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- Effects of rizatriptan on the expression of calcitonin gene-related peptide and cholecystokinin in the periaqueductal gray of a rat migraine model. [JOURNAL ARTICLE]
- Neurosci Lett 2014 Dec 15.
Triptans are serotonin 5-hydroxytryptamine receptor 1B/D agonists that are highly effective in the treatment of migraine. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system. Calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) are mainly responsible for antagonizing the analgesic effects of opioid peptides in the endogenous pain modulatory system. In this study, we investigated the effects of rizatriptan on the expression of CGRP and CCK in the periaqueductal gray (PAG), a key structure of the endogenous pain modulatory system, in a rat migraine model induced by nitroglycerin. We found that the mRNA and protein levels of CGRP and CCK in the PAG of migraine rats were significantly increased compared to those in control rats, and these levels were significantly reduced upon treatment with rizatriptan in migraine rats (P<0.05). Our results suggest that the expression of CGRP and CCK in the endogenous pain modulatory system may be increased during migraine attacks, which further antagonizes the analgesic effects of endogenous opioid peptides and induces sustained migraine. Rizatriptan, however, significantly reduces the levels of CGRP and CCK to enhance the inhibition of pain signals via the endogenous pain modulatory system, resulting in effective treatment of migraine.
- Innovative approach to preparing radial artery cocktails in response to manufacturer shortages of nitroglycerin and verapamil. [Journal Article]
- Hosp Pharm 2014 Jul; 49(7):628-33.
Transradial access has gained popularity over transfemoral access for cardiac catheterization, because of the decreased risk of bleeding, time to ambulation, and length of stay leading to improved patient satisfaction. One disadvantage of the radial artery approach is vasospasm, which can be prevented with the administration of verapamil and nitroglycerin in a pre- and postradial cocktail. Unfortunately, there have been manufacturer shortages for both of these medications.The utilization of radial artery cocktails and other nitroglycerin compounding practices were evaluated in response to cost containment and waste reduction initiatives and to medication shortages.A modified process for supplying verapamil and nitroglycerin for the transradial approach via separate syringes enabled physicians to have quick access to the medications and to customize the cocktail based on the patient's needs. This process also decreased costs and minimized wastage. The change in practice decreased waste from 44% for preradial cocktail syringes and 66% for postradial cocktail syringes to 8.7%.This process for supplying the medications necessary to perform a radial artery catheterization and intracoronary nitroglycerin has allowed for conservation of commercial product supply.
- [Investigation of adjuvant treatment for difficult weaning from mechanical ventilation]. [English Abstract, Journal Article]
- Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2014 Dec; 26(12):849-54.
To investigate the value of drug intervention for difficult weaning from mechanical ventilation.A prospective single-blind randomized controlled trial was conducted. 120 patients with difficult weaning from mechanical ventilation encountered in Department of Critical Care Medicine of Peking University Third Hospital from January 2008 to December 2013 were included, and the patients were divided into treatment group and control group according to random number table, with 60 cases in each group. Patients received furosemide therapy in the treatment group 3 days before weaning up to 48 hours after weaning in order to control negative liquid balance. Enema was given the day before weaning to reduce abdominal pressure. On the weaning day, all of the patients received nitroglycerin and beta blocker or cedilanid to prevent or control elevation of blood pressure and heart rate in the process of weaning. All patients in treatment group received anisodamine in small dosage 2 hours before extubation. The patients in control group received conventional treatment without drug intervention. Baseline indexes of two groups were compared, including the heart rate, respiration rate (RR), mean arterial pressure (MAP), pulse blood oxygen saturation (SpO2), blood gas, hemoglobin (HG), albumin (ALB) and creatinine (Cr). The main reasons of difficulty in weaning, sedative and analgesic drug selection, presence of abdominal discomfort before weaning, interval between sputum suction before extubation, liquid balance at the beginning of the investigation and at time of weaning, 24 hours and 48 hours after weaning, failures of spontaneous breathing test (SBT),length of mechanical ventilation,length of ICU stay, and total length of mechanical ventilation and total length of ICU stay during hospitalization.There was no statistically significant difference in the heart rate, RR, MAP, SpO2, blood gas, HG, ALB, Cr at the beginning of the investigation between the two groups. The main reasons for difficult weaning in both groups of patients were respiratory dysfunction, cardiac insufficiency, and central nervous system dysfunction. The use of propofol combined dexmedetomidine in the treatment group was more frequent than the control group [16.7%(10/60)vs. 1.7% (1/60),χ (2)=8.107, P=0.004], and there was no statistically significant difference in the use of other combinations of sedative drugs between the two groups. Abdominal discomfort before weaning was milder in treatment group as compared with control group [10.0%(6/60)vs. 25.0%(15/60), χ (2)=4.675, P=0.031]. The interval between sputum suction before extubation in the treatment group was significantly longer than that of the control group [hours: 1 (1, 2) vs. 1 (1, 1), Z=-2.209, P= 0.027]. SBT failure was less frequent in treatment group compared with control group [times: 0 (0, 1) vs. 1 (1, 2), Z=-6.561, P=0.000]. Liquid balance was better in the treatment group than the control group at time of weaning, 24 hours and 48 hours after weaning [at time of weaning: -567.71(-755.95,-226.41) vs. 1 256.76 (472.48, 1 796.63), Z=-9.038, P=0.000; 24 hours after weaning: -5.03(-530.28, 245.09)vs. 342.28 (125.36, 613.25), Z=-4.711, P=0.000; 48 hours after weaning: 115.50 (-450.26,485.00) vs. 330.00 (16.25,575.25), Z=-1.932, P=0.053]. Compared with control group, length of mechanical ventilation [days: 1.0 (1.0, 2.0) vs. 2.0 (2.0, 3.0), Z=-6.545, P=0.000], ICU stay time [days: 3.0 (3.0, 4.0) vs. 4.0 (4.0, 5.0), Z=-6.545, P=0.000], and total length of mechanical ventilation [days: 8.0 (6.0,12.0) vs. 11.0 (8.0, 15.0), Z=-4.091, P=0.000] and total length of ICU stay during hospitalization [days: 12.5 (9.2, 19.0) vs. 17.0 (12.0, 29.5), Z=-2.722, P=0.000] were all significantly shorter in the treatment group.Adjuvant drugs therapy is helpful in patients weaning from the mechanical ventilation, and can shorten length of mechanical ventilation and ICU stay time. Propofol, combined dexmedetomidine, is helpful for weaning.
- The origin of nausea in migraine-A PET study. [Journal Article]
- J Headache Pain 2014.:84.
Nausea is a common and disabling symptom of migraine. The origin of nausea is not well understood although functional connections between trigeminal neurons and the nucleus tractus solitarius may explain occurrence of nausea with pain. However, nausea occurs as a premonitory symptom in about a quarter of patients, suggesting that a primary brain alteration unrelated to the experience of pain may be the reason for nausea.We performed positron emission tomography scans with H215O PET in premonitory phase of nitroglycerin-induced migraine and compared patients with and without nausea.The results showed activation in rostral dorsal medulla and periaqueductal grey (PAG) in the nausea group, which was absent in the no nausea group. The rostral dorsal medullary area included the nucleus tractus solitarius, dorsal motor nucleus of the vagus nerve and the nucleus ambiguus, all of which are thought to be involved in brain circuits mediating nausea.The results demonstrate that nausea can occur as a premonitory symptom in migraine, independent of pain and trigeminal activation. This is associated with activation of brain structures known to be involved in nausea. We conclude that nausea is a centrally driven symptom in migraine.
- The efficacy of trimetazidine on stable angina pectoris: A meta-analysis of randomized clinical trials. [REVIEW]
- Int J Cardiol 2014 Oct 24; 177(3):780-785.
This meta-analysis aimed to evaluate the efficacy of trimetazidine in combination with other anti-anginal drugs versus other anti-anginal drugs in the treatment of stable angina pectoris (SAP). Randomized controlled trials (RCTs) published in English and Chinese were retrieved from computerized databases: Embase, PubMed, and CNKI. Primary outcomes consist of clinical parameters (numbers of weekly angina attacks and nitroglycerin use) and ergometric parameters (time to 1mm ST-segment depression, and total work (in Mets) and exercise duration (in seconds) at peak exercise) in stable angina pectoris treated by trimetazidine or not. The quality of studies was evaluated using Jadad score. Data analysis of 13 studies was performed using Stata 12.0 software. Results showed that treatment of trimetazidine and other anti-anginal drugs was associated with a smaller weekly mean number of angina attacks (WMD=-0.95, 95%CI: -1.30 to -0.61, Z=5.39, P<0.001), fewer weekly nitroglycerin use (WMD=-0.98, 95%CI: -1.44 to -0.52, Z=4.19, P<0.001), longer time to 1mm ST-segment depression (WMD=0.30, 95%CI: 0.17 to 0.43, Z=4.46, P<0.001), higher total work (WMD=0.82, 95%CI: 0.44 to 1.20, Z=4.22, P<0.001) and longer exercise duration at peak exercise (WMD=49.81, 95%CI: 15.04 to 84.57, Z=6.38, P<0.001) than treatment of other anti-anginal drugs for stable angina pectoris. Sensitivity analysis was performed. Sub-group analysis showed that treatment duration was not a significant moderator and patients treated within 8weeks and above 12weeks had no difference in the outcomes addressed in this meta-analysis. No publish bias was detected. This meta-analysis confirms the efficacy of trimetazidine in the treatment of stable angina pectoris, in comparison with conventional antianginal agents, regardless of treatment duration.
- Implementation of standardized dosing units for i.v. medications. [Journal Article]
- Am J Health Syst Pharm 2014 Dec 15; 71(24):2153-8.
The implementation of standardized dosing units for six i.v. medications at an academic medical center is described.During the implementation of an electronic health record system at an academic medical center, it was noticed that providers could order some i.v. medications in multiple dosing units, including epinephrine, isoproterenol, midazolam, nitroglycerin, norepinephrine, and phenylephrine. Possible options to standardize i.v. medications along with their pros and cons were presented for discussion to key providers in all of the intensive care units. Once the providers agreed on a solution, the information was presented to the pharmacy and therapeutics committee for final approval. A nursing education plan was created and administered before the standardization of dosing units was implemented. A nursing survey was conducted before and after implementation of dosing-unit standardization to determine the effectiveness of nursing education on compliance with the standardization of the dosing units for the listed medications. The survey was designed to evaluate, when given a choice, what dosing units nurses would use to administer epinephrine, isoproterenol, midazolam, nitroglycerin, norepinephrine, and phenylephrine. The decision was made by the key providers to use weight-based dosing-micrograms per kilograms per minute-to allow for consistency of use of these medications for pediatric and adult patients. Nursing education was completed to ensure that nurses were aware of how to safely administer these medications using the new dosing units.Dosing-unit standardization for dose-adjustable i.v. infusions can provide improved consistency and decrease the potential for dosing errors when administering epinephrine, isoproterenol, midazolam, nitroglycerin, norepinephrine, and phenylephrine.
- The CHADS2 and CHA2DS2-VASc scores predict adverse vascular function, ischemic stroke and cardiovascular death in high-risk patients without atrial fibrillation: Role of incorporating PR prolongation. [Journal Article]
- Atherosclerosis 2014 Dec; 237(2):504-13.
To investigate whether the CHADS2 and CHA2DS2-VASc scores have clinical utility for prediction of adverse vascular function and vascular dysfunction-mediated incident cardiovascular (CV) events among high-risk patients without atrial fibrillation (AF), and the additional value of incorporating PR prolongation to the scores.We analyzed 579 high-risk CV outpatients without clinical AF in a prospective cohort for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and CV death. Brachial flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD), carotid intima-media thickness (IMT) and pulse wave velocity (PWV) were determined.Baseline CHADS2 score was associated with lower FMD (Pearson r = -0.16, P < 0.001) and NMD (r = -0.17, P < 0.001), higher carotid IMT (r = 0.30, P < 0.001) and PWV (r = 0.35, P < 0.001; similar for CHA2DS2-VASc score: All P < 0.05). After follow-up of 63 ± 11 months, 82 patients (14.2%) developed combined CV endpoint. ROC curve analysis showed that both CHADS2 and CHA2DS2-VASc scores were predictors for ischemic stroke (C-Statistic: CHADS2 0.70, P = 0.004; CHA2DS2-VASc 0.68, P = 0.010), MI (CHADS2 0.63, P = 0.030; CHA2DS2-VASc 0.70, P = 0.001), and CV death (CHADS2 0.63, P = 0.022; CHA2DS2-VASc 0.65, P = 0.011). Higher CHADS2 score was associated with reduced event-free survival from combined CV endpoints (log-rank = 16.7, P < 0.001) with differences potentiated if stratified by CHA2DS2-VASc score (log-rank = 29.2, P < 0.001). Incorporating PR prolongation, the CHA2DS2-VASc-PR score achieved the highest C-Statistic for CV death prediction (0.70, P < 0.001) superior to the CHADS2 score (chi-square: 12.1, P = 0.0005).The CHADS2 and CHA2DS2-VASc predict vascular dysfunction and cardiovascular events in high-risk CV patients without clinical AF, with further improved performance incorporating PR prolongation.
- Organic nitrates: Update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. [REVIEW]
- Vascul Pharmacol 2014 Dec; 63(3):105-113.
Given acutely, organic nitrates, such as nitroglycerin (GTN), isosorbide mono- and dinitrates (ISMN, ISDN), and pentaerythrityl tetranitrate (PETN), have potent vasodilator and anti-ischemic effects in patients with acute coronary syndromes, acute and chronic congestive heart failure and arterial hypertension. During long-term treatment, however, side effects such as nitrate tolerance and endothelial dysfunction occur, and therapeutic efficacy of these drugs rapidly vanishes. Recent experimental and clinical studies have revealed that organic nitrates per se are not just nitric oxide (NO) donors, but rather a quite heterogeneous group of drugs considerably differing for mechanisms underlying vasodilation and the development of endothelial dysfunction and tolerance. Based on this, we propose that the term nitrate tolerance should be avoided and more specifically the terms of GTN, ISMN and ISDN tolerance should be used. The present review summarizes preclinical and clinical data concerning organic nitrates. Here we also emphasize the consequences of chronic nitrate therapy on the supersensitivity of the vasculature to vasoconstriction and on the increased autocrine expression of endothelin. We believe that these so far rather neglected and underestimated side effects of chronic therapy with at least GTN and ISMN are clinically important.
- Human ALDH1B1 Polymorphisms may Affect the Metabolism of Acetaldehyde and All-trans retinaldehyde-In Vitro Studies and Computational Modeling. [JOURNAL ARTICLE]
- Pharm Res 2014 Nov 21.
To elucidate additional substrate specificities of ALDH1B1 and determine the effect that human ALDH1B1 polymorphisms will have on substrate specificity.Computational-based molecular modeling was used to predict the binding of the substrates propionaldehyde, 4-hydroxynonenal, nitroglycerin, and all-trans retinaldehyde to ALDH1B1. Based on positive in silico results, the capacity of purified human recombinant ALDH1B1 to metabolize nitroglycerin and all-trans retinaldehyde was explored. Additionally, metabolism of 4-HNE by ALDH1B1 was revisited. Databases queried to find human polymorphisms of ALDH1B1 identified three major variants: ALDH1B1*2 (A86V), ALDH1B1*3 (L107R), and ALDH1B1*5 (M253V). Computational modeling was used to predict the binding of substrates and of cofactor (NAD(+)) to the variants. These human polymorphisms were created and expressed in a bacterial system and specific activity was determined.ALDH1B1 metabolizes (and appears to be inhibited by) nitroglycerin and has favorable kinetics for the metabolism of all-trans retinaldehyde. ALDH1B1 metabolizes 4-HNE with higher apparent affinity than previously described, but with low throughput. Recombinant ALDH1B1*2 is catalytically inactive, whereas both ALDH1B1*3 and ALDH1B1*5 are catalytically active. Modeling indicated that the lack of activity in ALDH1B1*2 is likely due to poor NAD(+) binding. Modeling also suggests that ALDH1B1*3 may be less able to metabolize all-trans retinaldehyde and that ALDH1B1*5 may bind NAD(+) poorly.ALDH1B1 metabolizes nitroglycerin and all-trans-retinaldehyde. One of the three human polymorphisms, ALDH1B1*2, is catalytically inactive, likely due to poor NAD(+) binding. Expression of this variant may affect ALDH1B1-dependent metabolic functions in stem cells and ethanol metabolism.