Intravenous Bolus Injection Research Articles

Pharmacokinetics and Safety of a Diclofenac Sodium 75mg/1mL Solution (Akis®/Dicloin®) Administered as a Single Intravenous Bolus Injection in Healthy Men and Women.

BackgroundA 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-β-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration.ObjectivesThe study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products.MethodsThe study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation.ResultsThe extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00–125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus.ConclusionsDiclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.

Comparing perioperative magnesium sulphate, lidocaine, and their combination in preventing ventricular arrhythmia in off-pump coronary artery bypass grafting

BackgroundTechniques of coronary artery bypass grafting (CABG) have developed rapidly over the last decades. However, dysrhythmia is a common feature during off pump CABG. The aim of this work was to study effect of perioperative magnesium sulphate infusion on the incidence of cardiac arrhythmia in off-pump CABG: and comparing such effects to lidocaine alone or combined to magnesium.MethodologyNinety patients undergoing elective coronary artery bypass grafting surgery were randomly divided into three equal groups: magnesium group received magnesium over 12 h prior to off-pump surgery and over 30 min intraoperatively; lidocaine group were given an intravenous bolus injection of lidocaine followed by a continuous infusion; and combination group received half the doses of magnesium and lidocaine prescribed for the other two groups. The patients’ perioperative hemodynamic data (heart rate and mean arterial pressure) and the occurrence of intraoperative and postoperative arrhythmia were recorded.ResultsThere was statistically significant difference between study groups as regards mean intraoperative heart rate and intraoperative mean arterial pressure. In addition, the need for intraoperative beta-blockers was significantly higher in lidocaine group; there was no need for intraoperative beta-blockers for combination group. Also, the need for perioperative aortic balloon pump was significantly higher in lidocaine group (20.0%), followed by 6.7% in magnesium group, and none in combination group. The percentage of ventricular tachycardia was significantly higher in lidocaine group (16.7%), followed by magnesium group (3.3%) and none in combination group.ConclusionResults of the present study revealed that combination of both perioperative magnesium and lidocaine when compared to each of both drugs separately has a better effect in controlling hemodynamics (heart rate and mean arterial blood pressure intraoperatively), less ventricular tachycardia, and reduction in the need for beta blockers and aortic balloon pump perioperatively. In addition, magnesium was superior to lidocaine, although both are effective.

Rapid screening of nine unradiolabeled candidate compounds as PET brain imaging agents using cassette-wave microdosing and LC-MS/MS

The R&D of PET imaging agents is a complex system engineering, simplifying screening steps and increasing screening efficiency have become popular issues. The purpose of this study is to develop a new screening procedure using cassette-wave microdosing and LC-MS/MS to enhance the screening throughput of unradiolabeled candidate compounds as PET imaging agents. Nine compounds were divided into 3 sets and made into 3 cassettes. Fifteen rats were randomly divided into 3 groups, and every animal received three intravenous bolus injections at three different time points; the doses were at microdose levels. This dosing approach takes advantage of temporal and spatial differences and is likened to an input wave; therefore, this approach was named cassette-wave microdosing. The samples of different brain regions such as the hypothalamus, striatum, hippocampus, cortex, cerebellum and the remainder of the brain were detected by LC-MS/MS analysis. The research potential of the compounds as PET imaging agents is evaluated in terms of brain biodistribution data. The screening method is rapid, highly efficient, reliable and reduces animal usage. Additionally, it can shorten the evaluation process of radiopharmaceuticals and enhance the screening throughput of PET radiopharmaceuticals without the use of radioactive agents.

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Apolipoprotein A-I Crosses the Blood-Brain Barrier through Clathrin-Independent and Cholesterol-Mediated Endocytosis.

Recent studies suggest that apolipoprotein A-I (ApoA-I), the major protein constituent of high-density lipoprotein particles, plays a critical role in preserving cerebrovascular integrity and reducing Alzheimer's risk. ApoA-I present in brain is thought to be primarily derived from the peripheral circulation. Although plasma-to-brain delivery of ApoA-I is claimed to be handled by the blood-cerebrospinal fluid barrier (BCSFB), a contribution by the blood-brain barrier (BBB), which serves as a major portal for protein delivery to brain, cannot be ruled out. In this study, we assessed the permeability-surface area product (PS) of radioiodinated ApoA-I (125I-ApoA-I) in various brain regions of wild-type rats after an intravenous bolus injection. The PS value at the cortex, caudate putamen, hippocampus, thalamus, brain stem, and cerebellum was found to be 0.39, 0.28, 0.28, 0.36, 0.69, and 0.76 (ml/g per second × 10-6), respectively. Solutes delivered into brain via the BCSFB are expected to show greater accumulation in the thalamus due to its periventricular location. The modest permeability for 125I-ApoA-I into the thalamus relative to other regions suggests that BCSFB transport accounts for only a portion of total brain uptake and thus BBB transport cannot be ruled out. In addition, we show that Alexa Flour 647-labeled ApoA-I (AF647-ApoA-I) undergoes clathrin-independent and cholesterol-mediated endocytosis in transformed human cerebral microvascular endothelial cells (hCMEC/D3). Further, Z-series confocal images of the hCMEC/D3 monolayers and Western blot detection of intact ApoA-I on the abluminal side demonstrated AF647-ApoA-I transcytosis across the endothelium. These findings implicate the BBB as a significant portal for ApoA-I delivery into brain.

Transfusion of Resting Platelets Reduces Brain Hemorrhage After Intracerebral Hemorrhage and tPA-Induced Hemorrhage After Cerebral Ischemia.

BackgroundExacerbated blood-brain barrier (BBB) damage is related with tissue plasminogen activator (tPA)-induced brain hemorrhage after stroke. Platelets have long been recognized as the cellular orchestrators of primary haemostasis. Recent studies have demonstrated further that platelets are required for supporting intact mature blood vessels and play a crucial role in maintaining vascular integrity during inflammation. Therefore, we sought to investigate whether platelets could reduce tPA-induced deterioration of cerebrovascular integrity and lead to less hemorrhagic transformation.MethodsMice were subjected to models of collagenase-induced intracerebral hemorrhage (ICH) and transient middle cerebral artery (MCA) occlusion. After 2 h of MCA occlusion, tPA (10 mg/kg) was administered as an intravenous bolus injection of 1 mg/kg followed by a 9 mg/kg infusion for 30 min. Immediately after tPA treatment, mice were transfused with platelets. Hemorrhagic volume, infarct size, neurological deficit, tight junction and basal membrane damages, endothelial cell apoptosis, and extravascular accumulation of circulating dextran and IgG, and Evans blue were quantified at 24 h.ResultsPlatelet transfusion resulted in a significant decrease in hematoma volume after ICH. In mice after ischemia, tPA administration increased brain hemorrhage transformation and this was reversed by resting but not activated platelets. Consistent with this, we observed that tPA-induced brain hemorrhage was dramatically exacerbated in thrombocytopenic mice. Transfusion of resting platelets ameliorated tPA-induced loss of cerebrovascular integrity and reduced extravascular accumulation of circulating serum proteins and Evans blue, associated with improved neurological functions after ischemia. No changes were found for infarct volume. Inhibition of platelet receptor glycoprotein VI (GPVI) blunted the ability of platelets to attenuate tPA-induced BBB disruption and hemorrhage after ischemia.ConclusionOur findings demonstrate the importance of platelets in safeguarding BBB integrity and suggest that transfusion of resting platelets may be useful to improve the safety of tPA thrombolysis in ischemic stroke.

Comparison between Bolus Intracoronary versus Bolus Intravenous Injection Regimens of Eptifibatide during Primary Percutaneous Coronary Intervention in Patients with Anterior ST-Segment Elevation Myocardial Infarction

Background.Eptifibatide achieves high local concentration via direct intracoronary (I/V) injection as it promotes clot disaggregation, but it remains unclear if it is of superior benefit than the routine intravenous (I/V) administration. Aim. The current study aimed to examine the safety and efficacy of I/C vs I/V bolus regimen dose of eptifibatide during primary percutaneous coronary intervention (PPCI).Material and methods. Prospective, controlled, randomized study enrolled 100 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) eligible for PPCI equally divided into 2 groups (group A received bolus I/C eptifibatide and group B received it I/V) followed by 12-hour continuous I/V infusion. Features related to of myocardial salvage in the form of TIMI flow grade 3, myocardial blush grade 3, ST segment resolution and left ventricular systolic function were evaluated with short-term follow up for 1 month.Results. Mean age of the study population was 50.95±8.45years, there was statistically insignificant difference between both groups regarding baseline characteristics in age (p=0.062), gender (p=0.488), coronary artery disease risk factors (p>0.05), time from onset of pain to admission (p=0.86) or door to balloon (p=0.12). Group A achieved statistically significant better myocardial blush grade 3 (42% vs 10%, p=0.005), ejection faction 30 days after PPCI (46.11±7.81% vs 40.88±6.26%, p=0.005) but statistically insignificant TIMI flow grade 3 (p=0.29) and ST resolution (p=0.34). Incidence of complications in the hospital and 30 days after discharge was statistically insignificant (p>0.05).Conclusion. Both regimens were safe and effective in STEMI patients undergoing PPCI and regimen of I/C bolus eptifibatide achieved better myocardial blush grade and systolic function.

Diagnostic Value of Quantitative Perfusion Computed Tomography Technique in the Assessment of Tumor Response to Sorafenib in Patients With Advanced Hepatocellular Carcinoma

The aim of this study was to assess the role of dynamic contrast-enhanced perfusion computed tomography (pCT) imaging in the early detection of blood flow changes related to antiangiogenic treatment with sorafenib, in patients with advanced hepatocellular carcinoma (HCC), being the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria the standard of reference. Between 2012 and 2016, 43 cirrhotic patients (male, n = 39; female, n = 4) with biopsy-proven multifocal HCC underwent multi-detector-row computed tomography, and pCT examinations were performed before and every 2 months after sorafenib administration. Perfusion CT technique is based on the acquisition of 16 dynamic slices/scan per 40 scans, performed on a 256-slice multi-detector-row computed tomography scanner, after intravenous bolus injection of 50 mL of iodinated contrast agent (350 mg I/mL) at a flow rate of 5 mL/s. According to mRECIST, patients were stratified into complete (CR) or partial response (PR) and stable (SD) or progressive disease (PD). The following pCT parameters were calculated: hepatic perfusion (mL/s per 100 g), time to peak (seconds), arterial perfusion (mL/s), and hepatic perfusion index (%). Perfusion CT values at baseline and first follow-up were reported for all mRECIST groups and then compared between the nonprogressor (CR, PR, SD) and progressor groups (PD). Most pCT values were significantly higher (P < 0.01) between baseline and follow-up in the CR and PR groups, whereas nonsignificant differences were found among SD patients, and a nonsignificant trend (P > 0.05) toward increase was observed among PD patients. Moreover, pCT values were significantly higher (P = 0.05) at baseline in the nonprogressor group compared with the progressor. Preliminary results suggest that pCT adds quantitative data of vascularization, thus demonstrating its usefulness in the assessment of therapeutic response to sorafenib in advanced HCC, in line with mRECIST criteria, offering 1-step information on tissue cellularity and vascularization.

Pattern of Skeletal Metastasis in Breast Cancer Patients Attending INMAS, Rajshahi

Breast cancer is the most common malignant tumor of females, the incidence increases with age. Bone is the most common site to which breast cancer metastasizes. Between 30% to 85% of patients with metastatic breast cancer develop bone metastases during the course of the disease. Bone scan is the most commonly used means of detecting bone metastasis; it visualizes increases in osteoblastic activity and skeletal vascularity. Many radio-pharmaceuticals (radionuclides) have been used in bone scan including technetium-99m bound to methylene diphosphonate (MDP). Published sensitivity and specificity rates of bone scan for diagnosis varies, with sensitivity ranging from 62% to 100% and specificity from 78% to 100%. However, bone scan is generally considered sensitive for detecting bone metastases on whole-body images.The aim of this study was to evaluate the pattern of distribution of skeletal metastases in patients with breast carcinoma by using Tc-99m MDP bone scan. A retrospective study was conducted on 245 consecutive female breast carcinoma patients irrespective of clinical staging, menopausal status and pre-operative / post- mastectomy status, referred for bone scan to Institute of Nuclear Medicine and Allied Sciences, Rajshahi from July 2015 to June 2017. The mean age of the patients was 43.4 ± 13.8 years (mean ± SD) with range from 29 to 66 years. Bone scan was performed by an intravenous bolus injection of 20 mCi Tc99m-MDP. Bone phase images were taken at three hours after injection of the radiotracer. Out of 245 studied patients, 163 patients (66.53%) were negative for skeletal metastasis and 82 patients (33.47%) were positive for skeletal metastasis. Out of 82 patients with positive skeletal metastasis, 68 (82.93%) patients had multiple sites (two or more) and 14 (17.07%) patients had solitary site of bony involvement. Out of 68 patients with multiple sites of skeletal metastasis, highest number was noted in thoraco-lumbar spine (80.89%), followed by ribs including sternum and clavicle (57.35%), pelvic bones (47.06%), upper extremities including scapula (41.18%), lower extremities (33.82%), cervical spine (23.53%) and skull bone (8.82%). Among 14 patients with solitary skeletal metastasis, maximum number was noted in thoraco-lumbar spine (64.29%), followed by cervical spine (14.29%), pelvic bone (07.14%), ribs (07.14%) and sternum (07.14%). Skeletal metastases were much more common in multiple sites than solitary lesion in breast cancer patients. Thoraco-lumbar spine was the most common site of involvement in both solitary and multiple lesions in our study. Axial skeleton was more commonly involved than the appendicular skeleton. Bone scan may pick up bone metastases up to 18 months earlier than conventional radiology, with an average lead of four months. 99m Tc- MDP bone scan is very cost effective in comparison to other imaging modalities (CT, MRI, and PET) and play a major role in early detection of skeletal metastasis in breast cancer patients.&#x0D; Bangladesh J. Nuclear Med. 21(1): 21-25, January 2018

Efficacy of dexmedetomidine in reducing post-operative pain and improving the quality of recovery in patients with burn wounds undergoing tangential excision skin grafting.

Burn-induced acute post-operative pain and the associated stress response may result in prolonged convalescence. The present study investigated the effects of dexmedetomidine (DEX) administration on post-operative pain and the quality of recovery following surgical treatment of moderate-to-severe burn injuries. A total of 60 adult patients undergoing tangential excision skin grafting were randomized into two groups. The DEX group (Group D) received an intravenous (i.v.) single-dose bolus injection of DEX 0.5 µg/kg >10 min prior to induction of anesthesia. Patient-controlled intravenous analgesia (PCIA) was provided to the patients from the end of the surgery, which consisted of 100 µg sufentanil plus 200 µg DEX. The control group (Group C) received an equal volume of normal saline as a pre-operative bolus and post-operative PCIA of 100 µg sufentanil infusion. The Visual Analogue Scale (VAS) score at rest and during movement, the cumulative dose of sufentanil and the 40-item quality of recovery questionnaire (QoR-40) score were assessed at various time-points after the surgery. During the first 24 h post-surgery, patients in Group D exhibited a lower VAS score at rest and during movement, a lower number of PCIA pump presses (29.17±1.91 vs. 34.13±2.73) and lower sufentanil consumption (62.58±0.96 vs. 65.27±1.26) compared with those in Group C (P<0.05). Furthermore, the QoR-40 recovery score of patients in Group D at 24 h post-surgery was higher compared with that in Group C (P<0.01). In conclusion, the present study indicated that a pre-operative bolus of DEX (0.5 µg/kg) followed by DEX plus sufentanil by PCIA subsequent to surgery improved the quality of analgesia and promoted the quality of recovery at 24 h following tangential excision skin grafting treatment of patients with moderate-to-severe burn injuries compared to PCIA of 100 µg sufentanil only. The present study was retrospectively registered with the trial registration no. ChiCTR1800016646 (date of registration, 14/06/2018).

Effect of Fentanyl and Nalbuphine for Prevention of Etomidate-Induced Myoclonus.

Background:Etomidate is a potent intravenous inducing agent with known undesirable side effects such as myoclonus and pain on injection in nonpremedicated patients.Aims:The aim of this study is to compare the effect of fentanyl and nalbuphine in the prevention of etomidate-induced myoclonus.Settings and Design:Randomized double-blind, placebo-controlled, and prospective comparative study.Materials and Methods:A total of 120 patients were randomly allocated to one of the three groups containing 40 patients each for intravenous administration of fentanyl 2 μg/kg diluted in 10 mL normal saline (NS) (Group 1), nalbuphine 0.3 mg/kg diluted in 10 mL NS (Group 2), and only 10 mL NS (Group 3) over 10 min. All groups subsequently received 0.3 mg/kg etomidate by intravenous bolus injection over 15–20 s and were assessed for the severity of pain using Grade IV pain scale and observed for myoclonus for 2 min and graded according to clinical severity. Serum creatinine phosphokinase (CPK) levels were obtained prior and postetomidate injection.Statistical Analysis:Statistical analysis was performed by the SPSS program version 17.0 for Windows. Tests used are Shaipro–Wilk test, ANOVA, Tukey's multiple comparison test, Tamhane's T2, and the Chi-square test. For all statistical tests, P < 0.05 was considered statistically significant with 5% level of significance (α).Results:The incidence of myoclonus in Group 1 and 2 was 52.5% and 17.5%, respectively, whereas it was 92.45% in Group 3. There was no pain observed in 70%, 92.5%, and 50% of patients in Group 1, 2, and 3, respectively. There was a statistically significant difference in mean CPK level after induction among three groups (P < 0.001).Conclusion:Nalbuphine is more effective than fentanyl in the prevention of etomidate-induced myoclonus and pain with the minimum rise in CPK levels.

Effect of nonpharmacological methods on incidence of postspinal hypotension during cesarean delivery

Introduction Hypotension is caused by upward spread of anesthetic into the subarachnoid space; this results in venous pooling in the capacitance vessels of the lower limbs as a result of block of sympathetic tone and unopposed activity of parasympathetic tone. It also may be caused by aorto-caval syndrome and is accompanied by bradycardia, nausea, and vomiting. Hypotension may have deleterious effects on mother and fetus and may result in uteroplacental hypoperfusion, as placental perfusion is pressure dependent, and lack of autoregulation of placental blood vessels, if persisted, may threaten the life of the fetus. Aim The primary aim of the work is to compare incidence of intraoperative hypotension between the three groups. The secondary outcome is to assess Appearance, Pulse, Grimace, Activity, Respiration (Apgar) score, vasopressor consumption, and occurrence of complications (nausea, vomiting, and bradycardia). Patients and methods A total of 150 patients undergoing cesarean delivery under spinal anesthesia were included. Patients were divided into three equal groups, using simple randomization method, with 50 patients each: group S, in which the patient will sit for 1 min after induction of spinal anesthesia and then will lie down; group E, in which patient's legs will be elevated to 30° from the horizontal plane; and group C in which the patient will lie down immediately after induction of spinal anesthesia as a control group. Then, heart rate, systolic blood pressure, diastolic blood pressure, and mean blood pressure were measured every 2 min until delivery of fetus and then every 5 min until the end of surgery. Sensory level was assessed before start of surgery, subsequently after lying down, and every 1 min using hot and cold test until it reaches T6 sensory level. Fetal well-being was assessed by Appearance, Pulse, Grimace, Activity, Respiration (Apgar) score measured by a pediatrician blinded to the study protocol at 1 and 5 min after delivery. Incidence of hypotension is defined as ‘at least one episode of decrease in systolic blood pressure to less than 90 mmHg or decrease in systolic pressure more than 20% from the baseline till the end of surgery’. It was treated immediately by 200 ml intravenous bolus fluids and injection of 5 mg ephedrine intravenous bolus every 2 min until elevation of blood pressure, and the total of ephedrine consumption was calculated. Duration of surgery and intraoperative complications was recorded as bradycardia, defined by heart rate below 60 beats/min, which was treated by 0.5 mg atropine sulfate, and nausea and vomiting, which were treated by ondansetron intravenous 4 mg after correction of hypotension. Results A total of 150 cesarean delivery patients between 22 and 34 years of age were included in the study. Regarding basic clinical and demographic data, it was found that the median age of all cesarean delivery patients was 30 years. The median BMI of all cesarean delivery patients was 32.5. Regarding the surgery duration, the median surgery duration of all cesarean delivery patients was 40 min. Regarding level of sensory block, most patients had sensory block at T6 (70%), and 30% at T4 in groups C, E, and S, correspondingly. Regarding primary outcome (incidence of hypotension mean arterial blood pressuer (MAP)&lt;70 mmHg), there was a highly significant increase in incidence of hypotension in group C compared with other groups of patients, with highly significant statistical difference (P=0.0092). The incidence of hypotension in group C was 70%, in group E was 50%, whereas in group S was 40% (P=0.0092). Regarding secondary outcomes (ephedrine consumption, Apgar scores, and complications), there was a highly significant increase in ephedrine consumption in group C compared with other groups (P=0.000002). The median value of ephedrine consumption in group C was 7.5 mg, in group E was 2.5 mg, whereas no ephedrine was consumed in group S (P=0.000002). Moreover, there was a nonsignificant difference regarding Apgar score at 1 min (P&gt;0.05). There was a highly significant increase in Apgar score at 5 min in group S compared with other groups (P=0.0047). There was a highly significant increase in bradycardia in group C compared with the other groups (P=0.0015). There was a highly significant increase in nausea in group C compared with the other groups (P=0.0008). There was a highly significant increase in vomiting in group C compared with the other groups (P=0.0008). Conclusion Incidence of hypotension in patients undergoing cesarean delivery under spinal anesthesia markedly decreased in patients who sat for 1 min after induction of spinal anesthesia and then lied down (group S) compared with patients who lied down immediately after induction of spinal anesthesia.

EVALUATION OF GASTRIC CONDUIT BLOOD SUPPLY WITH FLUORESCENT ANGIOGRAPHY WITH INDOCYANINE GREEN AFTER ESOPHAGECTOMY FOR CANCER

Anastomotic leak and conduit necrosis are severe complications after esophagectomy. Fluorescent angiography with indocyanine green provides an opportunity to objectively evaluate conduit perfusion and, potentially, reduce the number of leaks. Material and methods. We analyzed short-term outcomes of 26 esophagectomies performed with laser fluorescent evaluation of conduit perfusion. All patients had esophagogastic anastomosis, 14 in the neck, 12 in the pleural cavity. Conduit perfusion was assessed 30 sec after intravenous bolus injection of 6 mg of indocya-nine green with SPY2000 laser technology. The results were compared with short-term outcomes of 35 esophagectomies performed without fluorescent assessment of gastric tube perfusion. Results. There were 6 leaks or conduit necrosis in control group while in the ICG group there were only 2 leaks on the neck: 1 in a patient with a massive intraoperative bleeding and shock, 1 in a patient with severely compromised blood supply of the gastric tube tip according to ICG imaging. No cases of conduit necrosis were found, which led to significantly lower number of severe (grade III-V Dindo-Clavien) complications, p=0,033. Conclusion Laser fluorescent angiography with indocyanine green is a useful tool which affords an objective evaluation of gastric tube perfusion and, potentially, reduces the number of severe postoperative complications after esophagectomy.

Melatonin release by exocytosis in the rat parotid gland.

Several beneficial effects on oral health are ascribed to melatonin. Due to its lipophilic nature, non-protein-bound circulating melatonin is usually thought to enter the saliva by passive diffusion through salivary acinar gland cells. Recently, however, using transmission electron microscopy (TEM), melatonin was found in acinar secretory granules of human salivary glands. To test the hypothesis that granular located melatonin is actively discharged into the saliva by exocytosis, i.e. contrary to the general belief, the β-adrenergic receptor agonist isoprenaline, which causes the degranulation of acinar parotid serous cells, was administered to anaesthetised rats. Sixty minutes after an intravenous bolus injection of isoprenaline (5mgkg-1 ), the right parotid gland was removed; pre-administration, the left control gland had been removed. Samples were processed to demonstrate melatonin reactivity using the immunogold staining method. Morphometric assessment was made using TEM. Gold particles labelling melatonin appeared to be preferentially associated with secretory granules, occurring in their matrix and at membrane level but, notably, it was also associated with vesicles, mitochondria and nuclei. Twenty-six per cent of the total granular population (per 100μm2 per cell area) displayed melatonin labelling in the matrix; three-quarters of this fraction disappeared (P<0.01) in response to isoprenaline, and melatonin reactivity appeared in dilated lumina. Thus, evidence is provided of an alternative route for melatonin to reach the gland lumen and the oral cavity by active release through exocytosis, a process which is under the influence of parasympathetic and sympathetic nervous activity and is the final event along the so-called regulated secretory pathway. During its stay in granules, anti-oxidant melatonin may protect their protein/peptide constituents from damage.

Evaluation of Skeletal Metastases in Different Clinical Stages of Breast Cancer Patients

Background: Breast cancer is a common form of cancer among women globally. Bone is the most common site to which breast cancer metastasizes. Between 30% and 85% of patients with metastatic breast cancer will develop bone metastases during the course of the disease.Objective: To evaluate the pattern and distribution of skeletal metastases in different clinical stages of breast cancer patients by using Tc-99m MDP bone scan.Materials and methods: A retrospective study was conducted on 305 consecutive female breast carcinoma patients referred for bone scan to Institute of Nuclear Medicine and Allied Sciences, Rajshahi from January 2015 to June 2017. All patients were categorized in one of the three groups; early breast cancer (EBC, comprises clinical stage I and II), locally advanced breast cancer (LABC, clinical stage III) and metastatic breast cancer (MBC, clinical stage IV). Bone scan was performed by an intravenous bolus injection of 20 mCi Tc99m-MDP and bone phase images were taken at three hours after injection of the radiotracer.Results: Out of 305 studied patients, 16 patients (5.25%) were in EBC group, LABC patients were 173 (56.72%) and MBC were 116 (38.03%). 98 patients (32.13%) were positive for skeletal metastases. In 16 EBC patients only 01 patient (6.25%) had skeletal metastasis in thoracic spine. Skeletal metastases were 20.81% in LABC and 52.59% in MBC group. Thoraco-lumbar spine was the commonest site in both groups followed by ribs, pelvic bones, upper and lower extremities, cervical spine, sternum, scapula and skull bone.Conclusion: Bone scan should be done in all LABC and MBC patients and in symptomatic EBC at disease presentation. Parts of bone to focus are thoracic and lumbar spine in all stages, followed by ribs, pelvis and extremities. Tc-99m MDP bone scan play a major role in early detection of skeletal metastasis in breast cancer patients.TAJ 2017; 30(2): 47-53

Subgroup Analysis of Patients with Biochemical or Symptomatic Relapse at the Time of Enrollment in the Endeavor Study

Introduction: The randomized phase 3 ENDEAVOR trial demonstrated superior progression-free survival (PFS), overall survival (OS), and health-related quality of life in patients with relapsed or refractory multiple myeloma (RRMM) for patients treated with carfilzomib (56 mg/m2) and dexamethasone (Kd56) compared with bortezomib and dexamethasone (Vd). In patients with relapsed MM, the time of therapy initiation might impact treatment outcome. Prior studies have demonstrated a median of 5 months between the presence of biochemical and symptomatic relapse (Lopez. Leuk Res Rep. 2015;4:64-69). Herein, we report a post hoc subgroup analysis from the ENDEAVOR study to evaluate the impact of initiating Kd56 therapy upon biochemical relapse.Methods: Adults with RRMM who previously received 1-3 lines of therapy and had measurable disease were eligible to participate in the ENDEAVOR trial. Symptomatic disease was not required for eligibility. Kd56 patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 as a 30-minute intravenous infusion and dexamethasone (20 mg) on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Vd patients received bortezomib (1.3 mg/m2; intravenous bolus or subcutaneous injection) on days 1, 4, 8 and 11 and dexamethasone (20 mg) on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Treatment continued until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or death. This post hoc subgroup analysis evaluated PFS, OS, and safety in subgroups defined according to the presence of symptoms at the time of enrollment. Patients with RRMM who experienced biochemical progression without CRAB symptoms (hypercalcemia, renal impairment, anemia, or bone lesions) upon relapse were considered asymptomatic, whereas symptomatic patients were those who had CRAB symptoms upon relapse. In each subgroup, PFS and OS were compared between treatment arms using an unstratified Cox proportional hazards model.Results: Of the 929 patients enrolled and randomized in ENDEAVOR, 117 (12.6%) were asymptomatic (Kd56, n=60; Vd, n=57) and 812 (87.4%) were symptomatic (Kd56, n=404; Vd, n=408). In the asymptomatic group, the median PFS was not estimable (NE) for Kd56 vs 13.7 months for Vd (hazard ratio [HR]: 0.462; 95% confidence interval [CI]: 0.232-0.922), and the median OS was NE for either treatment arm (HR: 0.768; 95% CI: 0.350-1.683) (Table). In the symptomatic group, median PFS was 17.7 months for Kd56 vs 8.8 months for Vd (HR: 0.539; 95% CI: 0.439-0.662), and median OS was 44.0 months for Kd56 vs. 36.8 months for Vd (HR: 0.801; 95% CI: 0.653-0.982) (Table). Kaplan-Meier PFS and OS curves are shown in the Figure. The rate of grade ≥3 treatment-emergent adverse events (Kd56 vs Vd) was 78.3% vs 58.9% in the asymptomatic group and 81.9% vs 72.8% in the symptomatic group (Table).Conclusions: Kd56 demonstrated superior survival outcomes compared with Vd in patients with RRMM, regardless of presence of CRAB symptoms at study randomization. As expected, outcomes were improved when Kd56 was initiated early in the disease course, before CRAB symptoms occurred. The small size of the subgroups in this study is a limitation. However, the findings warrant further investigation. The safety profile of Kd56 in both subgroups was consistent with that in the overall population as previously reported (Dimopoulos. Lancet Oncol. 2016;17:27-38; Siegel, Clin Lymphoma Myeloma Leuk. 2017;17:e142). Overall, Kd56 had a favorable benefit-risk profile in both patients with biochemical and symptomatic relapse. [Display omitted] DisclosuresMoreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Goldschmidt:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; ArtTempi: Honoraria; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding. Niesvizky:Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Bringhen:Takeda: Consultancy; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Orlowski:Spectrum Pharma: Research Funding; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Sanofi-Aventis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Kite Pharma: Consultancy. Blaedel:Amgen: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Dimopoulos:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria.

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

IntroductionDamage-associated molecular patterns, such as high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA), play critical roles in mediating ischemia-reperfusion injury (IRI). HMGB1 activates RAGE to exacerbate IRI, but the mechanism underlying cfDNA-induced myocardial IRI remains unknown. We hypothesized that the infarct-exacerbating effect of cfDNA is mediated by HMGB1 and receptor for advanced glycation end products (RAGE). MethodsC57BL/6 wild type mice, RAGE knockout (KO), and Toll-like receptor 9 KO mice underwent 20- or 40-minute occlusions of the left coronary artery followed by up to 60 minutes of reperfusion. Cardiac coronary perfusate was acquired from ischemic hearts without reperfusion. Exogenous mitochondrial DNA was acquired from livers of normal C57BL/6 mice. Myocardial infarct size (IS) was reported as percent risk region, as measured by 2,3,5-triphenyltetrazolium chloride and Phthalo blue (Heucotech, Fairless Hill, Pa) staining. cfDNA levels were measured by Sytox Green assay (Thermo Fisher Scientific, Waltham, Mass) and/or spectrophotometer. ResultsFree HMGB1 and cfDNA levels were increased in the ischemic myocardium during prolonged ischemia and subsequently in the plasma during reperfusion. In C57BL/6 mice undergoing 40′/60′ IRI, deoxyribonuclease I, or anti-HMGB1 monoclonal antibody reduced IS by approximately half to 29.0% ± 5.2% and 24.3% ± 3.5% (P < .05 vs control 54.3% ± 3.4%). However, combined treatment with deoxyribonuclease I + anti-HMGB1 monoclonal antibody did not further attenuate IS (29.3% ± 4.9%). In C57BL/6 mice undergoing 20′/60′ IRI, injection of 40′/5′ plasma upon reperfusion increased IS by more than 3-fold (to 19.9 ± 4.3; P < .05). This IS exacerbation was abolished by pretreating the plasma with deoxyribonuclease I or by depleting the HMGB1 by immunoprecipitation, or by splenectomy. The infarct-exacerbating effect also disappeared in RAGE KO mice and Toll-like receptor 9 KO mice. Injection of 40′/0′ coronary perfusate upon reperfusion similarly increased IS. The levels of HMGB1 and cfDNA were significantly elevated in the 40′/0′ coronary perfusate and 40′/reperfusion (min) plasma but not in those with 10′ ischemia. In C57BL/6 mice without IRI, 40′/5′ plasma significantly increased the interleukin-1β protein and messenger RNA expression in the spleen by 30 minutes after injection. Intravenous bolus injection of recombinant HMGB1 (0.1 μg/g) or mitochondrial DNA (0.5 μg/g) 5 minutes before reperfusion did not exacerbate IS (P = not significant vs control). However, combined administration of recombinant HMGB1 + mitochondrial DNA significantly increased IS (P < .05 vs individual treated groups) and this infarct-exacerbating effect disappeared in RAGE KO mice and splenectomized C57BL/6 mice. The accumulation of cfDNA in the spleen after combined recombinant HMGB1 + mitochondrial DNA treatment was significantly more elevated in C57BL/6 mice than in RAGE KO mice. Conclusions:Both HMGB1 and cfDNA are released from the heart upon reperfusion after prolonged ischemia and both contribute importantly and interdependently to post-IRI by a common RAGE-Toll-like receptor 9–dependent mechanism. Depleting either of these 2 damage-associated molecular patterns suffices to significantly reduce IS by approximately 50%.

Renal perfusion parameters measured by contrast-enhanced ultrasound in healthy dogs demonstrate a wide range of variability in the long-term.

Contrast-enhanced ultrasound may be helpful for detecting early renal microvascular damage and dysfunction in dogs. However, before this noninvasive imaging method can be tested as an early-stage screening tool in clinical patients, an improved understanding of long-term variation in healthy animals is needed. In this prospective, secondary, longitudinal, serial measurements study, variability of contrast-enhanced ultrasound renal perfusion parameters was described for eight healthy dogs, using seven time points and a period of 83weeks. Dogs were sedated with butorphanol (0.4mg/kg), and contrast-enhanced ultrasound of each kidney was performed after an intravenous bolus injection of a microbubble contrast agent (0.04mL/kg). Time-intensity curves were created from regions-of-interest drawn in the renal cortex and medulla. Intensity-related parameters representing blood volume and time-related parameters representing blood velocity were determined. A random-effects model using restricted maximum likelihood was used to estimate variance components. Within-dog coefficient of variation was defined as the ratio of the standard deviation over the mean. Time-related parameters such as time-to-peak, rise and fall time had lowest within-dog variability. Intensity-related parameters such as peak enhancement, wash-in and wash-out area under the curve, total area under the curve, and wash-in and washout rates had high within-dog variability (coefficient of variation>45%). Authors therefore recommend the use of time-related parameters for future studies of renal perfusion. Within-dog variability for bilateral kidney measurements was extremely low, therefore contrast-enhanced ultrasound may be particularly useful for detecting unilateral changes in renal perfusion. Future studies are needed to compare contrast-enhanced ultrasound findings in healthy dogs versus dogs with renal disease.

Application of thermography for cerebral perfusion imaging during aneurysm surgery

Abstract The success of aneurysm surgery depends on complete clipping of the aneurysmal sacculation without compromising quality of cerebral perfusion of vessels concerned. An established intraoperative method to visualize cerebral blood flow i n a pparent v essels i s fl uorescence vi deo angiography based on indocyanine green (ICG). However, major disadvantages of indocyanine green video angiography (ICG VA) are the need of a specialized imaging system, potential drug side effects as well as the limited number of repetitions due to long decay time of ICG in blood circulation. In particular the last drawback prevents brain parenchymal perfusion monitoring with ICG VA. The application of time-resolved thermography as a fast, contactless, noninvasive, marker-free and harmless imaging tool became a promising approach for perfusion imaging and thus offers several advantages compared to ICG. Measurements of deep structures in heat traps for identification of i nternal patterns, e ssential f or e .g. s uccess monitoring of aneurysm clipping, are still unsolved challenges of thermography. This work reveals as a proof of concept that the combination of thermography and an intravenous cold saline bolus injection as a contrast agent is capable to detect arterial and parenchymal perfusion located in the surgical cavity during aneurysm surgery in comparison to state-of-the-art ICG VA. The investigations provide evidence that thermography has the capability to perform intraoperative imaging of cerebral perfusion at an advanced stage in surgery for vessels and parenchyma located both cortically and in the surgical cavity.

Evaluation of asymptomatic skeletal metastasis by 99mTc MDP bone scans in NSCLC patients attending INMAS, Rajshahi

&lt;p&gt;&lt;strong&gt;&lt;em&gt;Background: &lt;/em&gt;&lt;/strong&gt;Lung cancer is the leading cause of cancer deaths worldwide. Lung cancer is often insidious, producing no symptoms until the disease is well advanced. In approximately 7-10% of cases, lung cancer is diagnosed in asymptomatic patients. Some patients are asymptomatic for skeletal metastasis and a recent prospective study showed that in staging of non-small cell lung cancer (NSCLC), failure to perform a bone scan could miss asymptomatic bone metastasis in 14–22% of patients. Radionuclide bone scintigraphy with &lt;sup&gt;99m&lt;/sup&gt; Tc MDP (Technetium-99mmethylene diphosphonate) is very useful nuclear imaging tool to detect skeletal metastasis with a sensitivity of 98.2% and a specificity of 95.2%. The aim of this study was to detect the asymptomatic skeletal metastasis of non-small cell lung cancer patients by &lt;sup&gt;99m&lt;/sup&gt;Tc MDP bone scan.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Patients and methods:&lt;/em&gt;&lt;/strong&gt; It is a retrospective study, carried out from January 2015 to December 2016 in Institute of Nuclear Medicine and Allied Sciences, Rajshahi. Bone scan was performed by an intravenous bolus injection of 20 m Ci &lt;sup&gt;99m&lt;/sup&gt;Tc MDP. Bone phase images were taken at three hours after injection of the radiotracer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Results:&lt;/em&gt;&lt;/strong&gt; A total of 52 patients were enrolled in the study. The mean age of the patients was 57.6 ± 14.5 years (mean ± SD) with range from 36 to 75 years and 42 (80.77%) were male and 10 (19.23%) were female. Out of 52 patients, only 06 (11.54%) patients were diagnosed as positive and 46 (88.46%) were negative for bone metastasis. Out of 06 patients with positive skeletal metastasis 04 (66.67%) patients had multiple sites (two or more) and 02 (33.33%) patients had solitary site of bone involvement. Common sites of metastasis were in thoracic (83.33%) and lumbar spine (83.33%), ribs (50%), pelvic bones (33.33%), long bones (16.66%), skull (16.66%) and other bony sites including clavicle, sternum, scapula, sacrum (16.66%). Regarding staging prior to bone scan, out of 06 bone scan positive patients 03 (50%) patients were in stage III, 02 (33.33%) patients were in stage IV and 01(16.67%) patient was in stage II. On the basis of histopathology, out of 06 skeletal metastatic patients 04 (66.67%) patients had adenocarcinoma, 01 (16.67%) patient had squamous cell carcinoma and 01 (16.67%) had large cell carcinoma. The exclusion of bone metastasis is important in the initial staging of non-small cell lung cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Conclusion:&lt;/em&gt;&lt;/strong&gt; There is debate about whether bone scans should be performed routinely or restricted to patients who present with clinical or laboratory indicators suggesting skeletal metastasis. The present study indicates that if bone scans were done only in patients reporting skeletal symptoms an important number of patients (11.54%) would have been miss-staged due to asymptomatic bone metastasis. As bone scan is very cost effective in comparison to other imaging modalities (MRI / PET-CT), it can play a vital role in detecting asymptomatic skeletal metastasis in NSCLC patients.&lt;/p&gt;&lt;p&gt;Bangladesh J. Nuclear Med. 20(2): 110-114, July 2017&lt;/p&gt;