Angioplasty with Nitroglycerin for Vasospasm after Subarachnoid Hemorrhage: Case Series and Review

Introduction Vasospasm is a common and potentially devastating complication in patients with subarachnoid hemorrhage, causing high morbidity and mortality. There is no effective and consistent way to prevent or treat cerebral vasospasm capable of altering the morbidity and mortality of this complication. Animal and human studies have attempted to show improvement in aneurysmal vasospasm. Some sought their prevention; others, the treatment of already installed vasospasm. Some achieved only angiographic improvement without clinical correlation, others achieved both, but with ephemeral duration or at the expense of very harmful associated effects. Endovascular techniques allow immediate and aggressive treatment of cerebral vasospasm and include methods such as mechanical and chemical angioplasty. These methods have risks and benefits. Objectives To analyze the results of chemical angioplasty using nitroglycerin (GTN). In addition, to perform a comprehensive review and analysis of aneurysmal vasospasm. Methods We describe our series of 77 patients treated for 8 years with angioplasty for vasospasm, either mechanical (with balloon), chemical (with GTN) or both. Results Eleven patients received only balloon; 37 received only GTN; 29 received both. Forty-four patients (70.1%) evolved with delayed cerebral ischemia and 19 died (mortality of 24.7%). Two deaths were causally related to the rupture of the vessel by the balloon. The only predictors of poor outcome were the need for external ventricular drainage in the first hours of admission, and isolated mechanical angioplasty. Conclusions Balloon angioplasty has excellent results, but it is restricted to proximal vessels and is not without complications. Chemical angioplasty using nitroglycerin has reasonable but short-lived results and further research is needed about it. It is restricted to vasospasm angioplasties only in hospitals, like ours, where better and more potent vasodilator agents are not available.

Effect of Ellagic Acid, Cilostazol and Their Combination on Amikacin Induced Nephrotoxicity in Rats

Amikacin(AK) has the largest spectrum of aminoglycosides. However, its use is limited due to nephrotoxicity and ototoxicity. Ellagic acid (EA) is a plant phenolic structure. it has antioxidant, anticarcinogenic and antimutagenic properities. Cilostazol (CTZ) is a PDE Ш inhibitor, it is a potent vasodilator and antiplatelet drug. This study aimed to determine if EA and cilostazol have a protective effect against nephrotoxicity caused AK. Forty nine rats were divided into seven equal groups: control normal; AK 400mg/kg; EA 10 mg/kg; CTZ 10mg/kg; AK 400mg/kg plus EA 10mg/kg; AK 400mg/kg plus CTZ 10mg/kg; AK 400mg/kg plus EA 10mg/kg and CTZ 10mg/kg. For seven days, Drugs were given orally one hour before intramuscular injection of AK. After twenty-four hours from the last dosage, samples of blood were obtained to determine blood urea nitrogen (BUN) and creatinine levels in serum, kidneys were extracted and longitudinally divided into two parts, part for measuring the following parameters: malondialdehyde (MDA), catalase (CAT), reduced glutathione (GSH), interleukin 6 (IL6), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNFα), nuclear factor kappa B (NFκB) and Bcl-2 associated x protein (Bax), the other part was placed in formaldehyde solution and examined under light microscopy for routine histopathologic examination. The results of the present study proved that EA, CTZ and their combination protected rats against AK - induced nephrotoxicity; This effect might be a result of the antioxidant, anti-inflammatory and anti-apoptotic properties of these compounds.

Reduced levels of prostaglandin I2 synthase: a distinctive feature of the cancer-free trichothiodystrophy

The cancer-free photosensitive trichothiodystrophy (PS-TTD) and the cancer-prone xeroderma pigmentosum (XP) are rare monogenic disorders that can arise from mutations in the same genes, namely ERCC2/XPD or ERCC3/XPB. Both XPD and XPB proteins belong to the 10-subunit complex transcription factor IIH (TFIIH) that plays a key role in transcription and nucleotide excision repair, the DNA repair pathway devoted to the removal of ultraviolet-induced DNA lesions. Compelling evidence suggests that mutations affecting the DNA repair activity of TFIIH are responsible for the pathological features of XP, whereas those also impairing transcription give rise to TTD. By adopting a relatives-based whole transcriptome sequencing approach followed by specific gene expression profiling in primary fibroblasts from a large cohort of TTD or XP cases with mutations in ERCC2/XPD gene, we identify the expression alterations specific for TTD primary dermal fibroblasts. While most of these transcription deregulations do not impact on the protein level, very low amounts of prostaglandin I2 synthase (PTGIS) are found in TTD cells. PTGIS catalyzes the last step of prostaglandin I2 synthesis, a potent vasodilator and inhibitor of platelet aggregation. Its reduction characterizes all TTD cases so far investigated, both the PS-TTD with mutations in TFIIH coding genes as well as the nonphotosensitive (NPS)-TTD. A severe impairment of TFIIH and RNA polymerase II recruitment on the PTGIS promoter is found in TTD but not in XP cells. Thus, PTGIS represents a biomarker that combines all PS- and NPS-TTD cases and distinguishes them from XP.

Effect of Adrenomedullin on Migraine-like Attacks in Patients With Migraine: A Randomized Crossover Study

ObjectiveTo determine whether the intravenous infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients.MethodsTwenty migraine without aura patients participated in a placebo-controlled and double-blinded clinical study. In a randomized and crossover design the patients received an intravenous infusion of human adrenomedullin (19.9 picomole/kg/min) or placebo (saline) administrated via an automated intravenous pump (20 minutes). The patients participated in two study days with washout period of minimum of seven days. The primary outcome of the study was predefined as a difference in migraine incidence (0–12 h) and the secondary outcome were the headache intensity score’s area under curve (AUC0-12 h) and the (AUC 0-90 min) for MAP, flushing and HR.ResultsEleven migraine without aura patients (55%) fulfilled migraine attacks criteria after adrenomedullin infusion in comparison to only three patients reported attack (15%) after placebo (P= 0.039). We found that patients reported in a period of (0-12 hours) stronger headache intensity after adrenomedullin in comparison to placebo infusion (P= 0.035). AUC0-90 min for HR and, flushing (P < 0.05) were significant and MAP (P = 0.502) remain unchanged. Common adverse events reported were facial flushing, heat sensation and palpitation (P <0.001)ConclusionOur data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin and/or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount for the possibility that adrenomedullin may be acting through the canonical CGRP receptor.

Anti-migraine agents from an immunological point of view

The new wave of anti-migraine agents is nothing less than a milestone in our battle to manage this devastating disease. However, concerns have recently increased regarding the safety of these drugs. CGRP, while known as a potent vasodilator, is also a key neural and immune modulator. The roles of CGRP in immune determination, have been studied in depth, with particular focus on its functional significance with respect to common immune challenges i.e., bacterial, viral, fungal and parasitic infections. This review discusses many potential areas of concern in regard to blocking CGRP function and its potential influence on immune milieus during infection, and the risk of adverse effects. Finally, this review recommends specific measures to be taken into consideration when administering anti-CGRP/CGRPR agents.

The Utilization of a Nitric Oxide Generating Serum for Improving Vascularity in Wound Healing

Introduction: Poor vascularity in injured or operated tissue predisposes the patient to poor healing. Many disease states such as diabetes mellitus, atherosclerosis, and Raynaud’s Disease exhibit delayed or compromised healing. Post-radiated tissue is another example of poor healing potential. Any surgical wound, local, regional, or free flap reconstruction, can see delayed healing or lack of healing with poor blood supply. Nitric oxide (NO) is an endothelial cell, endogenously produced, free radical gas. It is a potent vasodilator and inhibitor of platelet aggregation. A NO producing serum has recently been developed (Pneuma Nitric Oxide, Austin Texas). This is the first study to examine the potential efficacy of a NO generating serum in the wound healing population. Objective: The objective of this study is to examine the potential efficacy of a Nitric oxide generating serum in the wound healing patient population Method: Twenty-five patients were studied in two centers between December 2018 and June 2020. Prior to utilizing NO serum, a double-blind, placebo controlled (glycerin) safety study was performed on 10 patients. There were no allergic or irritation reactions to NO serum in this population. NO serum was applied to non-healing diabetic ulcers, vascular compromised non-healing wounds, surgical incisions, split thickness grafts, full thickness grafts, regional and free flaps. Patients were followed weekly and photographed regularly to monitor healing until total healing was reached. Results: Without exception, the study population showed a more rapid and improved quality of healing in the wounds that were treated with Nitric oxide generating serum as compared to control sites. Rapid reepithelialization, wound contraction, less bruising and edema were commonly seen. Neo-vascularization was more rapid in surgical flap cases. Burn wounds healed dramatically. Conclusion: This study shows the benefits of a Nitric oxide- generating serum in the wound healing patient population. The vasodilatory and capillary recruitment capabilities of Nitric oxide are hypothesized as key factors leading to this improved healing. NO is also paramount in the differentiation and proliferation of fibroblasts, keratinocytes, monocytes, and macrophages. Topically, NO has also been shown in the literature to have strong anti-bacterial, anti-fungal, and anti-viral roles. NO serum is a valuable addition to the armamentarium of wound healing protocols.

Fluorescent Analogues of Human α-Calcitonin Gene-Related Peptide with Potent Vasodilator Activity

Human α-calcitonin gene-related peptide (h-α-CGRP) is a highly potent vasodilator peptide that belongs to the family of calcitonin peptides. There are two forms of CGRP receptors in humans and rodents: α-CGRP receptor predominately found in the cardiovascular system and β-CGRP receptor predominating in the gastrointestinal tract. The CGRP receptors are primarily localized to C and Aδ sensory fibers, where they are involved in nociceptive transmission and migraine pathophysiology. These fibers are found both peripherally and centrally, with extensive perivascular location. The CGRP receptors belong to the class B G-protein-coupled receptors, and they are primarily associated to signaling via Gα proteins. The objectives of the present work were: (i) synthesis of three single-labelled fluorescent analogues of h-α-CGRP by 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis, and (ii) testing of their biological activity in isolated human, mouse, and rat arteries by using a small-vessel myograph setup. The three analogues were labelled with 5(6)-carboxyfluorescein via the spacer 6-aminohexanoic acid at the chain of Lys24 or Lys35. Circular dichroism (CD) experiments were performed to obtain information on the secondary structure of these fluorescently labelled peptides. The CD spectra indicated that the folding of all three analogues was similar to that of native α-CGRP. The three fluorescent analogues of α-CGRP were successfully prepared with a purity of >95%. In comparison to α-CGRP, the three analogues exhibited similar efficacy, but different potency in producing a vasodilator effect. The analogue labelled at the N-terminus proved to be the most readily synthesized, but it was found to possess the lowest vasodilator potency. The analogues labelled at Lys35 or Lys24 exhibited an acceptable reduction in potency (i.e., 3–5 times and 5–10 times less potent, respectively), and thus they have potential for use in further investigations of receptor internalization and neuronal reuptake.

Migraine and calcitonin gene-related peptide pathway antibodies: a treatment route in tertiary care

Inhibiting the calcitonin gene-related peptide (CGRP) pathway is a new treatment to prevent migraines. CGRP is a potent vasodilator and is a key neuropeptide which plays a crucial role in migraine pathophysiology. Following the European Medicines Agency's approval of three CGRP pathway monoclonal antibodies (mAbs), erenumab, fremanezumab and galcanezumab, the authors proceeded with early adoption in practice. Here they summarise and share their patient treatment pathway using erenumab, the first mAb to become clinically available.

Potent Vasodilator and Cellular Antioxidant Activity of Endemic Patagonian Calafate Berries (Berberis microphylla) with Nutraceutical Potential

Hydroalcoholic extracts of Patagonian Calafate berry (Berberis microphylla) contain mono or disaccharide conjugated anthocyanins and flavonols. The Liquid Chromatography-Mass Spectrometry (LC-MS) chemical extract profile identified glycosylated anthocyanidins such as delphinidin-, petunidin- and malvidin-3-glucoside as the major constituents. The predominant flavonols were 3-O substituents quercetin-rutinoside or -rhamnoside. Anthocyanins doubled flavonols in mass (13.1 vs. 6 mg/g extract). Polyphenols vascular actions were examined in the rat arterial mesenteric bed bioassay; extract perfusion elicited concentration-dependent vasodilatation mimicked by conjugated anthocyanins standards. Vascular responses of main glycosylated anthocyanins were endothelium-dependent (p < 0.001) and mediated by NO production (p < 0.05). The anthocyanins antioxidant activity determined in isolated endothelial cells (CAA) showed a reduced redox potential as compared to the extract or quercetin. While in the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay, the anthocyanins showed an equivalent quercetin potency, the extract was 15-fold less active, proposing that the anthocyanin-induced vasodilation is not due to an antioxidant mechanism. The extract shows promising commercial nutraceutical potential.

Affinity Isolation and Mass Spectrometry Identification of Prostacyclin Synthase (PTGIS) Subinteractome

Prostacyclin synthase (PTGIS; EC 5.3.99.4) catalyzes isomerization of prostaglandin H2 to prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. At present, limited data exist on functional coupling and possible ways of regulating PTGIS due to insufficient information about protein–protein interactions in which this crucial enzyme is involved. The aim of this study is to isolate protein partners for PTGIS from rat tissue lysates. Using CNBr-activated Sepharose 4B with covalently immobilized PTGIS as an affinity sorbent, we confidently identified 58 unique proteins by mass spectrometry (LC-MS/MS). The participation of these proteins in lysate complex formation was characterized by SEC lysate profiling. Several potential members of the PTGIS subinteractome have been validated by surface plasmon resonance (SPR) analysis. SPR revealed that PTGIS interacted with full-length cytochrome P450 2J2 and glutathione S-transferase (GST). In addition, PTGIS was shown to bind synthetic peptides corresponding to sequences of for GSTA1, GSTM1, aldo-keto reductase (AKR1A1), glutaredoxin 3 (GLRX3) and histidine triad nucleotide binding protein 2 (HINT2). Prostacyclin synthase could potentially be involved in functional interactions with identified novel protein partners participating in iron and heme metabolism, oxidative stress, xenobiotic and drugs metabolism, glutathione and prostaglandin metabolism. The possible biological role of the recognized interaction is discussed in the context of PTGIS functioning.