Currently, there is no short-acting, nonparenteral drug available for the acute termination of supraventricular tachycardia (SVT) that can be self-administered. Etripamil is a new intranasal calcium-channel blocker designed for self-administration to rapidly terminate SVT episodes. A phase 2 clinical trial tested the efficacy and safety of etripamil nasal spray in terminating induced SVT in electrophysiology laboratories. The study found that etripamil converted 65% to 95% of SVTs to sinus rhythm within 15 minutes, significantly higher than the 35% conversion rate for placebo. Etripamil had a median conversion time of less than 3 minutes and its safety profile was acceptable
How to Improve the Accuracy of the Initial Evaluation, Using a System Developed By Johns Hopkins Hospital Doctors by Nelson Hendler in Examines in Physical Medicine & Rehabilitation
EMGuideWire's Radiology Reading Room: Spontaneous PneumothoraxSean M. Fox
The Department of Emergency Medicine at Carolinas Medical Center is passionate about education! Dr. Michael Gibbs is a world-renowned clinician and educator and has helped guide numerous young clinicians on the long path of Mastery of Emergency Medical Care. With his oversight, the EMGuideWire team aim to help augment our understanding of emergent imaging. You can follow along with the EMGuideWire.com team as they post these monthly educational, self-guided radiology slides or you can also use this section to learn more in-depth about specific conditions and diseases. This Radiology Reading Room pertains to Spontaneous Pneumothorax and is brought to you by Elizabeth Olson, MD, and Janet Lorenz, NP.
How to Improve the Accuracy of the Initial Evaluation, Using a System Developed By Johns Hopkins Hospital Doctors by Nelson Hendler in Examines in Physical Medicine & Rehabilitation
EMGuideWire's Radiology Reading Room: Spontaneous PneumothoraxSean M. Fox
The Department of Emergency Medicine at Carolinas Medical Center is passionate about education! Dr. Michael Gibbs is a world-renowned clinician and educator and has helped guide numerous young clinicians on the long path of Mastery of Emergency Medical Care. With his oversight, the EMGuideWire team aim to help augment our understanding of emergent imaging. You can follow along with the EMGuideWire.com team as they post these monthly educational, self-guided radiology slides or you can also use this section to learn more in-depth about specific conditions and diseases. This Radiology Reading Room pertains to Spontaneous Pneumothorax and is brought to you by Elizabeth Olson, MD, and Janet Lorenz, NP.
The Midwest Stroke Action Alliance recently hosted a panel of health experts on the risks of venous thromboembolism (VTE which is commonly referred to as blood clots).
The health experts on the panel were:
- Mark J. Alberts, MD (Clinical Vice-Chair for Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center)
- Laurie Paletz, BSN, PHN, RN-BC (Stroke Program Coordinator, Cedars-Sinai Medical Center)
- Michael W. Wong, JD (Executive Director, Physician-Patient Alliance for Health & Safety)
Stroke is a leading cause of death and disability in the U.S., with 800,000 cases occurring each year. Each year in the United States, an estimated 300,000 cases of VTE occur. Mortality can be as high as 3.8 percent in patients with deep vein thrombosis (DVT) and 38.9 percent in those with pulmonary embolism (PE). VTE is associated with a high risk of death in the U.S. and Europe, with an estimated incidence rate of 1 in 1,000 patients. VTE is particularly common after a stroke. Approximately 20 percent of hospitalized immobile stroke patients will develop DVT, and 10 percent a PE.
"Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury, Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD"
Propofol versus dexmedetomidine in reducing emergence agitation after sevoflurane anaesthesia
Authors:Anurag kondum , SS kang , Ajit Bhardwaj, Shivinder Singh
Int J Biol Med Res. 2024; 15(1): 7731-7734
Abstract:
Propofol versus Dexmedetomidine in Reducing Emergence Agitation after Sevoflurane Anaesthesia Original Article Abstract Introduction - Emergence agitation (EA) is defined as a state of disorientation associated with confusion, restlessness, involuntary movements, and inconsolability. EA causes an increased risk of postoperative complications. This study compares the effectiveness of dexmedetomidine and propofol in preventing EA in children undergoing surgeries using sevoflurane anesthesia. Methods -This prospective randomized double-blind study was conducted from March 2022 to Oct 2023. A total of one hundred were included in the study and randomized to two groups. One group received dexmedetomidine and the other propofol to prevent EA. Pain scores, agitation scores, and sedation levels were compared as per study protocol between the two groups. Results- In our study incidence of EA was higher in the dexmedetomidine (n = 13) group in comparison to the propofol group (n = 5) (p<0.05). A significantly lower mean Observational Pain Score (OPS)was observed among the dexmedetomidine group as compared to the propofol group after extubation (p < 0.05). Also, . Post extubation mean heart rate was significantly lower in Dexmedetomidine group as compared to Propofol Group. Conclusion- Dexmedetomidine may provide significant benefits in providing post-op pain relief in comparison to propofol however incidence of emergence agitation appears to be higher with dexmedetomodine when compared to propofol as found in this study. Larger, randomized multicentre trials with appropriate sample sizes will be required to further evaluate the efficiency of these drugs in the prevention of EA.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
2. Currently, there is no short-acting,
nonparenteral drug available for
the acute termination of supraven-
tricular tachycardia (SVT) that can be self-
administered. Such a drug would provide
individuals the ability to rapidly terminate
SVT episodes without the need to visit a
health care facility.
Etripamil (Milestone Pharmaceuticals,
Montreal St.-Laurent, Quebec, Canada) is a
short-acting L-type calcium-channel blocker
with a rapid onset of action designed for intranasal
administration. It has been formulated as a nasal
spray for self-administration by patients who expe-
rience SVT recurrences. It has a high potency and a
short first half-life of about 20 min. Like other non-
dihydropyridine calcium-channel blockers, etripamil
slows atrioventricular nodal conduction and prolongs
atrioventricular nodal refractory periods by inhibiting
calcium ion influx through the calcium slow channels
in the atrioventricular node cells. A phase 1 trial in
healthy volunteers demonstrated that intranasal
administration of etripamil was well tolerated and
caused a dose-dependent PR interval prolongation
indicative of the desired pharmacological effect on
atrioventricular nodal conduction. There was no
observed prolongation of QRS or Fredericia-corrected
QT interval.
NODE-1 (Efficacy and Safety of Intranasal MSP-2017
[Etripamil] for the Conversion of PSVT to Sinus
Rhythm) was a phase 2 study designed to demon-
strate the superiority of etripamil over placebo for the
acute termination of SVT in the electrophysiology
laboratory, evaluate the safety of etripamil, and
identify dose(s) to be tested in future phase 3 studies
to be conducted outside the hospital environment.
METHODS
STUDY DESIGN AND PATIENTS. NODE-1 (NCT02296190)
was a multicenter, randomized, double-blind, placebo-
controlled, dose-ranging study designed to evaluate
the effects of etripamil nasal spray in male and female
patients 18 years of age and older with documented
histories of SVT who were scheduled to undergo elec-
trophysiological studies prior to planned catheter
ablation. The exclusion criteria were a history of
adverse reaction to intravenous (IV) verapamil, a sig-
nificant or chronic condition of the nasal cavity that
would interfere with intranasal drug administration,
systolic blood pressure (SBP) <100 mm Hg or diastolic
blood pressure <50 mm Hg at screening or at the treat-
ment visit, history or evidence of congestive heart
failure (except New York Heart Association functional
class I) or pulmonary edema, a prolonged Bazett-
corrected QT interval (>455 ms), ventricular pre-
excitation, second- or third-degree atrioventricular
block, pregnancy, breastfeeding, failure to agree to
use an acceptable form of contraception, concomitant
use of certain medications (e.g., digoxin, class I to IV
antiarrhythmic drug), and documentation of an
arrhythmia other than SVT.
This study was carried out in accordance with In-
ternational Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for
Human Use and Good Clinical Practice guidelines. All
sites obtained Institutional Review Board or ethics
committee approval, and study-specific procedures
were not conducted until after patient informed con-
sent was obtained. A complete list of study sites and
primary investigators is available in the Online
Appendix.
RANDOMIZATION. During a pre-study visit patients
were randomly assigned to 1 of the 5 following study
groups in a 1:1:1:1:1 ratio using an interactive web
response system: placebo or etripamil at 35, 70, 105,
or 140 mg.
BASELINE ELECTROPHYSIOLOGICAL STUDY DATA
COLLECTION. Before attempted induction of SVT,
vital signs, consisting of blood pressure and heart rate,
were recorded, and a continuous surface rhythm strip
was obtained. Baseline vital signs were the averages of
the measurements taken 10 and 20 min before SVT
induction, and the time 0 vital signs were the averages
of the measurements during SVT between 5 and 0 min
before study drug administration. Sedation could be
given during the study via single or multiple admin-
istrations using minimally necessary doses of benzo-
diazepines and/or narcotics at the investigator’s
discretion, but a continuous sedative or analgesic or
inhaled anesthetic drug was not permitted until min-
ute 30 after study drug administration.
SVT INDUCTION. Induction of SVT was attempted
using standard pacing and programmed stimulation
methods. If SVT could not be induced after a
reasonable number of attempts, or could be induced
but did not sustain for 5 min, IV isoproterenol was
infused at a rate of 1 mg/min, and attempts to induce
SVT were repeated. If SVT induction was unsuccess-
ful with isoproterenol 1 mg/min, the infusion rate
could be increased. If isoproterenol was used, a sur-
face rhythm strip was collected once the heart rate
had stabilized. If induction was successful with
SEE PAGE 498
A B B R E V I A T I O N S
A N D A C R O N Y M S
AVRT = atrioventricular
reciprocating tachycardia
CI = confidence interval
IV = intravenous
OR = odds ratio
PSVT = paroxysmal
supraventricular tachycardia
SBP = systolic blood pressure
SVT = supraventricular
tachycardia
Stambler et al. J A C C V O L . 7 2 , N O . 5 , 2 0 1 8
Conversion of Tachycardia With Etripamil Nasal Spray J U L Y 3 1 , 2 0 1 8 : 4 8 9 – 9 7
490
3. isoproterenol, the infusion was continued at 1 mg/min
for 5 min of sustained SVT and continuing for either
15 min after study drug administration or until
termination of SVT, whichever occurred first.
STUDY DRUG ADMINISTRATION. After a minimum of
5 min in sustained SVT, electrophysiology laboratory
personnel administered the study drug to the patient
using 4 prefilled Aptar Pharma unit-dose spray de-
vices via alternating nares over 30 s or less. Each
device delivered 100 ml of placebo or 35 mg of etri-
pamil. The appropriate combination of 4 devices
containing active compound or placebo was used to
deliver the assigned, randomized dose of etripamil (0,
35, 70, 105, or 140 mg). The devices were prefilled,
packaged into drug kits, and administered in a spe-
cific order, with sprays of etripamil delivered before
sprays containing placebo.
ASSESSMENTS AFTER STUDY DRUG ADMINISTRATION.
Starting at time 0, vital signs were recorded every
2 min for 30 min, and the cardiac rhythm was
continuously monitored. A successful conversion was
defined as conversion of SVT to sinus rhythm lasting
at least 30 s within 15 min after study drug adminis-
tration. For patients who did not convert within
15 min after study drug administration, SVT was then
terminated by standard intracardiac stimulation
techniques. Surface rhythm strips were collected in
all patients at the time of conversion and at 15 min
after study drug administration. At any time beyond
30 min after study drug administration, the patient’s
scheduled ablation (outside the scope of this study)
could be performed at the discretion of the treating
physician.
FOLLOW-UP PROCEDURES. From 12 h to 5 days after
the procedure, physical examination, assessment of
vital signs, 12-lead electrocardiography, and clinical
laboratory analysis were performed. Adverse events
and concomitant medications were recorded.
STATISTICAL METHODS. Efficacy analyses were
performed in randomized patients in whom SVT was
induced and sustained for 5 min, had received study
drug, and completed the assessment of conversion to
sinus rhythm (i.e., evaluable population). Safety an-
alyses were based on all randomized patients who
were induced into SVT and received study drug.
Sample size determination. It was expected that
there would be a 50 percentage point difference in the
SVT conversion rate between patients receiving pla-
cebo and any dose of etripamil within 15 min after
study drug administration (i.e., 30% for placebo, 80%
for etripamil). Accounting for a 2-sided test with a
type I error rate of a ¼ 0.05, 20 patients per group
provided 84% power when using the Fisher exact
test. Therefore, a sample size of at least 100 evaluable
patients (i.e., at least 20 evaluable patients per group)
was considered appropriate to meet study objectives.
Statistical analyses. The primary efficacy endpoint
was the rate of successful SVT conversion to sinus
rhythm lasting at least 30 s within 15 min of study
drug administration. The primary efficacy analysis
was performed using the Fisher exact test to compare
the conversion rate between each etripamil group and
the placebo group. To control the type I error rate of
a ¼ 0.05, a hierarchical procedure was used for hy-
pothesis testing. The hierarchy first compared the
conversion rate in the highest etripamil dose (140 mg)
versus placebo; if that comparison resulted in a
p value <0.05, the next highest etripamil dose
(105 mg) was compared with placebo. These com-
parisons continued in a stepwise fashion until either
all doses were tested or a comparison yielded a
p value of $0.05, in which case all doses prior to that
comparison were considered to have statistically
significant conversion rates versus placebo. A 2-sided
test with a significance level of 0.05 was used for each
comparison. The odds ratio (OR), 95% confidence in-
terval (CI), and p value for the OR were calculated and
tabulated for each pairwise treatment comparison.
Conversion rates were analyzed using a Cochran-
Mantel-Haenszel test and stratified by isoproterenol
to test for an association between treatment and
conversion rate. Secondary and exploratory efficacy
analyses were performed as follows. 1) The Cochran-
Armitage test for trend was used to assess the
presence of an association between conversion rate
and the etripamil dose groups. 2) The dose-response
relationship (percentage conversion at time 15) was
assessed using a generalized linear model with logit
link and binomial distribution. 3) Time to conversion
was summarized for patients whose SVT was suc-
cessfully converted to sinus rhythm after study drug
administration. The distribution of conversion times
from initiation of treatment to SVT termination and
conversion to sinus rhythm during a 15-min period of
observation was estimated using the Kaplan-Meier
method. Patients who did not convert within 15 min
after study drug administration were censored at that
time point. In a post hoc analysis, the hazard ratio and
95% CI were based on a Cox proportional hazards
regression model with treatment as a factor. 4) The
interaction test between etripamil and isoproterenol
was carried out in an analysis-of-covariance model.
Continuous safety data are summarized with
descriptive statistics. Discrete safety data are sum-
marized with frequency counts.
J A C C V O L . 7 2 , N O . 5 , 2 0 1 8 Stambler et al.
J U L Y 3 1 , 2 0 1 8 : 4 8 9 – 9 7 Conversion of Tachycardia With Etripamil Nasal Spray
491
4. RESULTS
BASELINE PATIENT CHARACTERISTICS. A total of
199 patients were randomized into the double-blind
study; 95 patients withdrew prior to dosing: 70
patients because of inability to induce (n ¼ 42) or
sustain (n ¼ 28) SVT, 5 patients on the basis of
physician discretion, 1 patient lost to follow-up, 1
because of withdrawal of consent, and 18 patients for
other reasons. A total of 104 patients had SVT induced
and sustained for $5 min and were dosed with study
drug. The median age was 55.0 years (mean 52.2;
range: 19 to 85 years), and the median body mass
index was 28.57 kg/m2
(mean 29.35 kg/m2
; range: 19.0
to 64.1 kg/m2
). Overall, there were more female than
male patients (n ¼ 59 [56.7%] vs. n ¼ 45 [43.3%],
respectively). The predominant races were white
(80.8%) and black or African American (12.5%). There
were no imbalances in baseline characteristics across
the 5 treatment groups. Isoproterenol was given to
46.2% of patients. The mean heart rate in SVT at time
0 was 177 beats/min in the placebo group and 168,
173, 180, and 155 beats/min in the etripamil 35-, 70-,
105-, and 140-mg groups, respectively. The mecha-
nism of induced SVT was atrioventricular nodal
re-entrant tachycardia in 87% of patients. A total of
29 sites dosed patients. Twenty-six sites dosed be-
tween 1 and 5 patients, and 3 sites dosed between 10
and 13 patients (i.e., 33% of the study population).
The percentage of patients dosed by number of
patients per site is shown in Figure 1.
EFFICACY. Conversion rates from SVT to sinus
rhythm. Of the 104 patients in the evaluable popu-
lation, 20 received etripamil 35 mg, 23 received
70 mg, 20 received 105 mg, 21 received 140 mg, and 20
received placebo. The percentages of patients in
whom SVT converted to sinus rhythm within 15 min
after study drug administration and in whom sinus
rhythm was maintained for at least 30 s (primary ef-
ficacy endpoint) were 35%, 65%, 87%, 75%, and 95%
in the placebo and etripamil 35-, 70-, 105-, and 140-
mg groups, respectively (Table 1). Applying the pre-
specified hierarchy for determining significance, the
3 highest etripamil doses of 140, 105, and 70 mg
showed statistically significant higher conversion
rates compared with placebo, with respective
conversion rate differences from placebo of 60%
(OR: 37.14; 95% CI: 3.84 to 1,654.17; p < 0.0001),
40% (OR: 5.57; 95% CI: 1.19 to 27.63; p ¼ 0.0248),
and 52% (OR: 12.38; 95% CI: 2.28 to 82.26;
p ¼ 0.0006). There was a statistically significant
trend between treatment with etripamil and
conversion to sinus rhythm (p < 0.0001, Cochran-
Armitage test). A maximal-efficacy dose-response
model best fit the dose-response relationship; the
conversion rate increased with the dose with a steep
slope until 70 mg and reached a plateau at higher
doses (Figure 2).
Overall, no differences in conversion rates were
observed on the basis of the administration or lack of
administration of isoproterenol.
Time to conversion from SVT to sinus rhythm. For the 3
etripamil doses with statistically significant conver-
sion rates compared with placebo (70, 105, and
140 mg), the time at which 50% of patients converted
FIGURE 1 Percentage of the Study Population Dosed by the
Number of Patients Dosed per Site
24%
7%
15%
6%
15%
33%
Number of Patients Dosed per Site
2 3 4 5 7 10-13
3 sites dosed 10, 11, and 13 patients (i.e., 33% of the total
number of dosed patients); 5 sites dosed 5 patients (i.e., 24%
of the total number of dosed patients); 21 sites dosed 1 to 4
patients (i.e., 43% of the total number of dosed patients).
TABLE 1 Summary of Conversion of Induced, Sustained Supraventricular Tachycardia to
Sinus Rhythm Within 15 min After Study Drug Administration
Placebo
(n ¼ 20)
Etripamil
35 mg
(n ¼ 20)
Etripamil
70 mg
(n ¼ 23)
Etripamil
105 mg
(n ¼ 20)
Etripamil
140 mg
(n ¼ 21)
Patients converted
to sinus rhythm
7 (35) 13 (65) 20 (87) 15 (75) 20 (95)
p value (vs. placebo),
Fisher exact test
0.1128 0.0006 0.0248 <0.0001
Values are n (%).
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492
5. was <3 min, with the shortest time in the etripamil
140-mg group (1.8 min). Because only 35% patients
converted to sinus rhythm within 15 min in the pla-
cebo group, the time at which 50% of patients con-
verted cannot be determined.
Distribution of time to conversion for each patient
is reported as a Kaplan-Meier plot (Figure 3). Patients
who did not convert within 15 min after study drug
administration were censored at 15 min. On the basis
of a Cox proportional hazards regression model with
treatment as a factor, the 3 highest etripamil doses of
140, 105, and 70 mg showed statistically significant
shorter time to conversion compared with placebo
(Table 2).
SAFETY. At least 1 adverse event, per patient,
considered related to the study drug according to the
investigators’ assessment, was reported in 17 patients
(85.0%) in the etripamil 35-mg group, 18 (78.3%) in
the 70-mg group, 15 (75.0%) in the 105-mg group, 20
(95.2%) in the 140-mg group, and 4 (20.0%) in the
placebo group. The incidence of adverse events was
not dose dependent.
Most adverse events were mild (44.2%) or moder-
ate (24.0%) across all treatment groups. A total of 3
severe adverse events were considered possibly
related to etripamil. One patient who received 35 mg
experienced facial flushing, shortness of breath, and
chest discomfort; 1 patient who received 105 mg had
nausea and vomiting; and 1 patient who received
105 mg had a serious adverse event of cough. There
were no adverse events that led to study discontin-
uation or death.
Adverse events that occurred with an incidence of
>10% in any etripamil group and $10% in the placebo
group were nasal discomfort, nasal congestion,
oropharyngeal pain, rhinorrhea, cough, dysgeusia,
increased lacrimation, vomiting, and nausea. One
patient had an episode of second-degree atrioven-
tricular block with hypotension beginning 5 min after
conversion to sinus rhythm immediately following
administration of etripamil 140 mg, which resolved
after 43 min, and ablation was subsequently
performed.
Vital signs were recorded before induction into
SVT and every 2 min for 30 min after study drug was
given. The mean SBP decreased from the baseline
measurements (20 and 10 min before SVT induction)
to measurements done while in SVT before study
drug administration (time 0). Compared with baseline
prior to SVT induction, SBP measurements recorded
from 2 to 16 min after study drug administration
demonstrated no statistically significant decrease in
mean SBP in the placebo, 35-mg, and 70-mg groups,
and a maximum statistically significant decrease of
17 mm Hg 6 min post-dose when 65% of the patients
were in sinus rhythm in the 105-mg group, and
20 mm Hg 6 min post-dose when 80% of the patients
were in sinus rhythm in the 140-mg group. There was
no decrease in mean SBP compared with baseline
from 16 to 30 min after study drug administration
when all the patients were in sinus rhythm (Figure 4).
In the placebo group and the combined active
substance groups, the minimum mean heart rates
(84.7 and 82.4 beats/min, respectively) were similar.
The minimum heart rate in any individual patient
occurring within 30 min after study drug adminis-
tration was 58 beats/min in the placebo group and 70,
55, 71, and 47 beats/min in the etripamil 35-, 70-, 105-,
and 140-mg groups, respectively. There was no sta-
tistically significant change between baseline and
15 min post-dose in mean Bazett-corrected QT
intervals.
DISCUSSION
In this study, the 3 highest doses of etripamil tested
demonstrated the ability to terminate SVT with very
high and statistically significant conversion rates
compared with placebo (Central Illustration). The
median time to conversion for each of the etripamil
doses was <3 min. From an efficacy standpoint, this
makes this intranasal calcium-channel blocker an
FIGURE 2 Etripamil Dose Response Maximal Efficacy Model
0 4020 60
Etripamil Dose mg
%PatientsSuccessfullyConverted
Emax Model (E0 = 1-Emax; D50 = 32.5; Emax = 0.65) R2
= 0.915
10080 120 140
50
40
30
80
90
70
60
100
Actual % Conversion Emax Model Curve
D50 ¼ dose (milligrams) related to 50% of the maximal effect; E0 ¼ placebo effect;
Emax ¼ maximal efficacy.
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6. excellent drug candidate to fill the existing gap in
therapy for the rapid termination of SVT outside of
the health care setting. Judicious selection of etripa-
mil doses in future studies may be able to mitigate
decreases in SBP, which occurred most often and for
the longest duration in the etripamil 140-mg group.
During the course of the study it was recognized
that the discomfort and cough possibly related to the
presence of the drug in the throat could be dramati-
cally reduced by elevating the head of the bed to 30
,
keeping the chin close to the chest, and trying to
avoid inhaling or swallowing the drug. It is conceiv-
able that providing patients with this information
could reduce or eliminate these adverse events in the
future.
ETRIPAMIL PHARMACOLOGY AND CHARACTERISTICS.
Etripamil is a short-acting, phenylalkylamine class
L-type calcium-channel blocker. It follows a 2-
compartment pharmacokinetic model with a time
to maximum plasma concentration of approximately
8 min and a mean first half-life of about 20 min across
all doses tested when administered intranasally. The
drug is metabolized by ubiquitous serum esterases,
and the major metabolite is an inactive carboxylic
acid. Dose-dependent side effects (nasal congestion,
oropharyngeal pain) are most likely related to the
intranasal route of administration. Neither animal nor
human studies demonstrated prolongation of the QRS
duration or corrected QT interval. The shelf life of
etripamil is 1 year.
FIGURE 3 Kaplan-Meier Plot of Conversion 15 min After Study Drug Administration
0 5
Time Since First Study Drug Administration (Minutes)
CumulativeConversionRate(%)
10 15
+
+ censored
+
+
+
+
20 16 14 13
20 9 7 6
23 4 3 2
20 7 5 4
21
Placebo
35 mg
70 mg
105 mg
140 mg
Number at risk:
etripamil
etripamil
etripamil
etripamil 4 3 1
0.4
0.2
0.0
1.0
0.8
0.6
Placebo Etripamil 35 mg Etripamil 70 mg
Etripamil 105 mg Etripamil 140 mg
Patients who did not convert within 15 min after study drug administration were censored at 15 min.
TABLE 2 Survival Analysis of Patients Converted to Sinus Rhythm at 15 min After Study
Drug Administration
Placebo
(n ¼ 20)
Etripamil
35 mg
(n ¼ 20)
Etripamil
70 mg
(n ¼ 23)
Etripamil
105 mg
(n ¼ 20)
Etripamil
140 mg
(n ¼ 21)
Patients converted 7 (35.0) 13 (65.0) 20 (87.0) 15 (75.0) 20 (95.2)
Patients censored* 13 (65.0) 7 (35.0) 3 (13.0) 5 (25.0) 1 (4.8)
Kaplan-Meier estimate,
min
Q1 7.08 2.28 1.57 2.13 1.23
Median NC 4.38 2.82 3.54 1.92
95% CI 6.07–NC 2.20–NC 1.63–3.25 2.07–8.13 1.23–2.90
Q3 NC NC 3.88 NC 3.27
Treatment comparison
(vs. placebo)†
Hazard ratio 2.43 4.99 3.13 6.67
95% CI for hazard ratio 0.97–6.11 2.09–11.93 1.27–7.71 2.79–15.94
p value 0.0587 0.0003 0.0131 0.0001
Values are n (%) unless otherwise indicated. *Patients who did not convert within 15 min after study drug
administration are censored at 15 min after study drug administration. †The hazard ratio and 95% CI are based on
a Cox proportional hazards regression model with treatment as a factor.
CI ¼ confidence interval; Median ¼ time to conversion of 50% of the patients; NC ¼ not calculated; Q1 ¼ 25th
percentile; Q3 ¼ 75th percentile.
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494
7. CURRENT TREATMENTS FOR SVT. All medications
currently approved for the acute termination of SVT
must be administered in the presence of a trained
health care professional and require the establish-
ment of IV access along with real-time rhythm
monitoring. IV beta-blockers and calcium-channel
blockers are effective for acute treatment in patients
with hemodynamically stable SVT. Oral beta-blockers
and calcium-channel blockers alone or in combina-
tion may be self-administered (“pill-in-the-pocket”)
for acute treatment of well-tolerated SVT, with mean
times to conversion of approximately 30 min or
longer, but the overall efficacy and safety of the self-
administration of these medications remains unclear
because of the lack of scientific evidence and poten-
tial risk for hypotension and/or syncope (1,2). Anti-
arrhythmic drugs such as flecainide, which are not
approved for this indication, have been used as a
“pill-in-pocket” strategy (3), but with small studies
showing variable conversion rates of about 50%,
often approximating the placebo conversion rate.
Mean conversion times were 1 h or longer, although
by 2 h up to 80% of patients may spontaneously
convert. Additionally, multiple factors limit the abil-
ity to prescribe these and other antiarrhythmic drugs:
known or suspected coronary artery disease, left
ventricular dysfunction, borderline or prolonged QT
interval, and unfavorable or unknown metabolizer
status.
FUTURE EVALUATION. Etripamil will need to be
evaluated in future studies that are performed
outside of the electrophysiology laboratory in
nonsupine, nonsedated patients to confirm its
efficacy in a real-world environment and to demon-
strate an appropriate safety profile for self-
administration without medical supervision. The
observed balance between efficacy and safety in
the 70-mg group makes this dose a good candidate
for future studies.
STUDY LIMITATIONS. This study was carried out
during an electrophysiology study prior to a planned
ablation in a carefully monitored and controlled
hospital environment, which introduced elements
that differ from the real-world setting in which
etripamil nasal spray might ultimately be used. The
use of conscious sedation in the electrophysiology
laboratory reduces circulating catecholamines (4,5),
which could alter the time to spontaneous conver-
sion along with the etripamil-related conversion rate
due to effects on atrioventricular node conduction
properties. Sedation may also predispose patients to
hypotension, which may not be seen in a non-
procedural setting. The possibility of catheter
FIGURE 4 Mean Æ SE Systolic Blood Pressure Over Time
Baseline 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Time (Minutes, Post Dose)
SystolicBloodPressure(mmHg)
120
110
150
140
130
Placebo Etripamil 35 mg Etripamil 70 mg
Etripamil 105 mg Etripamil 140 mg
*
* *
*
** *
*
Baseline is defined as the average of the 20-min and 10-min pre-dose measurements. Time 0 is defined as the average of the measurements
during supraventricular tachycardia between 5 and 0 min before study drug administration. *p 0.05 versus baseline.
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8. movement causing SVT termination exists, which
could affect efficacy results. It is conceivable that at
least some of the adverse events associated with
drug administration (i.e., supine position) could be
eliminated or minimized if patients are allowed to
self-administer the drug in a more optimal position
outside of the electrophysiology laboratory envi-
ronment. Because all patients were converted, per
protocol, by overdrive pacing after 15 min in SVT,
the time to spontaneous conversion for the 13
remaining patients who received placebo is un-
known. Analysis of the time to conversion, for pa-
tients who were inducible into sustained SVT, was
limited to 15 min in this proof-of-concept study,
which could be considered too short to evaluate the
spontaneous time to conversion in the placebo
group. Almost 90% of patients had atrioventricular
nodal re-entrant tachycardia, and thus the efficacy
and safety in AVRT was less well established in this
study.
CONCLUSIONS
Etripamil, an intranasally administered, L-type
calcium-channel blocker, demonstrated high efficacy
for rapid SVT termination and conversion to sinus
rhythm and was generally well tolerated. The results of
this study are promising and support the ongoing
development of this new intranasal calcium-channel
blocker for the acute termination of SVT, with a goal of
providing this therapy for patient self-administration
in the “real world” outside a health care setting. This
has the potential to change the treatment paradigm for
the acute management of SVT.
ACKNOWLEDGMENTS The authors thank Data
Monitoring Committee members John P. DiMarco,
MD, PhD, Mark N.A. Estes, MD, Hussein R. Al-Khalidi,
PhD, and Murray Ducharme, PharmD, and Pavine
Lefevre, PhD, for the dose-effect analysis.
ADDRESS FOR CORRESPONDENCE: Dr. Francis Plat,
Milestone Pharmaceuticals, 1111 Dr.-Frederik-Philips
Boulevard, Suite 420, Saint-Laurent, Quebec H4M
2X6, Canada. E-mail: fplat@milestonepharma.com.
CENTRAL ILLUSTRATION Conversion Rate (%) of Induced Paroxysmal Supraventricular Tachycardia
Within 15 min of Study Drug Administration
Placebo Etripamil 35 mg Etripamil 70 mg Etripamil 105 mg Etripamil 140 mg
35
65
*
87
*
75
*
95
0
90
80
70
60
50
40
30
20
10
100
Stambler, B.S. et al. J Am Coll Cardiol. 2018;72(5):489–97.
*p 0.05 versus placebo.
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Etri-
pamil, a short-acting calcium-channel blocker, when
administered as a nasal spray, is more effective than
placebo in terminating induced SVT, though a high
dose was associated with lowering of blood pressure.
TRANSLATIONAL OUTLOOK: Larger clinical
studies are needed to confirm the safety and efficacy
of etripamil nasal spray for termination of spontane-
ously occurring episodes of SVT.
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Conversion of Tachycardia With Etripamil Nasal Spray J U L Y 3 1 , 2 0 1 8 : 4 8 9 – 9 7
496
9. R E F E R E N C E S
1. Alboni AP, Tomasi C, Menozzi C, et al. Efficacy
and safety of out-of-hospital self-administered
single-dose oral drug treatment in the manage-
ment of infrequent, well-tolerated paroxysmal
supraventricular tachycardia. J Am Coll Cardiol
2001;37:548–53.
2. Yeh SJ, Lin FC, Chou YY, Hung JS, Wu D.
Termination of paroxysmal supraventricular
tachycardia with a single oral dose of diltiazem
and propranolol. Circulation 1985;71:104–9.
3. Hamer AW, Strathmore N, Vohra JK, Hunt VD.
Oral flecainide, sotalol, and verapamil for the
termination of paroxysmal supraventricular
tachycardia. Pacing Clin Electrophysiol 1993;16 7
Pt 1:1394–400.
4. Tomicheck RC, Rosow CE, Philbin DM, Moss J,
Teplick RS, Schneider RC. Diazepam-fentanyl inter-
action-hemodynamic and hormonal effects in coro-
nary artery surgery. Anesth Analg 1983;62:881–4.
5. Dörges V, Wenzel V, Dix S, et al. The effect
of midazolam on stress levels during
simulated emergency medical service transport: a
placebo-controlled, dose-response study. Anesth
Analg 2002;95:417–22.
KEY WORDS atrioventricular nodal
re-entrant tachycardia, atrioventricular
reciprocating tachycardia, calcium-channel
blocker, conversion rate, episodic
treatment, paroxysmal supraventricular
tachycardia
APPENDIX For a complete list of study sites
and primary investigators, please see the online
version of this paper.
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