Delving into the Latest Updates on Sibenadet Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Sibenadet, Sibenadet hydrochloride (USAN), 西贝奈迪

+ [10]

Target

D2 receptor x β2-adrenergic receptor

Mechanism

D2 receptor agonists(Dopamine D2 receptor agonists), β2-adrenergic receptor agonists(Beta-2 adrenergic receptor agonists)

Therapeutic Areas

Respiratory DiseasesImmune System Diseases

Active Indication-

Inactive Indication

AsthmaPulmonary Disease, Chronic Obstructive

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

AstraZeneca Pharma India Ltd.AstraZeneca R&D Charnwood

AstraZeneca Pharmaceuticals Co. Ltd.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H29ClN2O5S2

InChIKeyYXOKBHUPEBNZOG-UHFFFAOYSA-N

CAS Registry154189-24-9

Molecular packing in two polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan™) is investigated using a combined experimental (1) H double-quantum (DQ) solid-state magic-angle spinning nuclear magnetic resonance and computational (gauge including projected augmented wave calculation of chemical shifts) approach. For Form I, NH-NH and NH-OH (1) H DQ peaks are observed corresponding to nearest distances of 2.62 and 2.87 Å, respectively, for the intermolecular hydrogen-bonding arrangement in the single-crystal X-ray diffraction structure. The same (1) H DQ peaks at the same (1) H chemical shifts are observed for Form II, for which there is no single-crystal diffraction structure, indicating the same intermolecular hydrogen-bonding arrangement of the benzothiazolone moieties as in Form I. (1) H DQ build-up (as a function of the DQ recoupling time) curves are presented for the resolved NH-NH and NH-OH DQ peaks for the two polymorphs. For Form I, the ratio of the maximum intensity for the NH-OH and NH-NH DQ peaks is in excellent agreement with the ratio of the summed squares of the H-H dipolar couplings, as determined using H-H distances from the crystal structure up to 4 Å. Small differences in the (1) H DQ build-up behaviour for the two polymorphs are attributed to differences in the longer-range NH-OH distances associated with different inter-layer arrangements.

01 Mar 2007·British journal of clinical pharmacologyQ2 · MEDICINE

Lack of correlation between exercise and sibenadet‐induced changes in heart rate corrected measurement of the QT interval

Q2 · MEDICINE

Article

Author: Nick Sanders ; Stots B. Reele ; Paul Newbold

What is already known about this subject:

• When this study was conducted it was already known that the ‘standard’ methods of correcting the QT interval for heart rate were not optimal and that bias could result in their use in certain circumstances, in particular when drugs or conditions also induced wide fluctuations in heart rate.• The use of subject specific correction methods had been advocated and whilst these had been shown to apparently correct QT interval over usual physiological heart rates, they had not been tested under conditions where drugs could potentially increase heart rate and ‘standard’ correction methods gave apparent increases in QT interval. Furthermore, subject specific correction methods had usually been generated over a normal physiological heart rate range and made the assumption that the relationship remained linear outside of this usual range.

What this study adds:

• A subject specific correction factor for QT correction can be calculated from a wide range of heart rates using exercise testing and the relationships between QT and RR are unique for a given individual.• The generation of subject specific correction factors from ECGs collected under resting conditions is not a robust method.• That subject specific correction factors derived from exercise testing are not appropriate to apply to drugs (with no evidence to suggest effects on the QT interval) that induce increases in heart rate and that the relationship between the QT and RR interval during exercise is clearly different to the QT/RR relationship of a drug that increases heart rate.

Aims:

We sought to investigate subject specific QT interval correction factors (SSCF) determined at rest and after exercise and to determine the validity of these factors after the administration of a probe drug known to increase heart rate without directly affecting cardiac repolarization.

Methods:

Thirty‐two healthy volunteers underwent graded exercise, multiple recordings of electrocardiogram during rest over a day and a treatment phase administering inhaled placebo or sibenadet (a β2‐adrenoceptor/dopamine D2‐receptor agonist) at 250, 500 or one of 750 or 1000 µg. SSCF were determined from linear regression of plots of log RR interval vs. log QT after exercise (QTcX), rest (QTcR), and combined data (QTcC). The SSCFs along with Bazett & Fridericia corrections were applied to the ECGs after inhalation of sibenadet.

Results:

SSCFs obtained from the combination of the exercise and resting day (mean QTcC = 0.41) and exercise alone (mean QTcX = 0.40) were similar with a good fit to the data (mean r2 = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r2 = 0.52). After the administration of sibenadet, none of the SSCFs, Bazett or Fridericia corrections adequately corrected QT for heart rate induced changes.

Conclusions:

Neither a SSCF from exercise, Bazett’s or Fridericia’s correction factors, adequately corrected the QT interval after the administration of a sympathomimetic agonist drug to increase heart rate in healthy volunteers demonstrating the potential need for QT/RR correction factors to be tailored for each drug studied.

01 Nov 2005·Journal of pharmaceutical sciencesQ3 · MEDICINE

Understanding the Polymorphic Behavior of Sibenadet Hydrochloride through Detailed Studies Integrating Structural and Dynamical Assessment

Q3 · MEDICINE

Article

Author: K.J. Roberts ; S.D. Cosgrove ; T.K. Austin ; B. Stensland ; G. Steele ; A.P. Plumb ; E. Ferrari

Three polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan) have been shown to exist at ambient temperature and have been characterized. Each undergoes a solid-state transition to a common high temperature form, which melts at approximately 220 degrees C. X-ray powder diffraction (XRPD) indicates that Polymorphs I and II share a similar layered structure not exhibited by Polymorph III. All three ambient temperature polymorphs show evidence of varying degrees of dynamic disorder of the terminal phenyl group as shown by solid-state NMR spectroscopy. Furthermore, the carbons alpha to the ether link also undergo different rates of mobility in Polymorphs I and II. This variation in the extent of dynamic disorder results in an alteration in the short-range structure resulting in distinct polymorphs. Polymorph I is the thermodynamically stable form at room temperature as indicated by solution calorimetry and assessment by thermodynamically driven solution mediated phase transition studies. The present study aims to address the types of discriminatory data required to make a clear distinction between physical forms and define, unequivocally, the presence of polymorphism.

100 Deals associated with Sibenadet Hydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
D05832	-	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Disease, Chronic Obstructive	Phase 3	US	AstraZeneca Pharma India Ltd.	-
Pulmonary Disease, Chronic Obstructive	Phase 3	-	-	-
Pulmonary Disease, Chronic Obstructive	Phase 3	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Asthma	Phase 1	GB	AstraZeneca R&D Charnwood	-