Development of ultra short-acting muscle relaxant agents: history, research strategies, and challenges

Author has reviewed the literature and his own work related to the chemistry, pharmacology, and clinical aspects of new muscle relaxants. Emphasis has been placed on the basic science concepts and technologies (e.g. structure-activity relationships, nicotinic receptor pharmacology, and investigation of side effects) behind the development of rapidly and short acting nondepolarizing muscle relaxants.     

Lymphocyte subsets in pediatric migraine

Aseptic inflammation due to activated immune cells has been implicated in the pathomechanism of migraine. We measured the prevalence of regulatory T cells (Tregs), along with that of CD4⁺/CD8⁺ lymphocytes and their Th1/Th2 commitment in pediatric migraine. Children and adolescents suffering from migraine without aura, migraine with aura and hemiplegic migraine ictally (n = 53, 27, and 20, respectively), also interictally (n = 33) were recruited and compared to 24 healthy children. Our results indicated comparable prevalence of Tregs, CD4⁺ and Th1/Th2 committed cells. CD8⁺ prevalence was lower, and CD4⁺/CD8⁺ ratio was higher in ictal phase irrespective of the subtype of migraine. No association between CD8⁺ prevalence and gender, body weight, disease onset and attack duration in migraine subtypes was found. CD8⁺ prevalence was normal in patients in interictal phase. These results suggest the absence of major systemic alteration of adaptive immunity in children and adolescents suffering from migraine; however, a transient decrease of CD8⁺ prevalence during the ictal phase was detected irrespective of the subtype of migraine.     

Ablation of Typical Atrial Flutter Using a Three-Dimensional Ultrasound Mapping System

Aims: The aim of the study was to test the feasibility of the new Realtime Position Management mapping system for ablation of typical atrial flutter. Methods and Results: The ultrasound multi-transducer catheters of the RPM Mapping System are placed in the coronary sinus and at the right ventricular apex. Position and movement of the ablation catheter can be depicted on the monitor at any time. Several guiding marks are set in the right atria and thus, define the subsequent lesion lines. A total of 15 patients were treated. In 13 patients complete bi-directional block was established after the ablation. In two patients only significant conduction delay was measured after the end of the procedure. A total of 10.2 ± 6.3 cooled RF-applications were needed to reach the end-point of the procedure. The total energy was 18.76 ± 13.23 J. The fluoroscopy time for ablation was 22.2 ± 8.34 min. During a mean follow-up of 8.4 ± 3.2 months no recurrence of atrial flutter occurred. One patient developed atypical flutter and another patient had atrial fibrillation. Both patients were treated with antiarrhythmic drugs. There was one ablation related complication, a pericardial effusion. Conclusion: The Realtime Position Management system is easy to manage and control. The precision of anatomical linear lesions is improved and fluoroscopic exposure time considerably reduced after learning curve.     

Alpha(4)beta(7)/alpha(4)beta(1) dual integrin antagonists block alpha(4)beta(7)-dependent adhesion under shear flow

The alpha(4) integrin, alpha(4)beta(7), plays an important role in recruiting circulating lymphocytes to the gastrointestinal tract, where its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is preferentially expressed on high endothelial venules (HEVs). Dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), N-(2,6-dichlorobenzoyl)-(L)-4-(2',6'-bis-methoxyphenyl)phenylalanine (TR14035) and N-(N-[(3,5-dichlorobenzene)sulfonyl]-2-(R)-methylpropyl)-(D)-phenylalanine (compound 1), were tested for their ability to block the binding of alpha(4)beta(7)-expressing cells to soluble ligand in suspension and under in vitro and in vivo shear flow. Compound 1 and TR14035 blocked the binding of human alpha(4)beta(7) to an (125)I-MAdCAM-Ig fusion protein with IC(50) values of 2.93 and 0.75 nM, respectively. Both compounds inhibited binding of soluble ligands to alpha(4)beta(1) or alpha(4)beta(7) on cells of human or rodent origin with similar potency. Under shear flow in vitro, TR14035 and compound 1 blocked binding of human alpha(4)beta(7)-expressing RPMI-8866 cells or murine mesenteric lymph node lymphocytes to MAdCAM-Ig with IC(50) values of 0.1 and 1 microM, respectively. Intravital microscopy was used to quantitate alpha(4)-dependent adhesion of fluorescent murine lymphocytes in Peyer's patch HEVs. When cells were prestimulated with 2 mM Mn(2+) to activate alpha(4)beta(7) binding to ligand, anti-alpha(4) monoclonal antibody (mAb) [10 mg/kg (mpk) i.v.] blocked adhesion by 95%, and anti-beta(1) mAb did not block adhesion, demonstrating that this interaction was dependent on alpha(4)beta(7). TR14035 blocked adhesion to HEVs [ED(50) of 0.01-0.1 mpk i.v.], and compound 1 blocked adhesion by 47% at 10 mpk i.v. Thus, alpha(4)beta(7)/alpha(4)beta(1) antagonists blocked alpha(4)beta(7)-dependent adhesion of lymphocytes to HEVs under both in vitro and in vivo shear flow.     

Establishment of reference distributions and decision values for thyroid antibodies against thyroid peroxidase (TPOAb), thyroglobulin (TgAb) and the thyrotropin receptor (TRAb).

BACKGROUND: The National Academy of Clinical Biochemistry (NACB) stresses that the reference intervals for thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) should be based on young men who lack certain risk factors and have serum TSH between 0.5 and 2.0 mIU/L. However, some young men without any of the risk factors have autoantibodies, and cannot be identified by the present tools. A model for reference intervals and cut-off values should not be influenced by the prevalence of risk factors. METHODS: We developed a model of "composite logarithmic Gaussian distributions" and tested it in 1441 well-characterised subjects without clinically overt thyroid disease. RESULTS: TPOAb and TgAb could be measured in all individuals. The 97.5% upper limits 1) on a traditional non-parametric scale, 2) according to the NACB criteria, and 3) for our model were 284, 24 and 9.8 kIU/L for TPOAb, and 84, 22 and 19 kIU/L for TgAb, respectively. The decision value (defined as the concentration corresponding to 0.1% false positives) was 15 kIU/L for TPOAb and 31 kIU/L for TgAb. Concentrations above our reference intervals affected the corresponding distribution of TSH values. For TRAb the upper reference limits were 1) 0.75 and 2) 0.75 IU/L, while our model was not applicable to TRAb because only 2-3% of the results were above the functional assay sensitivity. CONCLUSIONS: In contrast to the NACB guidelines, our model for TPOAb and TgAb is more robust, as it is independent of the characteristics of the reference population.     

The hyperkalemic Brugada sign

Background

A few case reports have indicated that hyperkalemia can induce a Brugada pattern in the electrocardiogram. The specific clinical and electrocardiographic features of the hyperkalemic Brugada sign, however, have not been previously described.

Methods

A case series was collected from hospitalized hyperkalemic patients with a type I Brugada pattern in the electrocardiogram, and a literature review was performed. Electrocardiograms were examined for rhythm and morphology, and clinical characteristics were analyzed.

Results

Nine new cases with the hyperkalemic Brugada sign were identified with an additional 15 cases found in the literature. Of the 9 cases, 8 were male patients, and all were critically ill; 5 of the 9 died within 48 hours. The mean (±SD) serum potassium level was 7.8 ± 0.5 mEq/L. The mean QRS width was 144 ± 31 milliseconds, and all had abnormal QRS axis. In 6 cases, there was a wide complex rhythm without visible P waves. The clinical and electrocardiographic characteristics of 15 cases found in the literature were remarkably similar to those in our series.

Conclusions

The hyperkalemic Brugada pattern differs in substantial ways from the electrocardiogram of patients with the genetic Brugada syndrome. Many patients have wide complex rhythms without visible P waves, marked QRS widening, and an abnormal QRS axis. Most patients are male, and many are critically ill. Prompt recognition of this clinical and electrocardiographic entity may expedite the initiation of appropriate treatment for hyperkalemia.     

Differential Rate and Potassium-Dependent Effects of the Class III Agents d-Sotalol and Dofetilide on Guinea Pig Papillary Muscle

The class III agents d-sotalol and dofetilide have been shown to exhibit differential effects in large controlled clinical trials. The aim of this study was to investigate the basic electrophysiological properties of these two antiarrhythmia agents in an in vitro experimental model with regard to potential antiarrhythmic and proarrhythmic action. Using standard microelectrode techniques, we evaluated the electrophysiological effects of d-sotalol and dofetilide on action potential parameters recorded from guinea pig papillary muscle at 2.5 mM, 3.5 mM, and 5.6 mM extracellular potassium concentrations. The following parameters were recorded: resting membrane potential (RMP), action potential amplitude (APA), action potential duration at 90% repolarization (APD 90), and maximum upstroke velocity (Vmax). Under all conditions studied, both d-sotalol and dofetilide exhibited highly selective reverse rate-dependent class III action. In contrast to dofetilide, the class III activity of d-sotalol was markedly influenced by changes in extracellular potassium concentrations, predominantly at low pacing rates. Hypokalemia enhanced the action potential–prolonging effects of d-sotalol, whereas hyperkalemia diminished this effect. In addition, reverse rate dependence associated with dofetilide was significantly more pronounced than reverse rate dependence associated with d-sotalol. Our observations provide a potential electrophysiological basis for differential antiarrhythmic and proarrhythmic mechanisms associated with these two drugs.