Nitroglycerin Patches Research Articles

English

OBJECTIVE: Comparison of oral nifedipine and transdermal nitroglycerin for tocolysis in preterm labour in the following effects, acute tocolytic effect, duration of prolongation of pregnancy, neonatal outcome. MATERIALS AND METHODS: Study on tocolysis in preterm labour was conducted in Government Rajaji Hospital from December 2010 to November 2011. 100 women with preterm labour randomly selected from the pregnant women attending antenatal OP and from labour ward from the department of obstetrics and gynecology. Out of which 50 women were recruited for oral nifedipine (initially 20mg, followed by 10mg till the contractions stop) and another 50 women were recruited for transdermal nitroglycerin patch (25 mg, directly applied over the skin of the abdomen). Inclusion criteria: Woman with singleton pregnancy with preterm labour from 28 – 36 weeks of gestation were selected for this study. Exclusion criteria: Pregnant women with preterm labour with premature rupture of membranes, fetal distress, major fetal congenital anomalies, chorioamnionitis antepartum hemorrhage, sensitivity or contra indication to nifedipine/nitrates, were excluded from this study. RESULTS: In both the groups time needed for tocolysis ranged from 2-12 hours. Mean time needed for tocolysis in group I was 4.55 hours and with group II, it was 6.09 hours. when acute tocolytic effect ( Prolongation of pregnancy beyond 48 hours) was considered, it was 45 women in group I and 36 women in group II. Mean duration of Prolongation of pregnancy with group I was 20.74 days and with group II, it was 13.5 days. In group I7 babies got admitted in new born ward, 16 babies in group II got admitted in new born ward. CONCLUSION: When compared with nitroglycerin, nifedipine is found to be safe and successful in achieving complete tocolysis and also effective in prolongation of pregnancy. Nifedipine has minimal maternal side effects and better neonatal outcome.

Effects of transdermal nitroglycerin and intravenous pancuronium added to lidocaine for intravenous regional anesthesia

Objective The aim of this study was to evaluate the effects of transdermal nitroglycerin patch, pancuronium, or a combination of both when added to low-dose lidocaine compared with standard-dose lidocaine alone in the intravenous regional anesthesia (IVRA) technique in adult healthy participants. Background Administration of neuromuscular blocking agents or nitroglycerin with local anesthetics in the upper limb during IVRA improves surgical conditions in adults. Patients and methods A total of 100 patients of both sexes aged 18 years or older undergoing elective forearm and hand surgeries were divided into four groups: group A received only lidocaine, group B received lidocaine + pancuronium, group C received lidocaine + nitroglycerin patch, and group D received lidocaine + pancuronium + nitroglycerin patch. Sensory and motor block onset and recovery times, Visual Analog Scale for Pain (VAS scores) for tourniquet pain, postoperative VAS score, and analgesic requirements were recorded. Results Sensory block onset times were shorter in groups D and C. Motor block onset times were shorter in groups D and B. Sensory block recovery time prolonged in group D. Motor block recovery time was prolonged in group D. There was a significant difference between the four groups in intraoperative pethidine requirements. The lowest dose of pethidine needed was in group D. Postoperative VAS scores showed significant differences between groups. Postoperative analgesic effect was the longest in group D. Conclusion A combination of 0.5 mg of pancuronium and 5 mg of transdermal nitroglycerin patch as adjuvant to 1.5 mg/kg lidocaine 0.25% improves the quality of IVRA without any side effects.

Comparison of Enhancement of Analgesic Effect of Intrathecal Neostigmine by Intrathecal Clonidine and Transdermal Nitroglycerin Patch on Bupivacaine Spinal Anesthesia.

Background:Relief of pain is very important goal intraoperatively and postoperatively. Neostigmine has been used successfully intrathecally with other agents such as clonidine and opioids for pain relief.Aims:This study aims to compare and evaluate the efficacy and safety of combining intrathecal (IT) neostigmine with IT clonidine and transdermal nitroglycerin (tNTG) patch for the relief of pain in patients after surgery.Settings and Design:This was a randomized, prospective, and comparative studyMaterials and Methods:In this study, recruited patients were randomly allocated into three groups. Groups I, II, and III received intrathecally 25 μg of neostigmine + 15 mg hyperbaric 0.5% bupivacaine, 25 μg of neostigmine + 25 μg clonidine + 15 mg hyperbaric 0.5% bupivacaine, and 25 μg of neostigmine + tNTG patch (3 cm × 5 cm, 5 mg/24 h) +15 mg hyperbaric 0.5% bupivacaine, respectively. Heart rate, mean arterial pressure, analgesic properties, and complications were assessed and compared among groups.Statistical Analysis:Mean and standard deviation were calculated. Test of analysis between two groups was done by t-test and among three groups by ANOVA, then P value was calculated.Results:Duration of analgesia was significantly longer in Group III in comparison to Group II (7.142 ± 1.81 vs. 4.408 ± 0.813 h) and was significantly longer in Group II in comparison to Group I (4.408 ± 0.813 vs. 2.583 ± 0.493 h). Analgesic requirement was significantly less in Group III in comparison to Group II (1.9 ± 0.76 vs. 2.5 ± 0.51) and was significantly less in Group II in comparison to Group I (2.5 ± 0.51 vs. 3.1 ± 0.48). Sedation score was found significantly high in Group II than other groups.Conclusion:Both IT clonidine and tNTG patch with bupivacaine + neostigmine spinal anesthesia were found effective in pain control. Results were found better with tNTG patch.

Effect of Transdermal Nitroglycerine on Doppler Velocity Waveforms of the Uterine, Umbilical and Fetal Middle Cerebral Arteries in Patients with Chronic Placental Insufficiency: A Prospective RCT.

Increase in Nitric Oxide (NO) may be important in vascular adaptation needed to accommodate increased uteroplacental blood flow as pregnancy advances. Hence, in certain conditions like Pregnancy Induced Hypertension (PIH) and Fetal Growth Restriction (FGR), NO donors may play an effective role in increasing uteroplacental perfusion. Transdermal route appears to be a safe and effective route. To evaluate the effect of nitroglycerine patch on Doppler velocity waveforms of the uterine, umbilical and fetal middle cerebral arteries in patients with chronic placental insufficiency. A prospective randomized controlled clinical trial was conducted on eighty consecutive pregnant women with FGR with or without PIH and having evidence of altered waveform velocimetry in uterine, umbilical and fetal middle cerebral artery. They were divided into two groups- study and control group. Transdermal nitroglycerine patch (10 mg per 24 hours) was applied in study group for three consecutive days. Changes in various Doppler indices were noted after three days of patch application and compared between the two groups. Analysis was carried out using SPSS (Statistical Package for Social Studies) for Windows version 20.0 and online GraphPad software (Prism 5 for Windows) version 5.01. A significant fall in the systolic and diastolic ratio (S/D), Pulsatility Index (PI) and Resistivity Index (RI) of the uterine (3.07±0.52, 1.04±0.14 and 0.54±0.10 respectively, p<0.001) and umbilical artery (3.73±3.30, 1.18±0.21and 0.64±0.07 respectively, p<0.001) was noted after three days of patch application. No such significant change was observed in the middle cerebral artery indices. The therapeutic approach of NO donor administration via transdermal route in pregnant patients with chronic placental insufficiency, apparently improved both maternal and fetoplacental haemodynamics, thus may help in improving perinatal outcome.

Evaluation of the effect of transdermal nitroglycerine patch on intrathecal dexmedetomidine as additive, on postoperative analgesia after abdominal hysterectomy

Aim: The aim of this study is to evaluate the effect of transdermal nitroglycerin on intrathecal dexmedetomidine as additive, on postoperative analgesia after abdominal hysterectomy. Materials and Methods : Totally 140 patients of the American Society of Anesthesiologists Grade I or II, posted for abdominal hysterectomy under spinal anesthesia, were randomized to four groups using computer-generated random number list. Group B received 3 ml of 0.5% hyperbaric bupivacaine with 0.5 ml normal saline and placebo patch, Group BN received 3 ml of 0.5% hyperbaric bupivacaine with 0.5 ml NS and transdermal nitroglycerin (t-NTG), Group BD received 3 ml of 0.5% hyperbaric bupivacaine with 5 mcg (0.5 ml) dexmedetomidine and placebo patch and Group BDN received 3 ml of 0.5% hyperbaric bupivacaine with 5 μg (0.5 ml) dexmedetomidine and t-NTG patch. Outcomes measured include the total duration of analgesia, onset, and duration of sensory and motor block and any adverse effects. Results: The total duration of analgesia was longest in Group BDN (349.9 ± 40.6 min). It was significantly longer than Group BD (252.3 ± 34.0 min) and Group B and BN (130.5 ± 18.8, 138.3 ± 19.2 min). Time taken for two segment regression was comparable in Group B (79.9 ± 14.4 min) and Group BN (87.1 ± 22.6 min), but it was significantly longer in Group BD (122.5 ± 17.2 min) and Group BDN (136.4 ± 25.5 min). There was no significant difference in other variables between the groups. Conclusion: Transdermal nitroglycerine itself does not exhibit any analgesic potential of its own but, it enhances the analgesic potential of intrathecal dexmedetomidine.

Randomized Clinical Trial of the Use of Glyceryl Trinitrate Patches to Aid Arteriovenous Fistula Maturation

Glycerol trinitrate (GTN) in external patches used for 24 hours after surgery does not improve arteriovenous fistula maturation.

Función cardiaca fetal en preeclámpticas tratadas con parches de nitroglicerina

ObjectiveTo identify modifications foetal cardiac function in pre-eclampsia patients treated with nitroglycerin patches. MethodThe sample consisted of 50 pre-eclampsia nulliparous patients with pregnancies of more than 25 weeks who attended the obstetric emergency service at Hospital Central Dr. Urquinaona, Maracaibo, Venezuela. Maternal haemodynamic changes and cardiac functions by M-mode, pulsed-wave, and tissue Doppler echocardiography were evaluated. Treatment consisted of 5mg transdermal nitroglycerin patches, applied in the anterior thoracic and lumbar region of patients for 12hours (total time of 48hours). After 24hours and 48hours of treatment beginning, maternal haemodynamic and foetal echocardiography variables were evaluated. All parameters were evaluated in each patient. ResultsMean age of patients was 24.4±3.9 years-old, and mean gestational age at beginning of research was 33.2±1.7 weeks. Treatment with nitroglycerin patches produced significant reduction in maternal blood pressure and a significant increase in maternal heart rate in both periods of evaluation (p<.0001). There were observed no changes in general foetal echocardiographic findings, echocardiographic findings in both ventricles and tissue Doppler values after 24hours and 48hours of treatment compared with values previous to treatment (p=ns). ConclusionThe use of transdermal nitroglycerin patches in pre-eclampsia patients did not produce significant changes in foetal cardiac function.

18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches

PurposeNitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival.MethodsA total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG.ResultsA 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159–0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively).ConclusionsThe decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.

Randomized clinical trial of the use of glyceryl trinitrate patches to aid arteriovenous fistula maturation.

Arteriovenous fistulas are critical for haemodialysis, but maturation rates remain poor. Experimental and anecdotal evidence has supported the use of transdermal glyceryl trinitrate (GTN) patches. The aim of this RCT was to determine whether use of a GTN patch aids arteriovenous fistula maturation. Patients referred for arteriovenous fistula formation were eligible. The GTN or placebo patch was applied immediately after surgery and left in situ for 24 h. The primary outcome measure was the change in venous diameter at 6 weeks after fistula formation. The secondary outcome measure was clinical fistula patency at 6 weeks. Of 200 patients recruited (533 screened), 101 were randomized to the placebo group and 99 to the GTN group. Of these, 81 and 86 respectively completed surgery, and had follow-up data available at 6 weeks. Improvements in venous diameter were similar in the two groups: mean(s.d.) increase 2·3(1·9) mm in the placebo group compared with 2·2(1·8) mm in the GTN group (P = 0·704). The fistula failure rate did not differ significantly between the two groups: 23 per cent for placebo and 28 per cent for GTN (P = 0·596). GTN transdermal patches used for 24 h after surgery did not improve arteriovenous fistula maturation. NCT01685710 (http://www.clinicaltrials.gov).

MP019: Systematic review of the management of lateral epicondylitis using transdermal nitroglycerin

Introduction: Lateral epicondylitis (LE), also known as tennis elbow, is an overuse-underuse tendinopathy originating from the forearm extensor tendons of the elbow. An emerging therapy for the treatment of LE is the use of transdermal nitroglycerin (NTG) patches for pain relief and improved function. Our systematic review assesses 18 to 65 year old patients with clinically diagnosed LE and no structural damage or longstanding elbow injury to determine if transdermal NTG patches provide improved short term and long term pain relief as well as improved function in comparison with placebo. Methods: We included randomised controlled trials (RCT’s) of NTG patch use versus placebo for the treatment of LE. Prospective comparison studies were also eligible for assessing the long term pain relief of NTG patch use. We performed a literature search using MEDLINE, EMBASE, SportDiscus and the Cochrane Database of Systematic Reviews. English language articles were retrieved for review up to November 2015. Risk of bias within the studies was assessed regarding randomisation, allocation sequence concealment, blinding and selective outcome reporting. Results: Three RCT’s were included that compared transdermal NTG patch use (two studies with 1.25mg/24h and one study comparing 0.72, 1.44 and 3.6mg/24h) versus a placebo to treat LE. One prospective comparison study of five years duration was included as a follow-up to one of the included RCT’s to assess pain and function five years after the discontinuation of therapy. Data was not pooled because of heterogeneity in study methods and outcomes. The use of transdermal NTG patches provided short term pain relief (2-6 weeks for dosing of 0.72mg/24h or 1.25mg/24h) compared with placebo as suggested by three RCT’s. Long term pain relief was improved by NTG patch use compared with placebo at six months in one RCT, but not at five years in a prospective comparison study. Function improved in two different RCT’s with NTG patch use at 0.72mg/24h and 1.25mg/24h when compared to placebo. Five years after cessation of treatment, there was no difference between NTG patch and placebo. Conclusion: Overall, the included studies demonstrate that the use of NTG patches compared to placebo improves short term and long term pain relief, as well as elbow function. However, more studies are required to bridge the gaps between the existing studies and reduce heterogeneity between the study designs.

Decreased Role for BKCa Channels in Endothelium‐Dependent Relaxation of Nitrate Tolerant Coronary Arteries

Prolonged exposure to nitroglycerin (NTG) leads to tolerance and impaired endothelium‐dependent vasodilation. Causes of endothelial dysfunction in nitrate tolerant arteries are well studied, but little is known about mechanisms that underlie the responses to endothelium‐derived mediators in nitrate tolerant blood vessels. Here we evaluated the role of large conductance, calcium‐activated K channels (BKCa) in acetylcholine (ACh)‐induced relaxation of isolated coronary arteries. Rats (Sprague‐Dawley, 250–300g) were treated with or without transdermal NTG patches (0.6 mg/hr) for 3 days. Isolated coronary arterial rings (diameter: 150–300 μm) were mounted in a multi‐wire myograph for isometric tension recording. Relaxation responses were determined in rings contracted with 5‐HT (0.1–1μM). In some experiments, arterial segments were incubated with the selective BKCa channel inhibitor, iberiotoxin (IBTx, 100 nM), for 20 min prior to contraction. Expression of BKCa channel proteins was determined by Western blot. Nitrate tolerance was confirmed by the impaired relaxation response to NTG (1 nM – 100 μM) observed in rings from rats treated with NTG patches (pD2= 7.28 ± 0.1 vs 6.45 ± 0.2, control vs NTG patch‐treated, respectively; p&lt;0.05). Relaxations to the endothelium‐dependent vasodilator, ACh (1 nM – 10 μM) were impaired in nitrate tolerant arteries (pD2 = 7.01 ± 0.1 vs 6.52 ± 0.1; control vs tolerant, respectively; n=8; p&lt;0.05). Incubation with the eNOS inhibitor, nitro‐l‐arginine (30 μM), or the guanylyl cyclase inhibitor, ODQ (10 μM), markedly inhibited the response to ACh in control and tolerant arteries, consistent with the release of endothelium‐derived NO in ACh‐induced relaxation of both control and tolerant arteries. Similarly, IBTx markedly reduced the response to ACh in control and tolerant arteries; however, IBTx was a more effective inhibitor of ACh‐induced relaxation in control arteries. Relaxations to 8‐Br‐cGMP (100 nM – 300 μM), a stable, cell‐permeable cGMP analog, were inhibited by IBTx in control arteries (pD2 = 5.37 ± 0.2 vs 4.21 ± 0.2; in the absence and presence of IBTx, respectively; n=4; p&lt;0.05), but not in tolerant arteries (pD2 = 4.45 ± 0.1 vs 4.03 ± 0.1; in the absence and presence of IBTx; n=3; p&gt;0.05). Protein expression of BKCa α‐subunits and β‐subunits was decreased by more than 40% in nitrate tolerant arteries (n=4–5; p&lt;0.05). Taken together, the data indicate that, under control conditions, BKCa channels play a pivotal role in endothelium‐dependent relaxation to ACh in rat coronary arteries. In nitrate tolerant coronary arteries, the response to ACh is impaired and the contribution of BKCa channels to ACh‐induced relaxation is diminished.Support or Funding InformationSupported in part by grant HL098896 from the National Institutes of Health

Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial.

To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Perimenopausal and postmenopausal women reporting at least seven hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hour nitroglycerin patch applied daily without patch-free periods. During 4 weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t tests examined change in outcomes between baseline and maximal-dose therapy and after discontinuation of nitroglycerin. Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hour, three to 0.4 mg/hour, two to 0.2 mg/hour, and one remained on 0.1 mg/hour nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P < 0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P = 0.041) and 96% increase in moderate-to-severe hot flashes (P < 0.001). Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel nonhormonal hot flash treatment.

Role of Transdermal Nitroglycerine Patch as Tocolytic in Preterm Labour

Role of Transdermal Nitroglycerine Patch as Tocolytic in Preterm Labour

The effect of transdermal nitroglycerin on pain control in diabetic patients with peripheral neuropathy.

BackgroundDespite high prevalence of diabetic peripheral neuropathy there is no definite treatment for the condition. The present study was conducted to assess the efficacy of transdermal nitroglycerin patch in pain control of patients with DPN.MethodsThis randomized, double-blind, crossover study was conducted on 30 patients with symmetric distal peripheral neuropathy and good glycemic control. The patients were randomly assigned to receive nitroglycerin transdermal and placebo patches in two 4-week stages. The severity of pain and other neuropathic sensory symptoms were assessed at the end of each course.ResultsMean reduction of pain severity was more prominent in the NTG group compared to placebo group of the study (p = 0.048) at least during the first phase of the study. Except for mood and sleep, a significant reduction in all Brief Pain Inventory scores was noted in the drug group (all corrected p < 0.05). SF-MPQ also showed the drug patch to be effective in improving different aspects of pain measured using McGill Pain Questionnaire, except for Role–emotional.ConclusionsIt could be concluded that nitroglycerin plasters can effectively help alleviate pain in patients with diabetic neuropathy.Trial registrationIRCT201308223213N1

A randomized phase II study comparing paclitaxel–carboplatin–bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)

BackgroundNitroglycerin (NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia-inducible-factor (HIF)-1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/cisplatin in patients with advanced nonsmall-cell lung cancer (NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF-1 inhibitors increases antitumor activity. Patients and methodsIn this randomized phase II trial, chemo-naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin (area under the curve 6)–paclitaxel (200mg/m2)–bevacizumab 15mg/kg on day 1 every 3 weeks with or without NTG patches 15mg (day -2 to +2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression-free survival (PFS). The study was powered (80%) to detect a decrease in the hazard of tumor progression of 33% at α = 0.05 with a two-sided log-rank test when 222 patients were enrolled and followed until 195 events were observed. ResultsBetween 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [95% confidence interval (CI)] PFS in control arm was 6.8 months (5.6–7.3) and 5.1 months (4.2–5.8) in experimental arm, hazard ratio (HR) 1.27 (95% CI 0.96–1.67). Overall survival (OS) was 11.6 months (8.8–13.6) in control arm and 9.4 months (7.8–11.3) in experimental arm, HR 1.02 (95% CI 0.71–1.46). In the experimental arm, no additional toxicity was observed except headache (6% versus 52% in patients treated with NTG). ConclusionAdding NTG to first-line carboplatin–paclitaxel–bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.

Glyceryl Trinitrate Patches: A Modern Treatment for Tendinopathies

C l i n M e d International Library Citation: Assem Y, Arora M (2015) Glyceryl Trinitrate Patches: A Modern Treatment for Tendinopathies. Int J Sports Exerc Med 1:018 Received: April 20, 2015: Accepted: August 20, 2015: Published: August 23, 2015 Copyright: © 2015 Assem Y. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Assem and Arora. Int J Sports Exerc Med 2015, 1:3

The use of nitroglycerin for treatment of progressive moyamoya disease: A prospective pilot study of safety and efficacy

No proven medical therapy exists for the treatment of moyamoya disease. Case reports have suggested that calcium channel blockers may be beneficial, potentially improving cerebral blood flow through a vasodilatory effect. The first objective of this pilot study was to prospectively evaluate whether intraarterial nitroglycerin, a potent vasodilator, could improve angiographic cerebral circulation in moyamoya patients. The second objective was to monitor the safety profile of transdermal nitroglycerin in our cohort of patients. Intraarterial nitroglycerin was infused in five patients with moyamoya disease at escalating doses. Angiography was performed before and after the nitroglycerin infusion. Pre- and post-infusion angiograms were compared for angiographic improvement. The contralateral side was used as an internal control in patients with unilateral moyamoya disease. The patients were then placed on a transdermal nitroglycerin patch and followed with serial neurological exams, blood pressure measurements, and either follow-up angiography or single photon emission computed tomography scans. All five patients had evidence of angiographic improvement after nitroglycerin infusion in the affected arteries, but no change was identified in the control arteries of patients with unilateral disease. No patient had adverse effects from either intraarterial or transdermal nitroglycerin. This small pilot study demonstrates angiographic improvement after intraarterial nitroglycerin in affected moyamoya arteries, but not in control arteries in the same patients, if present. There were no complications associated with transdermal nitroglycerin in these patients.

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Objective: Intolerance of antihypertensive medications is a major cause of non-adherence to pharmacotherapy leading to poor blood pressure control in the hypertensive population. We investigated the role of a central iliac arteriovenous (AV) anastomosis in a woman with uncontrolled hypertension due to multidrug intolerances. Design and method: A sixty-one year old Caucasian female with long-standing poorly-controlled hypertension was referred with multiple drug intolerances. She was unable to take Amlodipine, Nifedipine, Lercanidipine, Lisinopril, Candesartan, Bendroflumethiazide, Indapamide, Spironolactone, Amiloride, Doxazosin, Bisoprolol due to unacceptable side effects. After multiple pharmacotherapeutic attempts over a one year period, she could only tolerate Nebivolol 2.5 mg daily, liquid Nifedipine solution 16 mg twice daily and one quarter Glyceryl trinitrate (GTN) 5 mg transdermal patch daily. Despite this BP control remained suboptimal and she was offered treatment with the ROX coupler device having declined renal denervation for personal reasons. Results: At baseline the office BP (OBP) was 165/92 mmHg and 24 hour ambulatory BP (ABP) confirmed suboptimal control with an average daytime mean of 158/83 mmHg, nocturnal mean 126/65 mmHg. At 6 months after creation of a right-sided iliac AV anastomosis, OBP was reduced by 24/21 mmHg), and 24 hour ABP daytime average by 14/12 mmHg. At this point her BP was sufficiently well controlled to allow discontinuation of the nebivolol and GTN patch with no further change in BP at 1 year follow up. Baseline and 6 month echocardiograms both showed mild LVH with no change in ventricular wall thickness or ejection fraction. There was no significant change in renal function post-AV anastomosis. Right heart catheterisation at 6 months showed normal pressure in the right heart and pulmonary system. Conclusions: This is the first report of a patient with multiple drug intolerances and uncontrolled hypertension undergoing treatment with a central iliac AV anastomosis resulting in early and sustained OBP lowering to target levels and reduction in daytime mean ABP. This novel therapy appears to target mechanical properties of the circulation and may be of benefit in the management of patients with uncontrolled hypertension including those with multiple medication intolerances.

Phase I dose escalation trial of nitroglycerin in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of operable rectal cancer

Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients. This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients. Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%. NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h).

Increased Role for Large Conductance, Calcium‐Activated K Channels (BKCa) in Endothelium‐Dependent Relaxation of Nitrate Tolerant Mesenteric Arteries

Prolonged exposure to nitroglycerin (NTG) leads to tolerance and impaired endothelium‐dependent vasodilation. Causes of endothelial dysfunction in nitrate tolerant arteries are well studied, but little is known about mechanisms that underlie the responses to endothelium‐derived mediators in nitrate tolerant blood vessels. Here we evaluated the role of BKCa in acetylcholine (ACh)‐induced relaxation of isolated mesenteric arterial rings from rats treated with or without application of transdermal NTG patches (0.6 mg/hr) for 3 days. Nitrate tolerance was confirmed by the impaired relaxation response to NTG (1 nM – 100 μM) observed in rings from rats treated with NTG patches (pD2= 5.6 + 0.1 vs 4.9 + 0.1, Emax= 86 + 7 vs 53 + 5% relaxation; control vs treated, respectively). ACh‐induced (1 nM – 3 μM) relaxation was also impaired in tolerant rings (pD2= 7.1+ 0.1 vs 6.5 + 0.1; control vs tolerant, respectively) Incubation with nitro‐l‐arginine (30 μM) or indomethacin (10 μM) had no effect on the response to ACh in control or tolerant arteries, consistent with the release of a non‐NO, non‐prostanoid endothelium‐derived mediator in both control and tolerant arteries. ACh‐induced relaxation was unaffected by the selective BKCa‐blocker, iberiotoxin (IBT), in control rings, but was nearly abolished in tolerant rings (Emax = 78 ± 9 vs 8 + 8% relaxation; without vs with IBT, respectively). Protein expression of BKCa β‐subunits was increased by 50% in nitrate tolerant arteries, while BKCa α‐subunit expression was unchanged. The data provide evidence that nitrate tolerance unmasks a pivotal role for BKCa in the smooth muscle relaxation evoked by a non‐NO, non‐prostanoid endothelium‐derived mediator in mesenteric arteries.