scholarly journals Rationale and Design of the Vasospastic Angina Treatment by Endothelin Receptor Antagonism (VERA) Trial

2021 ◽  
Author(s):  
Rutger G Feenstra ◽  
Matthijs Boekholdt ◽  
Yolande Appelman ◽  
Peter Damman ◽  
Marianne E Wittekoek ◽  
...  
Keyword(s):  
Coronary Artery Spasm ◽  
Random Order ◽  
Pain Scale ◽  
Vasospastic Angina ◽  
Primary Analysis ◽  
Double Blind ◽  
Microvascular Angina ◽  
Microvascular Spasm ◽  
Receive Treatment ◽  
Registration Date

Abstract Background Pharmacological treatment of patients diagnosed with vasospastic angina (VSA) or microvascular angina (MVA) is challenging and often patients remain symptomatic. Endothelin (ET)-1 plays an important role in the regulation of the vascular tone and stimulation of ET-1 receptors can induce a potent and long-lasting vasoconstriction. Macitentan is a potent, inhibitor of the ETA receptor. Purpose This prospective, randomized, double-blind, placebo-controlled, sequential cross-over proof-of-concept trial is designed to investigate macitentan as a potential novel treatment for patients with VSA due to epicardial spasm or MVA due to microvascular spasm, together defined as coronary artery spasm (CAS).Methods and Results A total of 30 patients with CAS will receive treatment with either 10 mg of macitentan daily for 4 weeks followed by placebo for 4 weeks, or vice versa, in random order. The primary outcome is the reduction in angina, calculated as (1) the frequency of angina attacks * severity (on a VAS scale 1-10); and (2) the duration (in minutes) * severity (on a Visual Analogue Scale (VAS) pain scale 1-10) during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication. The primary analysis will assess the within-subject differences in the burden of anginal symptoms following treatment with macitentan versus placebo.Conclusions The VERA trial will be the first to evaluate the efficacy of the ETA receptor antagonist, macitentan, in the treatment of VSA due to epicardial spasm and MVA due to microvascular spasm.Trial Registration trialregister.nl, Identifier: NL7546. Registration date: 20 February 2019.

scholarly journals Disposition of MDMA and Metabolites in Human Sweat Following Controlled MDMA Administration

2009 ◽  
Vol 55 (3) ◽  
pp. 454-462 ◽  
Author(s):  
Allan J Barnes ◽  
Bruno S De Martinis ◽  
David A Gorelick ◽  
Robert S Goodwin ◽  
Erin A Kolbrich ◽  
...  
Keyword(s):  
Solid Phase ◽  
Random Order ◽  
Research Unit ◽  
Sweat Test ◽  
Test Results ◽  
Double Blind ◽  
Scientific Database ◽  
Sweat Testing ◽  
Clinical Research Unit ◽  
Sweat Tests

Abstract Background: Understanding the excretion of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites in sweat is vital for interpretation of sweat tests in drug treatment, criminal justice, and workplace programs. Methods: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were given double-blind in random order to healthy volunteers (n = 15) with histories of MDMA use. Participants resided on the closed clinical research unit for up to 7 days after each dose. Volunteers wore PharmChek® sweat patches (n = 640) before, during, and after controlled dosing. Patches were analyzed by solid phase extraction and GC-MS for MDMA, methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification (LOQ) were 2.5 ng/patch for MDMA and 5 ng/patch for HMA, HMMA, and MDA. Results: MDMA was the primary analyte detected in 382 patches (59.7%), with concentrations up to 3007 ng/patch. MDA was detected in 188 patches (29.4%) at <172 ng/patch, whereas no HMMA or HMA was detected; 224 patches (35.0%) and 60 patches (9.4%) were positive for MDMA and MDA, respectively, at the 25-ng/patch threshold proposed by the Substance Abuse and Mental Health Services Administration. Conclusions: Sweat testing was shown to be an effective and reliable method for monitoring MDMA use in this controlled MDMA administration study. However, variability in sweat excretion suggests that results should be interpreted qualitatively rather than quantitatively. These data provide a scientific database for interpretation of MDMA sweat test results.

Analysis of acute naproxen administration on memory in young adults: A randomized, double-blind, placebo-controlled study

2017 ◽  
Vol 31 (10) ◽  
pp. 1374-1376
Author(s):  
Jack H Wilson ◽  
Amy H Criss ◽  
Sean A Spangler ◽  
Katherine Walukevich ◽  
Sandra Hewett
Keyword(s):  
Young Adults ◽  
Healthy Adult ◽  
Adult Population ◽  
Critical Role ◽  
Random Order ◽  
Controlled Study ◽  
High Dose ◽  
Short Term ◽  
Double Blind ◽  
Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs work by non-selectively inhibiting cyclooxygenase enzymes. Evidence indicates that metabolites of the cyclooxygenase pathway play a critical role in the process of learning and memory. We evaluated whether acute naproxen treatment impairs short-term working memory, episodic memory, or semantic memory in a young, healthy adult population. Participants received a single dose of placebo or naproxen (750 mg) in random order separated by 7–10 days. Two hours following administration, participants completed five memory tasks. The administration of acute high-dose naproxen had no effect on memory in healthy young adults.

Symptomatic Treatment With Lanreotide Microparticles in Inoperable Bowel Obstruction Resulting From Peritoneal Carcinomatosis: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

2012 ◽  
Vol 30 (35) ◽  
pp. 4337-4343 ◽  
Author(s):  
Pascale Mariani ◽  
Joëlle Blumberg ◽  
Alain Landau ◽  
Daniela Lebrun-Jezekova ◽  
Estelle Botton ◽  
...  
Keyword(s):  
Peritoneal Carcinomatosis ◽  
Bowel Obstruction ◽  
Well Being ◽  
Symptomatic Treatment ◽  
Phase Iii ◽  
Primary Analysis ◽  
Open Label ◽  
Double Blind ◽  
Parallel Group ◽  
Intent To Treat

Purpose To investigate the somatostatin analog lanreotide as symptomatic treatment for inoperable bowel obstruction due to peritoneal carcinomatosis. Patients and Methods In all, 80 patients with peritoneal carcinomatosis, inoperable malignant digestive obstruction, and two or more vomiting episodes per day or nasogastric tube (NGT) who were previously treated with intravenous corticosteroids and proton pump inhibitors were randomly assigned to one 30-mg injection of lanreotide microparticles (n = 43) or placebo (n = 37) in a 10-day, double-blind, parallel-group phase. The primary end point was the proportion of patients responding on day 7 (one or fewer episodes of vomiting per day or no vomiting recurrence after NGT removal [for ≥ 3 consecutive days in both cases]). Vomiting frequency/NGT secretion volumes, nausea, abdominal pain, well-being, and safety were also assessed. Patients could then enter an open-label lanreotide-only phase. The study was conducted at 22 European hospitals. Results More patients receiving lanreotide than placebo were responders; this difference was not statistically significant for the intent-to-treat (ITT) population on the basis of diary cards (primary analysis; 41.9% [18 of 43] v 29.7% [11 of 37], respectively; odds ratio, 1.75; 95% CI, 0.68 to 4.49; P = .24) but was statistically significant for the corresponding supportive per protocol analysis (57.7% [15 of 26] v 30.4% [seven of 23]; P < .05) and ITT analysis, on the basis of investigators' assessments (50.0% [19 of 38] v 28.6% [10 of 35]; P < .05). Improvements in well-being were significantly greater with lanreotide on days 3, 6, and 7. No significant differences were observed for other secondary end points. Only two (mild/moderate) treatment-emergent adverse events were considered related to lanreotide. Conclusion These results show that lanreotide has some efficacy and is safe in the symptomatic treatment of patients with inoperable bowel obstruction due to peritoneal carcinomatosis.

scholarly journals Comparative Efficacy and Safety of Moxifloxacin and Clindamycin in the Treatment of Odontogenic Abscesses and Inflammatory Infiltrates: a Phase II, Double-Blind, Randomized Trial

2010 ◽  
Vol 55 (3) ◽  
pp. 1142-1147 ◽  
Author(s):  
Georg Cachovan ◽  
Rainer H. Böger ◽  
Ina Giersdorf ◽  
Olaf Hallier ◽  
Thomas Streichert ◽  
...  
Keyword(s):  
Comparative Efficacy ◽  
Primary Analysis ◽  
Double Blind ◽  
Once Daily ◽  
Odontogenic Infections ◽  
Perceived Pain ◽  
Clinical Responses ◽  
Efficacy Assessment ◽  
The Mean ◽  
Inflammatory Infiltrates

ABSTRACTMoxifloxacin penetrates well into oromaxillary tissue and covers the causative pathogens that show an increasing resistance to standard antibiotics. Clinical reports suggest that moxifloxacin may be effective for the treatment of odontogenic infections that can lead to serious complications. The objective of this prospective, randomized, double-blind, multicenter study was to compare the efficacies and safeties of moxifloxacin and clindamycin for the medical treatment of patients with gingival inflammatory infiltrates and as an adjuvant therapy for patients with odontogenic abscesses requiring surgical treatment. Patients received either 400 mg moxifloxacinper osonce daily or 300 mg clindamycinper osfour times daily for 5 days consecutively. The primary efficacy endpoint was the percent reduction in patients' perceived pain on a visual analogue scale at days 2 to 3 from baseline. Primary analysis included 21 moxifloxacin- and 19 clindamycin-treated patients with infiltrates and 15 moxifloxacin- and 16 clindamycin-treated patients with abscesses. The mean pain reductions were 61.0% (standard deviation [SD], 46.9%) with moxifloxacin versus 23.4% (SD, 32.1%) with clindamycin (P= 0.006) for patients with infiltrates and 55.8% (SD, 24.8%) with moxifloxacin versus 42.7% (SD, 48.5%) with clindamycin (P= 0.358) for patients with abscesses. A global efficacy assessment at days 2 to 3 and 5 to 7 showed faster clinical responses with moxifloxacin in both abscess and infiltrate patients. Rates of adverse events were lower in moxifloxacin- than in clindamycin-treated patients. In patients with inflammatory infiltrates, moxifloxacin was significantly more effective in reducing pain at days 2 to 3 of therapy than clindamycin. No significant differences between groups were found for patients with odontogenic abscesses.

scholarly journals Music for pain in healthy neonates

2021 ◽  
Vol 61 (2) ◽  
pp. 69-73
Author(s):  
Nessie Amelia Ramli ◽  
Afifa Ramadanti ◽  
Indrayady Indrayady ◽  
Yuli Doris Memy
Keyword(s):  
Heart Rate ◽  
Pain Perception ◽  
Periventricular Leukomalacia ◽  
Pain Scale ◽  
Injection Pain ◽  
Medical Procedure ◽  
Music Intervention ◽  
Older Children ◽  
Double Blind ◽  
Infant Pain

Background The neonatal pain threshold is 30-50% lower than in adults and older children because of immature pain inhibition function in nervous centers. Acute pain in neonates results in behavioral, physiological, and cerebral blood flow changes that may lead to intraventricular bleeding and periventricular leukomalacia. Music is believed to reduce pain perception as it distracts, influencing the parasympathetic and sympathetic nervous system by decreasing pulse rate, blood pressure, and breathing, hence, promoting a relaxed state. Objective To evaluate effects of music intervention on physiological parameters and pain perception in healthy newborns undergoing a painful medical procedure (immunization injection). Methods This was a double-blind, randomized control trial study. A recorded instrumental lullaby “Nina Bobo” was given for 5 minutes to the music group and no music for control, prior injection of Hepatitis B 0. The evaluation of heart rate and SpO2 were performed at baseline, 30 seconds, and 5 minutes after injection. Pain perception were measured by Neonatal Infant Pain Scale (NIPS) at 30 seconds and 5 minutes after injection. Results Total of 51 subjects were enrolled. There were no difference of SpO2 and NIPS between both music and control groups. Music improved heart rate after 30 seconds and 5 minutes after injection,  median 126 (range 55-149) bpm from median 136 (range 78-154) bpm, and even lower than baseline [mean 128.9 (SD 12.5) bpm; P=0.019]. The control showed no improvement of heart rate mean 124,34 (SD 18,45) from 124,73 (SD 18,39); P=0.875There were no significant differences between the 2 groups. Conclusion Music is not effective in improving oxygen saturation, heart rate, and is not effective in reducing the degree of pain.

Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 240-240
Author(s):  
Neal D. Shore ◽  
Karim Fizazi ◽  
Teuvo Tammela ◽  
Murilo Luz ◽  
Manuel Philco Salas ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Safety Profile ◽  
Final Analysis ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Open Label ◽  
Double Blind ◽  
Secondary Endpoints ◽  
The Impact

240 Background: DARO is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) based on significantly prolonged metastasis-free survival compared with PBO (median 40.4 vs 18.4 months; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.0001) and a favorable safety profile in the phase III ARAMIS trial. Following unblinding at the primary analysis, crossover from PBO to DARO was permitted for the subsequent open-label treatment phase. Sensitivity analyses were performed to assess the effect of PBO–DARO crossover on OS benefit. Methods: Patients (pts) with nmCRPC receiving androgen deprivation therapy were randomized 2:1 to DARO (n = 955) or PBO (n = 554). In addition to OS, secondary endpoints included times to pain progression, first cytotoxic chemotherapy, first symptomatic skeletal event, and safety. The OS analysis was planned to occur after approximately 240 deaths, and secondary endpoints were evaluated in a hierarchical order. Iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses were performed as pre-planned sensitivity analyses to adjust for the treatment effect of PBO–DARO crossover. The IPE method used a parametric model for the survival times and iteratively determined the model parameter describing the magnitude of the treatment effect, whereas a grid search and non-parametric log-rank test were used for the RPSFT analysis. The IPE and RPSFT analyses both generated a Kaplan–Meier curve for the PBO arm that predicts what would have been observed in the absence of PBO–DARO crossover. Results: After unblinding, 170 pts (30.7% of those randomized to PBO) crossed over from PBO to DARO; median treatment duration from unblinding to the final data cut-off was 11 months. Final analysis of the combined double-blind and open label periods was conducted after 254 deaths (15.5% of DARO and 19.1% of PBO pts) and showed a statistically significant OS benefit for DARO vs PBO (HR 0.69; 95% CI 0.53–0.88; P = 0.003). Results from the IPE (HR 0.66; 95% CI 0.51–0.84; P < 0.001) and RPSFT (HR 0.68; 95% CI 0.51–0.90; P = 0.007) analyses were similar to those from the intention-to-treat population, showing that the impact of PBO–DARO crossover was small. Additional analyses accounting for the effect of PBO–DARO crossover will be presented. The safety profile of DARO continued to be favorable at the final analysis, and discontinuation rates at the end of the double-blind period remained unchanged from the primary analysis (8.9% with DARO and 8.7% with PBO). Conclusions: Early treatment with DARO in men with nmCRPC is associated with significant improvement in OS regardless of pts crossing over from PBO to DARO. The safety profile of DARO remained favorable at the final analysis. Clinical trial information: NCT02200614.

Coronary artery spasm and microvascular angina

2019 ◽  
pp. 107-122
Author(s):  
Peter Ong ◽  
Udo Sechtem
Keyword(s):  
Coronary Artery ◽  
Coronary Artery Spasm ◽  
Coronary Spasm ◽  
Pharmacological Therapy ◽  
Coronary Microvascular Dysfunction ◽  
Channel Blockers ◽  
Pharmacological Management ◽  
Microvascular Angina ◽  
Drug Classes ◽  
Coronary Abnormalities

Ischaemic heart disease comprises a variety of coronary abnormalities, ranging from obstructive atherosclerotic stenoses to functional coronary vasomotor disorders. The latter comprise coronary spasm, as well as coronary microvascular dysfunction. Importantly, structural and functional abnormalities can coexist in a given patient, making it sometimes difficult to determine the underlying cause of angina. Thus, diagnostic algorithms should not only consider the evaluation of atherosclerotic epicardial disease, but also look for the presence of functional coronary disorders. This holds especially true for patients in whom obstructive coronary disease has been excluded, as many of these patients are labelled as having ‘non-cardiac chest pain’. Such an approach may enable the treating physician to adjust the pharmacological therapy more appropriately, in order to improve symptoms and prognosis. Often drug classes such as calcium channel blockers and nitrates are beneficial in these patients. This chapter gives an overview on the current pharmacological management of patients with coronary artery spasm and those suffering from microvascular angina.

scholarly journals A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
John DeVincenzo ◽  
Dereck Tait ◽  
John Efthimiou ◽  
Julie Mori ◽  
Young-In Kim ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Adverse Events ◽  
Disease Severity ◽  
Controlled Trial ◽  
Primary Analysis ◽  
Double Blind ◽  
Challenge Virus ◽  
F Protein ◽  
Syncytial Virus

ABSTRACT Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo orally every 12 h for 5 days. The primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR) of nasal wash samples. The primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. A total of 66 subjects were enrolled (n = 22 per group); 53 were included in the primary analysis set (RV521 350 mg: n = 16; 200 mg: n = 18; placebo: n = 19). The mean AUC of RT-qPCR-assessed RSV viral load (log10 PFU equivalents [PFUe]/ml · h) was significantly lower with RV521 350 mg (185.26; standard error [SE], 31.17; P = 0.002) and 200 mg (224.35; SE, 37.60; P = 0.007) versus placebo (501.39; SE, 86.57). Disease severity improved with RV521 350 mg and 200 mg versus placebo (P = 0.002 and P = 0.009, respectively, for AUC total symptom score [score × hours]). Daily nasal mucus weight was significantly reduced (P = 0.010 and P = 0.038 for RV521 350 mg and 200 mg, respectively, versus placebo). All treatment-emergent adverse events were grade 1 or 2. No subjects discontinued due to adverse events. There was no evidence of clinically significant viral resistance, and only three variants were detected. RV521 effectively reduced RSV viral load and disease severity in humans and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT03258502.)

scholarly journals The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD)

2019 ◽  
Vol 33 (9) ◽  
pp. 1141-1148 ◽  
Author(s):  
Charlotte M Pretzsch ◽  
Bogdan Voinescu ◽  
Maria A Mendez ◽  
Robert Wichers ◽  
Laura Ajram ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Functional Connectivity ◽  
Low Frequency ◽  
Random Order ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Double Blind ◽  
Drug Challenge ◽  
The Right ◽  
Post Hoc

Background: The potential benefits of cannabis and its major non-intoxicating component cannabidiol (CBD) are attracting attention, including as a potential treatment in neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the neural action of CBD, and its relevance to ASD, remains unclear. We and others have previously shown that response to drug challenge can be measured using functional magnetic resonance imaging (fMRI), but that pharmacological responsivity is atypical in ASD. Aims: We hypothesized that there would be a (different) fMRI response to CBD in ASD. Methods: To test this, task-free fMRI was acquired in 34 healthy men (half with ASD) following oral administration of 600 mg CBD or matched placebo (random order; double-blind administration). The ‘fractional amplitude of low-frequency fluctuations’ (fALFF) was measured across the whole brain, and, where CBD significantly altered fALFF, we tested if functional connectivity (FC) of those regions was also affected by CBD. Results: CBD significantly increased fALFF in the cerebellar vermis and the right fusiform gyrus. However, post-hoc within-group analyses revealed that this effect was primarily driven by the ASD group, with no significant change in controls. Within the ASD group only, CBD also significantly altered vermal FC with several of its subcortical (striatal) and cortical targets, but did not affect fusiform FC with other regions in either group. Conclusion: Our results suggest that, especially in ASD, CBD alters regional fALFF and FC in/between regions consistently implicated in ASD. Future studies should examine if this affects the complex behaviours these regions modulate.

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