Ajmaline

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Joachim Stockigt - One of the best experts on this subject based on the ideXlab platform.

  • the molecular architecture of major enzymes from Ajmaline biosynthetic pathway
    Phytochemistry Reviews, 2007
    Co-Authors: Joachim Stockigt, Santosh Panjikar, Martin Ruppert, Leif Barleben, Elke A Loris, Marco Hill
    Abstract:

    The biosynthetic pathway leading to the monoterpenoid indole alkaloid Ajmaline in Rauvolfia serpentiin serpentina is one of the most studied in the field of natural product biosynthesis. Ajmaline has a complex structure which is based on a six-membered ring system harbouring nine chiral carbon atoms. There are about fifteen enzymes involved, including some involving the side reactions of the Ajmaline biosynthetic pathway. All enzymes exhibit pronounced substrate specificity. In the recent years isolation and sequencing of their cDNAs has allowed a detailed sequence analysis and comparison with functionally related and occasionally un-related enzymes. Site-directed mutations of several of the Ajmaline-synthesizing enzymes have been performed and their catalytic residues have been identified. Success with over-expression of the enzymes was an important step for their crystallization and structural analysis by X-ray crystallography. Crystals with sufficient resolution were obtained from the major enzymes of the pathway. Strictosidine synthase has a 3D-structure with a six-bladed β-propeller fold the first time such a fold found in the plant kingdom. Its ligand complexes with tryptamine and secologanin, as well as structure-based sequence alignment, indicate a possible evolutionary relationship to several primary sequence-unrelated structures with this fold. The structure of strictosidine glucosidase was determined and its structure has as a (β/α)8 barrel fold. Vinorine synthase provides the first 3D structure of a member of BAHD enzyme super-family. Raucaffricine glucosidase involved in a side-route of Ajmaline biosynthesis has been crystallized. The Ajmaline biosynthetic pathway is an outstanding example where many enzymes 3D-structure have been known and where there is a real potential for protein engineering to yield new alkaloid.

  • structure and synthesis of a new indole alkaloid 19 s hydroxy nb methylraumacline obtained by the biotransformation of Ajmaline in plant cell cultures of rauwolfia serpentina benth
    Tetrahedron, 1992
    Co-Authors: Hiromitsu Takayama, Norio Aimi, Shinichiro Sakai, Mariko Kitajima, Shinya Suda, Susanne Endreβ, Joachim Stockigt
    Abstract:

    Abstract From the plant cell suspension cultures of Tauwolfia serpentina Benth., which were cultivated in the alkaloid-production medium after feeding of Ajmaline (1), a new indole alkaloid 19- (S)-hydroxy-Nb-methylraumacline (4) was isolated. The structure of 4 first elucidated by spectroscopic analysis was determined by the chemical synthesis from Ajmaline (1).

  • biotransformation of Ajmaline in plant cell cultures of rauwolfia serpentina benth the new indole alkaloids raumacline and n b methylraumacline
    Tetrahedron Letters, 1990
    Co-Authors: Leo Polz, Joachim Stockigt, Hiromitsu Takayama, Naoki Uchida, Norio Aimi, Shinichiro Sakai
    Abstract:

    Two novel indole alkaloids, raumacline (2) and N(b)-methylraumacline (3), were isolated from plant cell cultures of Rauwolfia serpentina Benth. after feeding experiments with the Rauwolfia alkaloid Ajmaline (1). The structures of the new alkaloids were elucidated by spectroscopic methods and chemical synthesis from Ajmaline (1).

Eberhard P. Scholz - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of cardiac kv1 5 and kv4 3 potassium channels by the class ia anti arrhythmic Ajmaline mode of action
    Naunyn-schmiedebergs Archives of Pharmacology, 2013
    Co-Authors: Fathima Fischer, Edgar Zitron, Hugo A. Katus, Nadine Vonderlin, Claudia Seyler, Daniel Scherer, Rudiger Becker, Eberhard P. Scholz
    Abstract:

    Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For Ajmaline, inhibitory effects on a variety of cardiac K+ channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of Ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that Ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 μM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that Ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas Ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that Ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of Ajmaline.

  • Class Ia anti-arrhythmic drug Ajmaline blocks HERG potassium channels: mode of action
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
    Co-Authors: Claudia Kiesecker, Edgar Zitron, Sonja Lück, Ramona Bloehs, Eberhard P. Scholz, Sven Kathöfer, Dierk Thomas, Volker A. W. Kreye, Hugo A. Katus, Wolfgang Schoels
    Abstract:

    Ajmaline is a class Ia anti-arrhythmic drug used in several European countries and Japan as first-line treatment for ventricular tachyarrhythmia. Ajmaline has been reported to induce cardiac output (QT) prolongation and to inhibit cardiac potassium currents in guinea pig cardiomyocytes. In order to elucidate the molecular basis of these effects, we examined effects of Ajmaline on human ether a-go-go related gene HERG potassium channels. Electrophysiological experiments were performed with human embryonic kidney (HEK) cells (whole-cell patch clamp) and Xenopus oocytes (double-electrode voltage clamp) expressing wild-type and mutant HERG channels. Ajmaline blocked HERG currents with an IC_50 of 1.0 μmol/l in HEK cells and 42.3 μmol/l in Xenopus oocytes. The onset of block was fast and reached steady-state conditions after 180 s. The inhibitory effect was completely reversible upon wash-out. In HERG mutant channels Y652A and F656A lacking aromatic residues in the S6 domain, the inhibitory effect of Ajmaline was completely abolished. Ajmaline induced a small shift in HERG current half-maximal activation voltage towards more negative potentials. Ajmaline did not markedly affect HERG inactivation. Inhibitory effects were not voltage-dependent. Ajmaline block exhibited positive frequency dependence. Ajmaline blocked HERG channels in the open, but not in the closed states. Binding of Ajmaline to inactivated HERG channels may also be possible. In inactivation-deficient HERG S620T channels, the sensitivity to Ajmaline was markedly reduced. The IC_50 of HERG channel blockade in HEK cells lies within the range of unbound therapeutic plasma concentrations of Ajmaline. Therefore, inhibitory effects on HERG channels may contribute to both the high anti-arrhythmic efficacy of Ajmaline and to its pro-arrhythmic potential.

Shinichiro Sakai - One of the best experts on this subject based on the ideXlab platform.

Juan Pablo Kaski - One of the best experts on this subject based on the ideXlab platform.

  • feasibility and outcomes of Ajmaline provocation testing for brugada syndrome in children in a specialist paediatric inherited cardiovascular diseases centre
    Open Heart 1 (1) Article e000023. (2014), 2014
    Co-Authors: Merlin R Mcmillan, Margarita Bartsota, Sarah Meadregan, Rory Bryant, Jasveer Mangat, Dominic Abrams, Martin Lowe, Juan Pablo Kaski
    Abstract:

    Objectives Brugada syndrome (BrS) is an inherited arrhythmia syndrome that causes sudden cardiac death in the young. The class Ia antiarrhythmic Ajmaline can be used to provoke the diagnostic ECG pattern. Its use has been established in adults, but little data exist on the Ajmaline provocation test in children. This study aims to determine the safety and feasibility of Ajmaline provocation testing in a large paediatric cohort in a specialist paediatric inherited cardiac diseases centre. Methods 98 consecutive Ajmaline tests were performed in 95 children between September 2004 and July 2012 for family history of BrS (n=46 (48%)); family history of unexplained sudden cardiac death (n=39 (41%); symptoms with suspicious ECG abnormalities (n=9 (10%)). Three patients were retested with age, due to the possibility of age-related penetrance. ECG parameters were measured at baseline and during maximal Ajmaline effect. Results The mean patient age was 12.55 years, 43% were female. Nineteen patients (20%) had a positive Ajmaline test. There were no arrhythmias or adverse events during testing. Ajmaline provoked significant prolongation of the PR, QRS and QTc in all patients. Mean follow-up was 3.62 years with no adverse outcomes reported in any patients with BrS. There were no predictors of a positive Ajmaline provocation test on multivariable analysis. One patient who tested negative at 12 years of age, subsequently tested positive at 15 years of age. Conclusions Ajmaline testing appears safe and feasible in children when performed in an appropriate setting by an experienced team. Test positivity may change with age in individuals, suggesting that the test should be repeated in the late teenage years or early adulthood.

  • 077 Ajmaline provocation testing for brugada syndrome in children the great ormond street experience
    Heart, 2013
    Co-Authors: Margarita Bartsota, Rory Bryant, Jasveer Mangat, Dominic Abrams, Martin Lowe, S Meadreagan, Juan Pablo Kaski
    Abstract:

    Background Brugada syndrome (BS) is a genetic disorder characterised by J point elevation in the right ventricular leads, ventricular arrhythmia and sudden cardiac death (SCD). The diagnostic ECG changes can be provoked by sodium channel blocking agents including Ajmaline. Although Ajmaline testing is well established in adults, there are few data on its safety and outcomes in paediatric cohorts3. Here we describe a single centre experience of Ajmaline testing for BS in a large cohort of children. Methods and results 100 consecutive patients aged 18 years or younger who underwent an Ajmaline challenge between September 2004 and May 2012 were included. Mean age at the time of Ajmaline challenge was 12.6 years (range 2.0–18.4 years), and 54 were male. The indication for Ajmaline challenge was a family history of BS in 49 patients, family history of unexplained sudden cardiac death (without a confirmed family history of BS) in 40, symptoms in 9 (syncope/collapse, n=5; chest pain, n=1; palpitations, n=3), family history of long QT syndrome in 1 patient, and development of bradycardia with abnormal ECG during general anaesthesia in 1 patient. There were no serious adverse events associated with the Ajmaline tests. A diagnostic type I response was seen in 19 individuals, of which 13 had a family history of BS, 5 had a family history of SCD without confirmed BS, and 1 patient had syncope as an indication for the challenge. Although a positive result was more common in those patients with a family history of BS, this association did not reach statistical significance. 5 individuals with a positive Ajmaline test underwent electrophysiological studies; ventricular arrhythmias were not inducible in any. All patients are alive with no documented ventricular arrhythmias after a median follow-up time of 3.6 years. Conclusions Ajmaline provocation testing in children is feasible and safe when performed in an appropriate setting by an experienced team. A type I response is more common in patients with a family history of BS, but the test may be helpful in identifying a diagnosis in families with unexplained SCD. Overall, BS appears to be associated with a very low risk of ventricular arrhythmia in the paediatric population.

  • Ajmaline provocation testing for brugada syndrome in children the great ormond street experience
    Journal of the American College of Cardiology, 2013
    Co-Authors: Margarita Bartsota, Rory Bryant, Jasveer Mangat, Dominic Abrams, Martin Lowe, S Meadreagan, Juan Pablo Kaski
    Abstract:

    Brugada syndrome (BS) is a genetic disorder characterised by J point elevation in the right ventricular leads, ventricular arrhythmia and sudden cardiac death (SCD). The diagnostic ECG changes can be provoked by sodium channel blocking agents including Ajmaline. Although Ajmaline testing is well

Giulio Conte - One of the best experts on this subject based on the ideXlab platform.

  • the clinical impact of Ajmaline challenge in elderly patients with suspected atrioventricular conduction disease
    International Journal of Cardiology, 2014
    Co-Authors: Giulio Conte, Juan Sieira, Andrea Sarkozy, Carlo De Asmundis, Giacomo Di Giovanni, Gian Battista Chierchia, Giuseppe Ciconte, Moises Levinstein, Giannis Baltogiannis, Kristel Wauters
    Abstract:

    Abstract Background The effects and the safety of Ajmaline challenge in elderly patients with suspected atrioventricular (AV) conduction disease have not been systematically investigated. The purpose of this study was to assess the response of intravenous administration of Ajmaline in patients older than 75years suspected to be affected by AV conduction disease with respect to unmask high-degree His-Purkinje block or the typical Brugada ECG pattern. Methods Consecutive patients older than 75years having undergone in our centre an electrophysiologic study with intravenous Ajmaline administration were eligible for this study. Results A total of 162 consecutive patients older than 75years (84 males; mean age: 78±4years) were included. Ajmaline induced prolongation of the H–V interval up to 100ms or more in 25 patients (15%). High degree His-Purkinje block was produced in 5 patients (3%). Moreover, Ajmaline challenge unmasked a Brugada type 1 ECG in 12 patients (7%). No ventricular tachyarrhythmia was observed during the pharmacologic challenge and no severe side effects occurred. Among the study population, 56 (34%) and 6 patients (4%) underwent a PM and ICD implantation, respectively. For the patients with BS, a family screening was performed in a total of 37 individuals. Eighteen family members (48%) presented a positive Ajmaline test and 1 (3%) a spontaneous Brugada type 1 ECG. Conclusions Ajmaline challenge in the elderly is a safe procedure to unmask AV conduction disease and can lead to an unexpected diagnosis of BS. Although the clinical impact is obvious, the therapeutic management remains controversial.

  • the challenges of performing Ajmaline challenge in children with suspected brugada syndrome
    Open Heart, 2014
    Co-Authors: Giulio Conte, Pedro Brugada
    Abstract:

    Brugada syndrome (BS) is an inheritable syndrome characterised by coved-type ST segment elevation in the right precordial leads (V1–V3) and increased risk of sudden death in the absence of structural heart disease.1 Intravenous administration of class IC antiarrhythmic drugs is an established tool to unmask the diagnostic Brugada ECG pattern in patients with suspected BS and non-diagnostic ECG.2 Current data indicate that Ajmaline is the most effective drug for the diagnosis of BS, mainly because of its kinetics and strength of rate-dependent sodium channel blocking effects.3 McMillan et al report on feasibility and outcomes of Ajmaline challenge in children. Ninety-five participants aged 18 years or less (mean age: 12.5±3.3 years) underwent Ajmaline challenge for suspected BS4. Forty-eight per cent of them were BS family members. Ajmaline unmasked diagnostic Brugada type I ECG in 20% of individuals. Drug infusion was discontinued in all patients before reaching the target dose in case of appearance of diagnostic Brugada …

  • life threatening ventricular arrhythmias during Ajmaline challenge in patients with brugada syndrome incidence clinical features and prognosis
    Heart Rhythm, 2013
    Co-Authors: Giulio Conte, Juan Sieira, Andrea Sarkozy, Carlo De Asmundis, Giacomo Di Giovanni, Gian Battista Chierchia, Giuseppe Ciconte, Moises Levinstein, Ruben Casadoarroyo, Giannis Baltogiannis
    Abstract:

    Background Sustained ventricular arrhythmias (sVAs), such as polymorphic ventricular tachycardia or ventricular fibrillation, can complicate Ajmaline challenge in patients with Brugada syndrome (BS). Objective To assess the incidence of life-threatening sVAs during Ajmaline administration in a large series of patients with BS. In addition, clinical characteristics as well as prognosis of these patients were evaluated. Methods All consecutive patients with Ajmaline-induced diagnosis of BS were eligible for this study. Results A total of 503 patients were included. Nine (1.8%) patients (44% men; mean age 26 ± 18 years) developed a life-threatening sVA during Ajmaline challenge. Three patients (33%)were children, and 2 (22%) patients experienced sVAs refractory to the first external defibrillation. One patient underwent venoarterial extracorporeal membrane oxygenation to restore sinus rhythm. Age at the time of Ajmaline challenge was significantly lower in patients with sVAs compared with patients without sVAs (26 ± 18 years vs 41 ± 18 years; P = .01). Moreover, patients with sVAs presented more frequently with sinus node dysfunction compared with patients with normal response to Ajmaline (22.2% vs 1.4%; P = .01). After a mean follow-up time of 29 ± 8 months, none of the patients who had developed a sVA during Ajmaline challenge died suddenly or developed further life-threatening ventricular arrhythmias. Conclusions sVA during Ajmaline challenge is not a rare event in BS occurring in 9 (1.8%) patients. Despite its challenging acute treatment, the occurrence of Ajmaline-induced sVAs in patients with BS might not identify a category at higher risk for further arrhythmic events.