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BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined brain frailty markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging brain frailty was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

Rodent migraine models have been developed to study the underlying molecular mechanisms of migraine, but these need further development and validation to stay relevant. The glyceryl trinitrate (GTN) mouse model with tactile hypersensitivity as the primary readout, has been highly used to understand the pathophysiology of migraine. Nevertheless, this readout has questionable translatability to the experience of spontaneous pain and additional readouts are needed to improve this model. We explored the applicability of several spontaneous behaviours and burrowing activity as additional markers to detect effects of repeated GTN injections in mice. We used the Laboratory Animal Behaviour Observation Registration and Analysis System (LABORAS) test system to understand the potential effect of GTN on locomotion and other behavioral parameters in two different experiments. Burrowing was used to investigate the potential effect on GTN on a voluntary innate behavior of mice. We found no clear effect of GTN on either locomotion or burrowing in these experiments. With our experimental design, there was no significant difference between GTN and vehicle and neither locomotion nor burrowing activity will readily supplement the von Frey test. The search for additional none-evoked markers of pain in rodent migraine models will continue. [ABSTRACT FROM AUTHOR]

Background: In addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors. Methods: In a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration. Results: Both doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP. Conclusions: The findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine is a severe and common neurological disorder, yet its precise physiological mechanisms remain unclear. The IGF1/IGF1r signaling pathway plays a crucial role in pain modulation. Studies have shown that IGF1, by binding to its receptor IGF1r, activates a series of downstream signaling cascades involved in neuronal survival, proliferation, autophagy and functional regulation. The activation of these pathways can influence nociceptive transmission. Furthermore, alterations in IGF1/IGF1r signaling are closely associated with the development of various chronic pain conditions. Therefore, understanding the specific mechanisms by which this pathway contributes to pain is of significant importance for the development of novel pain treatment strategies. In this study, we investigated the role of IGF1/IGF1r and its potential mechanisms in a mouse model of chronic migraine. Methods: Chronic migraine was induced in mice by repeated intraperitoneal injections of nitroglycerin. Mechanical and thermal hypersensitivity responses were assessed using Von Frey filaments and radiant heat, respectively. To determine the role of IGF1/IGF1r in chronic migraine (CM), we examined the effects of the IGF1 receptor antagonist ppp (Picropodophyllin) on pain behaviors and the expression of calcitonin gene-related peptide (CGRP) and c-Fos. Result: In the nitroglycerin-induced chronic migraine model in mice, neuronal secretion of IGF1 is elevated within the trigeminal nucleus caudalis (TNC). Increased phosphorylation of the IGF1 receptor occurs, predominantly co-localizing with neurons. Treatment with ppp alleviated basal mechanical hypersensitivity and acute mechanical allodynia. Furthermore, ppp ameliorated autophagic dysfunction and reduced the expression of CGRP and c-Fos. Conclusion: Our findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine. [ABSTRACT FROM AUTHOR]

BACKGROUND: While 0.2% topical Glyceryl Trinitrate has been extensively studied for managing chronic anal fissures, less attention has been paid to its specific application methodology, dosage, and patient compliance, potentially contributing to higher recurrence rates and lower cure rates. This study addresses these gaps by comparing the healing outcomes of chronic anal fissures treated with 0.2% Glyceryl Trinitrate (chemical sphincterotomy) versus surgical lateral internal sphincterotomy (surgical sphincterotomy) as its primary objective. Secondary objectives include assessing pain relief, reduction in rectal bleeding, risk of incontinence, and recurrence rates associated with both treatment methods. AIM AND OBJECTIVE: 1. To determine the age and gender distribution of anal fissure incidence. 2. To examine the various clinical presentations and types of anal fissures. 3. To assess the efficacy of 0.2% topical Glyceryl trinitrate in relieving symptoms and promoting healing of anal fissures. 4. To compare the effectiveness of lateral anal sphincterotomy versus chemical sphincterotomy in treating anal fissures. 5. To evaluate the potential of Glyceryl trinitrate as a primary treatment option for both acute and chronic anal fissures. PATIENTS AND METHODS: The clinical trial was conducted at Maharaja Krushna chandra Gajapati Medical College and Hospital, Berhampur between June 2022 to June 2024. Patients presented with severe cutting pain during defecation and bleeding per anum lasting over six weeks. Clinical examination included gentle separation of the buttocks to examine the anus for a linear ulcer in the anoderm, with or without a sentinel pile, after taking proper consent. INCLUSION CRITERIA Consenting patients aged 18 to 65 years with symptomatic chronic fissure in ano were included. Extreme age groups were excluded to avoid age-related bias. EXCLUSION CRITERIA a. Pregnant or lactating; b. Inflammatory bowel disease, tuberculosis, malignancy, or sexually transmitted diseases; c. Undergone prior anal surgery or were refractory to 0.2% topical glyceryl trinitrate; d. Associated haemorrhoids or fistula; e. Significant cardiovascular diseases; f. Opted for specific treatments (chemical/surgical). A total of 185 patients diagnosed with chronic anal fissure and attending the Surgical Out Patient Department were enrolled in the study. Patients were assigned to Group A or Group B based on an alternating pattern of odd and even patient numbers. - Group A (Chemical Sphincterotomy): Patients numbered 1, 3, 5, ..., 185 received treatment with 0.2% Topical Glyceryl Trinitrate. - Group B (Surgical Sphincterotomy): Patients numbered 2, 4, 6, ..., 184 underwent open lateral internal sphincterotomy under spinal or general anaesthesia as inpatients. The two groups were compared on various parameter like-Fissure Healing Rate, Recovery of Pain, Recovery of Bleeding per rectum, Recovery time, Risk of Anal Incontinence, Morbid aspects of the treatment, Recurrence rate, Work resume time, Conversion rate and conclusion were drawn. RESULTS: Surgical Sphincterotomy demonstrated statistically significant better healing compared to Chemical Sphincterotomy. Group A had an average pain score of 2.24, whereas Group B had a score of 0.55, indicating complete symptom resolution in Group B. Both groups showed early recovery by the 2nd week, with final recovery rates of 87.78% in Group A and 98.92% in Group B by the 10th week. Group A resumed work on average in 3.37 weeks, while Group B resumed in 3.19 weeks, showing no statistically significant difference. The average recovery time for fissure healing was 5.18 weeks in Group A and 4.84 weeks in Group B, indicating quicker recovery with Surgical Sphincterotomy. Group B had a higher incidence of fecal incontinence (29.03%) compared to Group A (2.22%, temporary). There was no recurrence in Group B, establishing it as the gold standard treatment. Group A had a recurrence rate of 6.67% and a conversion rate of 16.67%, indicating higher failure rates and the need to switch to surgical treatment. CONCLUSION: Surgical Sphincterotomy (Group B) showed superior recovery and treatment response compared to Chemical Sphincterotomy (Group A), despite a higher incidence of fecal incontinence. However, Chemical Sphincterotomy also demonstrated good recovery with less morbidity. [ABSTRACT FROM AUTHOR]

Nitroglycerin has been of considerable interest as a treatment for ischaemic stroke. Recent clinical trials with nitroglycerin transdermal patches during the acute phase of stroke failed to improve functional outcomes. Systematic review and meta-analysis of the effectiveness of nitroglycerin in preclinical models of ischaemic stroke has not previously been reported, despite several clinical trials. To conduct a systematic review and meta-analysis of preclinical evidence regarding the effect of nitroglycerin on infarct volume in animal models of ischaemic stroke. The protocol was registered in PROSPERO (CRD42023432644). Our search identified 238 publications. Three publications met inclusion criteria (including 10 comparisons of infarct size). Study quality was modest (median 6 out of 9), with no evidence of publication bias. Nitroglycerin did not significantly reduce infarct volume (NMD point estimate 20.2 % reduction, 95 % CI −1.52–52.7 %, p = 0.068). Subgroup analysis suggested greater efficacy of nitroglycerin with direct intracarotid administration to the ischaemic territory at the time of reperfusion. A small number of studies (three) were included in this review. Overall, nitroglycerin did not reduce infarct volume in experimental stroke models. However, nitroglycerin may be of benefit when administered directly into the ischaemic territory. Given nitroglycerin's short half-life, we propose this route may minimise harmful reduction of cerebral perfusion pressure resulting from hypotension following systemic administration. • Three publications met pre-specified inclusion criteria, with no evidence of publication bias. • Nitrolgycerin did not improve stroke outcome. • The route of nitroglycerin administration accounted for a significant amount of variability between studies. • Intra-arterial administration of nitroglycerin at the time of reperfusion improves stroke outcome independent of changes in cerebral blood flow. • Nitroglycerin may be of benefit when administered directly into the ischaemic territory. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine is closely related to the dysregulation of neurochemical substances in the brain, with metabolic imbalance being one of the proposed causes of chronic migraine. This study aims to evaluate the metabolic changes between energy metabolism and excitatory and inhibitory neurotransmitters in key brain regions of mice with chronic migraine-like state and to uncover the dysfunctional pathways of migraine. Methods: A chronic migraine-like state mouse model was established by repeated administration of nitroglycerin (NTG). We used von Frey filaments to assess the mechanical thresholds of the hind paw and periorbital in wild-type and familial hemiplegic migraine type 2 mice. After the experiments, tissue was collected from five brain regions: the somatosensory cortex (SSP), hippocampus, thalamus (TH), hypothalamus, and the spinal trigeminal nucleus caudalis (TNC). Proton magnetic resonance spectroscopy (1H-MRS) was employed to study the changes in brain metabolites associated with migraine, aiming to explore the mechanisms underlying metabolic imbalance in chronic migraine-like state. Results: In NTG-induced chronic migraine-like state model, we observed a significant reduction in energy metabolism during central sensitization, an increase in excitatory neurotransmitters such as glutamate, and a tendency for inhibitory neurotransmitters like GABA to decrease. The TNC and thalamus were the most affected regions. Furthermore, the consistency of N-acetylaspartate levels highlighted the importance of the TNC-TH-SSP pathway in the ascending nociceptive transmission of migraine. Conclusion: Abnormal energy metabolism and neurotransmitter imbalance in the brain region of NTG-induced chronic migraine-like state model are crucial mechanisms contributing to the chronicity of migraine. [ABSTRACT FROM AUTHOR]

Background: Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon. Methods: Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312). Results: Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase. Conclusions: Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved. [ABSTRACT FROM AUTHOR]

Cardiac CT, or coronary CT, is a medical imaging technique that involves injecting iodine contrast agents into blood vessels to visualize the heart's coronary arteries. Cardiovascular specialists utilize these images to diagnose coronary artery blockages and assess blood flow velocity. Prior to the examination, patients are required to maintain a stable heart rate, typically not exceeding 60 beats per minute. Medications such as β-receptor blockers and nitroglycerin may be administered to reduce heart rate if necessary. This technology offers rapid imaging, minimal side effects, and low rates of false negatives and false positives. [ABSTRACT FROM AUTHOR]

Systemic vasodilating agents like nitroglycerin (NG) or iloprost (Ilo) show beneficial effects on intestinal microcirculation during sepsis, which could be attenuated by activation of the sympathetic nervous system or systemic side effects of vasodilating agents. This exploratory study aimed to investigate the effects of topically administered vasodilators and the parasympathetic drug carbachol on colonic microcirculatory oxygenation (µHbO2), blood flow (µFlow) and mitochondrial respiration. A total of 120 male Wistar rats were randomly assigned to twelve groups and underwent either colon ascendens stent peritonitis (CASP) or sham surgery. After 24 h, animals received the following therapeutic regimes: (1) balanced full electrolyte solution, (2) carbachol, (3) NG, (4) Ilo, (5) NG + carbachol, and (6) Ilo + carbachol. Mitochondrial respiration was measured in colon homogenates by respirometry. In sham animals, NG (−13.1%*) and Ilo (−10.5%*) led to a decrease in µHbO2. Additional application of carbachol abolished this effect (NG + carbachol: −4.0%, non-significant; Ilo + carbachol: −1.4%, non-significant). In sepsis, carbachol reduced µHbO2 when applied alone (−10.5%*) or in combination with NG (−17.6%*). Thus, the direction and degree of this effect depend on the initial pathophysiologic condition. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. Background: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. Methods: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. Results: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin‐ versus vehicle‐treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. Conclusions: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine‐associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed. Plain Language Summary: The aim of this study was to determine if supportive immune cells in the brains of males and females are altered in an animal model of chronic migraine. Mice in the chronic migraine group showed significant activation of astrocytes, but not microglia, in male and female mice in pain and emotion‐processing brain regions. These results suggest that some supportive cells in the brain may play a role in regulating chronic migraine. [ABSTRACT FROM AUTHOR]

The article discusses the background and clinical implications of coronary computed (CT) tomography angiography (CCTA) and CT-based fractional flow reserve (CT-FFR). Topics covered include the practice of CCTA and CT-FFR, samples of CCTA and CT-FFR protocols and case studies involving CCTA and CT-FFR. It also cited the clinical relevance of CCTA and CT-FFR and the clinical effect of the PLATFORM trial on CT-FFR.

BACKGROUND: Nocturnal hemodialysis (nHD) restores the attenuated brachial artery vasodilator responsiveness of patients receiving conventional intermittent hemodialysis (iHD). Its impact on coronary vasodilatation is unknown. METHODS: We evaluated 25 patients on hemodialysis who fulfilled transplant criteria: 15 on iHD (4-hour sessions, 3 d/wk) and 10 on nHD (≈40 h/wk over 8-10-hour sessions) plus 6 control participants. Following diagnostic angiography, left anterior descending (LAD) coronary flow reserve and mean luminal diameter were quantified at baseline and during sequential intracoronary administration of adenosine (infusion and bolus), nitroglycerin (bolus), acetylcholine (infusion), acetylcholine coinfused with vitamin C, and, finally, sublingual nitroglycerin. RESULTS: Coronary flow reserve in those receiving nHD was augmented relative to iHD (3.28±0.26 versus 2.17±0.12 [mean±SEM]; P<0.03) but attenuated, relative to controls (4.80±0.63; P=0.011). Luminal dilatations induced by intracoronary adenosine and nitroglycerin were similar in nHD and controls but blunted in the iHD cohort (P<0.05 versus both). ACh elicited vasodilatation in controls but constriction in both dialysis groups (both P<0.05, versus control); vitamin C coinfusion had no effect. Sublingual nitroglycerin increased mid-left anterior descending diameter and reduced mean arterial pressure in controls (+15.2±2.68%; -16.00±1.60%) and in nHD recipients (+14.78±5.46%; -15.82±1.32%); iHD responses were markedly attenuated (+1.9±0.86%; -5.89±1.41%; P<0.05, all comparisons). CONCLUSIONS: Coronary and systemic vasodilator responsiveness to both adenosine and nitroglycerin is augmented in patients receiving nHD relative to those receiving iHD, whereas vasoconstrictor responsiveness to acetylcholine does not differ. By improving coronary conduit and microvascular function, nHD may reduce the cardiovascular risk of patients on dialysis. [ABSTRACT FROM AUTHOR]

An interview with Cardiologist Dr. Siddharth Dagli is presented. Topics include risk factors for cardiovascular disease, preventive care and lifestyle modifications, and the importance of regular health check-ups and screenings for early detection. Dr. Dagli emphasizes that managing these risk factors through lifestyle changes can significantly reduce the likelihood of developing heart disease.

Ambulance services are increasingly research active and the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is the largest United Kingdom (UK) ambulance-based randomized controlled trial in stroke. We explore the complexities and challenges encountered during RIGHT-2. Five hundred and sixteen of 1487 paramedics from eight UK ambulance services serving 54 comprehensive or primary stroke care centers screened and consented 1149 patients presenting within 4 h of FAST-positive stroke and with systolic blood pressure >120 mmHg; participants were randomized to treatment with transdermal glyceryl trinitrate versus sham patch in the ambulance. Working with multiple ambulance services demanded flexibility in the trial protocol to overcome variation in operating procedures to ensure deliverability. Many paramedics are novice researchers, and research concepts and practices are emerging including consent strategies in emergency stroke care. Regional variation in hospital participation and hours/days of operation presented paramedics with additional considerations prior to patient recruitment. The working hours of hospital research staff often do not reflect the 24/7 nature of ambulance work, which challenged deliverability until trial processes became fully embedded. Management of investigational medicinal product between ambulance stations, in-transit when on ambulance vehicles and on handover at hospital, necessitated an in-depth review to maintain accountability. RIGHT-2 demonstrated that although there are significant practical challenges to conducting multicenter ambulance-based research in a time-dependent environment, careful planning and management facilitated delivery. Lessons learned here will help inform the design and conduct of future ambulance-based trials. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of adding rocuronium and nitroglycerin to ropivacaine in intravenous regional anesthesia (IVRA) on pain and hemodynamic parameters. Methods: This randomized controlled trial was done in 2023. Participants were 177 candidates for forearm operation surgery under IVRA selected from Valiasr Hospital, Arak, Iran. They were allocated by block randomization to three different groups, namely nitroglycerin group, rocuronium group and control group. Hemodynamic parameters were recorded before tourniquet application up to postoperative recovery time. Sensory block and motor block onset and duration and pain were also evaluated. The data analysis was carried out by IMB SPSS software 20.0. Results: 177 Eligible patients were included in study, with 59 in each group. Time to sensory and motor block onset in the nitroglycerin group was significantly less than the other groups and the time of motor block in the rocuronium group was statistically higher than the control and the nitroglycerin groups (P

Background and purpose: Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre‐specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT‐2) was assessed. Methods: RIGHT‐2 was a pre‐hospital‐initiated multicentre randomized sham‐controlled blinded‐endpoint trial that randomized patients with presumed ultra‐acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2). Results: In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre‐morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70–3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09–13.59). Conclusions: Pre‐hospital ultra‐acute transdermal GTN did not improve overall functional outcome in patients with investigator‐diagnosed TIA compared with sham treatment. [ABSTRACT FROM AUTHOR]

The discovery of nitric oxide's role in biological processes like platelet function, vasodilation, cell permeability, and inflammation has advanced our understanding of organic nitrate therapy's hemodynamic and nonhemodynamic effects. Short-term use of organic nitrates prevents left ventricular enlargement and infarct expansion. However, information on their long-term impact on LV remodeling in post-acute cardiac dysfunction patients is limited. In this study, we utilized an innovative active hydrogel with gelatin (Gel)/polyethylene glycol (PEG)/polylactic acid (PLA) encapsulating gold nanoparticles (AuNPs)-based drug delivery system for the sustained release of nitroglycerin (NTG). Gel/PEG/PLA/NTG/AuNPs hydrogel-based system is a non-transplant surgical method that can adhere to the surface of the heart and deliver the drug directly to the epicardium. Cardiac dysfunction was induced by ligating the left anterior descending coronary artery. Echocardiograms were used to study the pre- and post-operative hemodynamics. Hematoxylin and eosin (H&E) and Masson's trichrome stain (MTS) staining revealed that the acute myocardial infarction (AMI) rats' group had irregularly shaped fibers and a lack of transverse striations, whereas Gel/PEG/PLA/NTG/AuNPs hydrogel group showed significant improvement. Rats in the Gel/PEG/PLA hydrogel group demonstrated marked vasodilation, compared to the AMI group. Mechanistically, we determined that hydrogel disrupts the initiation of post-cardiac dysfunction via inhibiting Wnt/β-catenin transcriptional activation. Hence, the Gel/PEG/PLA/NTG/AuNPs hydrogel group effectively protected against ischemic injury and inflammation in AMI, demonstrating a novel method for treating acute cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Canines are widely used for real-time detection of explosives and have proven to be on par with instrumental methods. Canines are thought to rely largely upon detection of volatile chemical constituents of the explosives, though not necessarily the explosive itself. Hence, it is crucial to understand the odor available to them as generated by training aids. Previous studies have established that the Training Aid Delivery Device (TADD) developed by SciK9 is a reliable training aid that reduces cross-contamination and doubles as a storage device. A TADD comprises a standardized container, a synthetic membrane, a membrane holder, and a lid. In the work presented, activated charcoal strips were placed above and below the TADD membrane to determine the relative amounts of volatiles emitted by dynamite (i.e., ethylene glycol dinitrate (EGDN) and trinitroglycerin (NG)). The strips were eluted and the extracts tested using gas chromatography–mass spectrometry in negative ion chemical ionization mode. A series of t-tests at 95% confidence level were performed to determine any differences in vapor composition above and below the membranes. Nine synthetic membranes and six glass fiber membranes were tested in this study. It was expected that the relative concentration of volatiles would remain the same on both sides of the membrane; however, selective removal of nitroglycerin by some membranes was observed. Synthetic membranes with larger pore sizes showed no alteration in the vapor composition. Both synthetic and glass fiber membranes did not show a significant change in relative concentration of the other volatile compound in dynamite, i.e., EGDN. Out of all the membranes tested, three synthetic membranes and four glass fiber membranes showed selective alteration in odor availability of nitroglycerin in dynamite. For training purposes, membranes that do not alter the vapor composition should be used in the training aid. [ABSTRACT FROM AUTHOR]

Background: Conventional anesthesia used to reduce central venous pressure (CVP) during hepatectomy includes fluid restriction and vasodilator drugs, which can lead to a reduction in blood perfusion in vital organs and may counteract the benefits of low blood loss. In this study, we hypothesized that milrinone is feasible and effective in controlling low CVP (LCVP) during laparoscopic hepatectomy (LH). Compared with conventional anesthesia such as nitroglycerin, milrinone is beneficial in terms of intraoperative blood loss, surgical environment, hemodynamic stability, and patients' recovery. Methods: In total, 68 patients undergoing LH under LCVP were randomly divided into the milrinone group (n = 34) and the nitroglycerin group (n = 34). Milrinone was infused with a loading dose of 10 µg/kg followed by a maintenance dose of 0.2–0.5 µg/kg/min and nitroglycerin was administered at a rate of 0.2–0.5 µg/kg/min until the liver lesions were removed. The characteristics of patients, surgery, intraoperative vital signs, blood loss, the condition of the surgical field, the dosage of norepinephrine, perioperative laboratory data, and postoperative complications were compared between groups. Blood loss during LH was considered the primary outcome. Results: Blood loss during hepatectomy and total blood loss were significantly lower in the milrinone group compared with those in the nitroglycerin group (P < 0.05). Both the nitroglycerin group and milrinone group exerted similar CVP (P > 0.05). Nevertheless, the milrinone group had better surgical field grading during liver resection (P < 0.05) and also exhibited higher cardiac index and cardiac output during the surgery (P < 0.05). Significant differences were also found in terms of fluids administered during hepatectomy, urine volume during hepatectomy, total urine volume, and norepinephrine dosage used in the surgery between the two groups. The two groups showed a similar incidence of postoperative complications (P > 0.05). Conclusion: Our findings indicate that the intraoperative infusion of milrinone can help in maintaining an LCVP and hemodynamic stability during LH while reducing intraoperative blood loss and providing a better surgical field compared with nitroglycerin. Trial registration: ChiCTR2200056891,first registered on 22/02/2022. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical course and treatment of 3 dogs with peripheral vasopressor extravasation. Case Series Summary: Although vasopressor extravasation (VE) is a well‐documented complication in human medicine, literature describing VE and its management in veterinary patients is sparse. VE increases patient morbidity by causing local tissue injury and necrosis. The gold standard treatment for VE, phentolamine, has been periodically limited in supply in human medicine and is not consistently available for use in veterinary medicine. An alternative protocol proposed for use in people with VE combines topical nitroglycerin application with subcutaneous terbutaline infiltration. In this report, a treatment protocol utilizing these therapies was used to treat 3 dogs with VE and secondary tissue injury. New or Unique Information Provided: This report describes 3 cases of VE‐induced tissue injury in dogs. In addition, this report describes the use of perivascular terbutaline infiltration and topical nitroglycerin application as therapeutic management for VE in dogs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Hemorrhoids are defined as swollen veins in the anus and lower rectum. Hemorrhoids are a common medical problem and have a negative impact on people’s lives. The drugs that are available on the market are limited, and therefore, the objective of the present research is to develop and evaluate a lidocaine and nitroglycerin ointment combination for enhanced external hemorrhoid treatment. Materials and Methods: Five formulations of 0.1% lidocaine and 0.1% nitroglycerin ointments (F1-F5) were developed using hydrocarbon bases (B1 and B2), hydrophilic petrolatum B3, hydrophilic B4, and emulsifying base B5. Different physicochemical parameters were conducted to evaluate the quality of the studied formulations. Results: Cracking was observed for F1 and F2 and phase transitions were noticed for F4 and F5. While, the hydrophilic petrolatum base formulation F3 showed the best physical stability up to one month with high uniformity with a drug content of 107.5% and a calibration curve R=0.9999. Docking study confirmed the activity of lidocaine and nitroglycerin towards hemorrhoids through conventional hydrogen bonds with target proteins 6s3a and 6t3w, respectively. F3 was tested by nine patients who suffered from external hemorrhoids for seven days. Patients reported a decrease in hemorrhoid grain sizes with excellent tolerability. Conclusion: The developed single formulation of two different drugs, lidocaine and nitroglycerin, has synergistic action and is well-tolerated treatment option for external hemorrhoids, as it not only decreases the hemorrhoid symptoms (pain and itchy) but also eliminates the side effects like headache that arise when the drugs are administered alone. [ABSTRACT FROM AUTHOR]

Background and Aims: Several methods have been used in plastic and reconstructive surgery to reduce post-surgical complications, such as partial or complete flap loss due to ischemia and necrosis. Nitroglycerine application has been introduced as a viable alternative to papaverine to act as a local vasodilator to improve perfusion and reduce vasospasm. However, the literature has not thoroughly studied its efficacy and administration dose. This systematic review and meta-analysis study has been designed to assess the efficacy of topical nitroglycerine applications in reducing post-surgical flap necrosis and complications. Methods and Materials: A systematic literature search was performed on PubMed, Scopus, and Web of Science from inception to January 2023 with relevant keywords and terms. Case reports, review articles, letters, articles in any language other than English, and animal studies were excluded. The Newcastle-Ottawa and Jadad scales were used to assess the quality of the included studies. The pooled effect sizes were calculated using the random effect model with the Mantel-Haenszel method. Results: Overall, 2031 studies were obtained, among which 454 articles were duplicated and removed. Of the remaining 1577 articles, based on the eligibility and exclusion criteria, 20 articles were retrieved for full-text review. Finally, eight articles were included in our study. Three thousand nine hundred six patients had undergone reconstructive microsurgery and received topical nitroglycerin for the prevention of possible complications. The pooled rate of flap complication was 15% (95% CI: 8% to 25%, I2 = 96%, p-value < 0.01), and the pooled odds ratio of flap complication was 0.35 (95% CI: 0.15 to 0.83, I2 = 91%, p-value = 0.02). The heterogeneity of the included studies was significantly high. The dose and regimen of application significantly differed between each study. Conclusion: Topical administration of nitroglycerin compounds post reconstructive microsurgery can reduce the risk of flap necrosis. However, the precise dosage, duration of application, and possible underlying factors affecting drug efficacy are yet to be discovered. [ABSTRACT FROM AUTHOR]

Introduction: The development of several experimental migraine provocation models has significantly contributed to an understanding of the signaling mechanisms of migraine. The early history of this development and a view to the future are presented as viewed by the inventor of the models. Methods: Extensive knowledge of the literature was supplemented by scrutiny of reference lists. Results: Early studies used methodologies that were not blinded. They suggested that histamine and nitroglycerin (Glyceryl trinitrate, GTN) could induce headache and perhaps migraine. The development of a double blind, placebo-controlled model, and the use of explicit diagnostic criteria for induced migraine was a major step forward. GTN, donor of nitric oxide (NO), induced headache in people with- and without migraine as well as delayed migraine attacks in those with migraine. Calcitonin gene-related peptide (CGRP) did the same, supporting the development of CGRP antagonists now widely used in patients. Likewise, pituitary adenylate cyclase activating peptide (PACAP) provoked headache and migraine. Recently a PACAP antibody has shown anti migraine activity in a phase 2 trial. Increase of second messengers activated by NO, CGRP and PACAP effectively induced migraine. The experimental models have also been used in other types of headaches and have been combined with imaging and biochemical studies. They have also been used for drug testing and in genetic studies. Conclusion: Conclusion. Human migraine provocation models have informed about signaling mechanisms of migraine leading to new drugs and drug targets. Future use of these models in imaging-, biochemistry- and genetic studies as well as in the further study of animal models is promising. [ABSTRACT FROM AUTHOR]

Introduction: Anal fissure, characterized by a painful ulcer in the anal canal, presents a significant medical challenge. While surgical approaches like lateral internal sphincterotomy (LIS) have been the gold standard for chronic anal fissures, they come with potential complications such as incontinence and abscess formation. In contrast, medical treatments, including topical glyceryl trinitrate and diltiazem, have emerged as alternatives, offering non-invasive options with potentially fewer complications. Method: In this retrospective study, we evaluated 136 patients treated for chronic anal fissures between June 2019 and December 2022 at Balikesir University Hospital, comparing surgical and medical interventions. The study encompassed demographic analysis, treatment modalities, complete recovery, recurrence rates, and side effects/complications. Statistical analyses, including logistic regression, were performed to assess the efficacy and risks associated with different treatments. Results: Our findings indicated a higher rate of complete recovery with surgical treatment (86.1%) compared to medical treatments (glyceryl trinitrate: 64.8%, diltiazem: 69.6%). However, no significant difference was observed in recurrence rates between treatment groups. Surgical intervention exhibited a higher incidence of complications such as incontinence and abscess formation, while medical treatments were associated with side effects like headache and gastrointestinal disturbances. Notably, diltiazem therapy showed outcomes comparable to other modalities, indicating its potential as an effective and safer alternative. Conclusion: Despite the favorable outcomes of surgical treatment, considerations of potential complications underscore the importance of tailored approaches. Prospective, randomized controlled trials with larger cohorts are warranted to further elucidate the efficacy and safety profiles of medical treatments in chronic anal fissures, facilitating informed decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to investigate the pharmacological activity and therapeutic mechanism of Mahuang Xixin Fuzi decoction (MXFD) on migraine. Methods: Migraine model rats induced by nitroglycerin were established, and then orally administered with MXFD for 7 days. Blood and urine samples were collected to identify differential metabolites with metabolomics. To integrate the findings from network pharmacology and metabolomics analysis, the metabolites and targets related to MXFD therapy for migraine were filtered. Key findings: MXFD was found to alleviate the symptoms of migraines in rats. After treatment with MXFD, nine metabolites were found to be regulated and returned to normal levels. MXFD acted directly on nine key targets including MAOB, MAOA, ADRB1, ADRB2, ADRB3, ADORA2A, ADORA2B, DRD5, and HTR4 and regulated two out of nine metabolites, namely deoxycholic acid and 5-methoxyindoleacetate. Conclusions: The study found that MXFD can alleviate migraines through multitarget and multicomponent interaction networks. Graphical Abstract [ABSTRACT FROM AUTHOR]

Central sensitization is an important pathophysiological mechanism underlying chronic migraine (CM). Previous studies have shown that microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to central sensitization. Toll-like receptor 2 (TLR2) is a receptor expressed on the membrane of microglia and participates in central sensitization in inflammatory and chronic pain; however, its role in CM is unclear. Therefore, this study investigated TLR2 involvement in CM in detail. Mice treated with recurrent nitroglycerin (NTG) were used as a CM model. Hyperalgesia was assessed using a 50% paw mechanical threshold and a 50% periorbital threshold on a Von Frey filament pain meter. Western blotting and immunofluorescence analyses were used to detect the expression of TLR2, microglia, c-fos and CGRP in TNC. The expression of inflammatory factors (IL-6, IL-1β、 IL-10、TNF-α and IFN-β1) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). A selective TLR2 antagonist (C29) was systematically administered to observe its effect on hyperalgesia, microglia activation and the expression of c-fos, CGRP and inflammatory factors. Recurrent administration of NTG resulted in acute and chronic hypersensitivity, accompanied by upregulation of TLR2 expression and microglial activation in TNC. C29 partially inhibited pain hypersensitivity. C29 suppressed microglial activation induced by NTG administration. Inhibition of TLR2 reduced the expression of c-fos and CGRP in TNC after NTG treatment. C29 inhibited the expression of inflammatory mediators in TNC. These data showed that microglial TLR2 plays a critical role in the pathogenesis of CM by regulating microglial activation in TNC. [ABSTRACT FROM AUTHOR]