Lactam sulfonamides as potent inhibitors of the Kv1.5 potassium ion channel.

A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.

Comparison of serum amyloid A and C-reactive protein as diagnostic markers of systemic inflammation in dogs.

The diagnostic performance of canine serum amyloid A (SAA) was compared with that of C-reactive protein (CRP) in the detection of systemic inflammation in dogs. Sera from 500 dogs were retrospectively included in the study. C-reactive protein and SAA were measured using validated automated assays. The overlap performance, clinical decision limits, overall diagnostic performance, correlations, and agreement in the clinical classification between these 2 diagnostic markers were compared. Significantly higher concentrations of both proteins were detected in dogs with systemic inflammation (SAA range: 48.75 to > 2700 mg/L; CRP range: 0.4 to 907.4 mg/L) compared to dogs without systemic inflammation (SAA range: 1.06 to 56.4 mg/L; CRP range: 0.07 to 24.7 mg/L). Both proteins were shown to be sensitive and specific markers of systemic inflammation in dogs. Significant correlations and excellent diagnostic agreement were observed between the 2 markers. However, SAA showed a wider range of concentrations and a significantly superior overall diagnostic performance compared with CRP.

Comparaison de la protéine amyloïde sérique A et de la protéine C réactive comme marqueurs diagnostiques de l'inflammation systémique chez les chiens. La performance diagnostique de l'amyloïde sérique canine A (SAA) a été comparée à celle de la protéine C réactive (PCR) dans la détection de l'inflammation systémique chez les chiens. Le sérum de 500 chiens a été inclus rétrospectivement dans l'étude. La protéine C réactive et la SAA ont été mesurées en utilisant des bioanalyses automatisées validées. La performance de chevauchement, les limites de décision cliniques, la performance diagnostique globale, les corrélations et la concordance dans la classification clinique entre ces 2 marqueurs diagnostiques ont été comparés. Des concentrations significativement supérieures des deux protéines ont été détectées chez les chiens avec une inflammation systémique (plage de la SAA : de 48,75 à > 2700 mg/L; plage de la PCR : de 0,4 à 907,4 mg/L) comparativement aux chiens sans inflammation systémique (plage de la SAA : de 1,06 à 56,4 mg/L; plage de la PCR : de 0,07 à 24,7 mg/L). Il a été démontré que les deux protéines étaient sensibles et des marqueurs spécifiques de l'inflammation systémique chez les chiens. Des corrélations significatives et une concordance diagnostique excellente ont été observées entre les deux marqueurs. Cependant, la SAA a indiqué un écart plus vaste pour les concentrations et une performance diagnostique significativement supérieure comparativement à la PCR.(Traduit par Isabelle Vallières).

Myocardial injury in dogs with snake envenomation and its relation to systemic inflammation.

OBJECTIVE: To investigate the presence of myocardial injury in dogs hospitalized for snake envenomation and to examine its relationship with systemic inflammation. DESIGN: Prospective case-control study. SETTING: University teaching hospital and small animal referral hospital. ANIMALS: Dogs naturally envenomed by the European viper (Vipera berus; n = 24), African puff adder (Bitis arietans; n = 5), or snouted cobra (Naja annulifera; n = 9). INTERVENTIONS: Blood was collected from dogs envenomed by V. berus at admission, 12-24 hours postadmission, and 5-10 days postadmission. Blood was collected from dogs envenomed by B. arietans or N. annulifera at admission, and 12, 24, and 36 hours postadmission. MEASUREMENTS AND MAIN RESULTS: Concentrations of cardiac troponin I (cTnI), a marker of myocardial injury, and C-reactive protein (CRP), a marker of systemic inflammation, were measured in each blood sample. Evidence of myocardial injury was found in 58% of dogs envenomed by V. berus at one or more time points. A significant correlation between cTnI and CRP concentrations was found at all time points. Evidence of myocardial injury was found in 80% of dogs envenomed by B. arietans at one or more time points; however, no correlation was found between cTnI and CRP concentrations. Evidence of myocardial injury was found in 67% of dogs envenomed by N. annulifera at one or more time points. A significant correlation between cTnI and CRP concentrations was found at admission, but not at other time points. CONCLUSIONS: Myocardial injury frequently occurred in dogs with snake envenomation. While the degree of systemic inflammation was significantly correlated with degree of myocardial injury in V. berus envenomation at all time points, this was not the case in dogs envenomed by N. annulifera or B. arietans. This could be due to differences in the toxic substances of the snake venoms or to differences in the cytokines induced by the venom toxins.

Canine serum amyloid A (SAA) measured by automated latex agglutination turbidimetry is useful for routine sensitive and specific detection of systemic inflammation in a general clinical setting.

Canine serum amyloid A (SAA) is a useful diagnostic marker of systemic inflammation. A latex agglutination turbidimetric immunoassay (LAT) was validated for automated measurements. The aim of the study was to evaluate the clinical applicability of SAA measured by the LAT. SAA was measured in 7 groups of dogs with and without systemic inflammation (n=247). Overlap performance was investigated. Diagnostic performance was compared to body temperature and leukocyte markers. Clinical decision limits for SAA were estimated. In dogs with neurological, neoplastic or gastrointestinal disorders (n=143), it was investigated whether a higher proportion of SAA positive dogs could be detected in cases of complications with risk of systemic inflammation. Significantly higher concentrations of SAA were measured in dogs with (range [48.75; 5,032 mg/l]), compared to dogs without systemic inflammation [0; 56.4 mg/l]. SAA was a more sensitive and specific marker of systemic inflammation (area under the receiver-operating characteristic curve (AUC) 1.00), compared to body temperature (0.6) and segmented neutrophils (best performing leukocyte marker, 0.84). A clinical decision limit of 56.4 mg/l was established giving close to perfect discrimination between dogs with and without systemic inflammation. Higher proportions of SAA-positive dogs were observed in dogs with neurological, neoplastic and gastrointestinal disorders with complications known to increase risk of systemic inflammation, compared to uncomplicated cases. The automated LAT makes SAA applicable as a relevant diagnostic marker of systemic inflammation in dogs for routine random-access real-time use in a general clinical setting.

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre.

AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of AZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. AZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC(50) of 11+/-2 microM. The late sodium current in isolated rabbit atrial and ventricular myocytes was also concentration dependently inhibited by AZD7009. Action potentials were recorded during exposure to 5 microM E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I(Kr)), and to E-4031 in combination with AZD7009 or lidocaine in rabbit atrial and ventricular tissue and Purkinje fibres. In Purkinje fibres, but not in ventricular tissue, AZD7009 and lidocaine attenuated the E-4031-induced action potential duration prolongation. In atrial cells, AZD7009, but not lidocaine, further prolonged the E-4031-induced action potential duration. E-4031 induced early afterdepolarisations (EADs) in Purkinje fibres, EADs that were totally suppressed by AZD7009 or lidocaine. In conclusion, excessive action potential duration prolongation induced by E-4031 was attenuated by AZD7009 and lidocaine in rabbit Purkinje fibre, but not in atrial or ventricular tissue, most likely by inhibiting the late sodium current. Furthermore, the opposite effect by AZD7009 on action potential duration in atrial tissue suggests that AZD7009, in addition to inhibiting I(Kr), also inhibits other repolarising currents in the atria.

Blocking characteristics of hKv1.5 and hKv4.3/hKChIP2.2 after administration of the novel antiarrhythmic compound AZD7009.

AZD7009 is a novel antiarrhythmic compound in early clinical development for management of atrial fibrillation. Electrophysiological studies in animals have shown high antiarrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. AZD7009 has previously been shown to inhibit hERG and hNav1.5 currents. The main objective of the present study was to characterize the effects of AZD7009 on hKv1.5 and hKv4.3/hKChIP2.2 currents to get a deeper understanding of the ion channel-blocking properties of the compound. hKv1.5 and hKv4.3/hKChIP2.2 currents were expressed in CHO cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited hKv1.5 and hKv4.3/hKChIP2.2 currents with equal potency: the IC50 for hKv1.5 block was 27.0 +/- 1.6 muM (n = 6), and the IC50 for hKv4.3/hKChIP2.2 block was 23.7 +/- 4.4 muM (n = 5). Block of the hKv4.3/hKChIP2.2 current was frequency dependent with larger block at higher frequency, whereas block of the hKv1.5 current was slightly decreased at higher frequency. In conclusion, AZD7009 inhibits both the hKv1.5 and the hKv4.3/hKChIP2.2 currents. These effects likely contribute to the effects described in animals in vivo.

Blocking characteristics of hERG, hNav1.5, and hKvLQT1/hminK after administration of the novel anti-arrhythmic compound AZD7009.

INTRODUCTION: AZD7009 is a novel anti-arrhythmic compound under development for short- and long-term management of atrial fibrillation and flutter. Electrophysiological studies in animals have shown high anti-arrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. The main aim of this study was to characterize the blocking effects of AZD7009 on the human ether-a-go-go-related gene (hERG), the hNav1.5, and the hKvLQT1/hminK currents. METHODS AND RESULTS: hERG, hKvLQT1/hminK, and hNav1.5 were expressed in CHO K1 cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited the hERG current with an IC50 of 0.6 +/- 0.07 microM (n = 6). AZD7009 1 microM hyperpolarized the potential for half-maximal activation from -8.2 +/- 0.1 mV to -18.0 +/- 0.6 mV (P < 0.001, n = 14) and induced pre-pulse potentiation at potentials near the activation threshold. The hNav1.5 current was blocked with an IC50 of 4.3 +/- 1.20 microM at 10 Hz (n = 6) and block developed use-dependently. Recovery from use-dependent block was slow, tau= 131 seconds. AZD7009 inhibited the hKvLQT1/hminK current only at high concentrations (IC50= 193 +/- 20 microM, n = 6). CONCLUSION: AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.