A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pK_a value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α₁-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.     

Deuterium Isotope Effect on the Metabolism of the Flame Retardant Tris(2,3-dibromopropyl) Phosphate in the Isolated Perfused Rat Liver

The metabolism of tris(2,3-dibromopropyl) phosphate (Tris-BP)was compared with that of completely deuterated Tris-BP (D15-Tris-BP)in an isolated, recirculating rat liver perfusion system inorder to determine the relative quantitative importance of twodifferent biotransformation pathways of Tris-BP: (i) cytochromeP450-mediated metabolism and (ii) GSH S-transferase-mediatedmetabolism. To accomplish this we quantitated the biliary excretionof S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolitefor cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl)glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediatedmetabolism. Completedeuterium substitution of Tris-BP significantlydecreased the formation of GSOH, whereas there was no effecton the formation of GSOHOH. Because our previous studies showeda large decrease in genotoxicity of D15-Tris-BP compared toTris-BP, the present results support our hypothesis that cytochromeP450-mediated metabolism is responsible for the genotoxic effectsof Tris BP in the rat liver.     

AMINOPEPTIDASE A IS A CONSTITUENT OF ACTIVATED PERICYTES IN ANGIOGENESIS

Monoclonal antibody (MAb) RC38 recognizes a human renal antigen of 160 kD recently identified as human aminopeptidase A (APA; EC 3.4.11.7). This ectoenzyme is able to hydrolyse selectively N-terminal glutamyl and aspartyl residues from oligopeptides. By enzyme histochemistry, APA activity has also been localized in the microvessels of all organs in animals and man. The purpose of this study was to investigate the distribution of human APA as recognized by MAb RC38 in the microvasculature of normal human tissues and pathological conditions associated with neovascularization. Unexpectedly, in normal tissues vascular staining with MAb RC38 was generally weak and often absent, while in tumours, granulation tissue, and chronic synovitis, marked microvascular staining was demonstrated. By immuno-electron microscopy, the antigen was found on the cell membrane of activated pericytes and their processes in the tumour vasculature. RC38 expression could not be detected on cultured human endothelial cells or pericytes. These observations suggest that pericyte expression of a subtype of APA (as recognized by MAb RC38) is markedly enhanced in the vasculature of tumours and wound healing tissue as compared with normal resting tissues. This provides further evidence of the altered state of pericytes in these conditions. Pericyte APA may be involved in the metabolism of biologically active oligopeptides during neovascularization, supporting a regulatory role of pericytes in this process. In addition, MAb RC38 may be useful as a marker of pericyte activation in tissue sections.     

Stressful life events and disability in early rheumatoid arthritis

The objective was to investigate the relationship of stressfullife events and disability in early rheumatoid arthritis (RA),taking into account a possible stress-buffering effect of thesocial network. As part of a European study (EURIDISS), 337early RA patients in France and The Netherlands (mean diseaseduration = 2.3 years) were interviewed for life events whichhad occurred in the past year. The social network compositionwas assessed using a standardized interview schedule and describedby network density and proximity characteristics. Disabilitywas assessed with the Health Assessment Questionnaire (HAQ)cross-culturally adapted to the French and Dutch languages.Subjects reported a median of 2 significant life events overthe past year. On average they had 20 persons in their socialnetwork. The disability was significantly higher when the numberof life events experienced was higher (r = 0.11; p<0.05)and when the number of social network members in monthly contactwith the subjects was lower (r = –0.13; p<0.05). Controllingfor country, the HAQ score increased significantly with thedisease duration, disease activity variables, number of lifeevents related to RA or to another health problem and decreasedwith the number of social network members. A significant (numberof health-related life events)x(number of social network members)cross-product term entered the model which fitted the data better(R² =0.51). Factors associated with disability are disease duration,disease activity, number of health-related life events and numberof social network members in monthly contact. The results suggesta stress-buffering effect of the social network in coping withstressful life events in early RA.     

Atrial Arrhythmias in Long-QT Syndrome under Daily Life Conditions: A Nested Case Control Study

Background: The long-QT syndromes (LQTS) are inherited electrical cardiomyopathies characterized by prolonged ventricular repolarization and ventricular arrhythmias. Several genetic reports have associated defects in LQTS-causing genes with atrial fibrillation (AF). We therefore studied whether atrial arrhythmias occur in patients with LQTS under daily-life conditions.
Methods: We systematically assessed atrial arrhythmias in LQTS patients and matched controls using implanted defibrillators or pacemakers as monitors of atrial rhythm in a nested case-control study. Twenty-one LQTS patients (3 male; 39 ± 18 years old; 18 on β blocker, ICD therapy duration 6.3 ± 2.7 years; 4 LQT1, 6 LQT2, 2 LQT3) were matched to 21 control subjects (13 male; 50 ± 19 years old; 3 on β blocker; pacemaker therapy duration 8.5 ± 5.5 years; 19 higher-degree AV block, 2 others). LQTS patients were identified by a systematic search of the LQTS patient databases in Münster and Munich.
Results: One-third (7 of 21) of the LQTS patients developed self-terminating atrial arrhythmias (atrial cycle lengths <250 ms). Only one control patient developed a single episode of postoperative AF (P < 0.05 vs LQTS).
Conclusions: LQTS patients at high risk for ventricular arrhythmias may develop short-lasting atrial arrhythmias under daily-life conditions, suggesting that prolonged atrial repolarization may contribute to the initiation of AF.     

European guidelines for the certification of professionals in sleep medicine: report of the task force of the European Sleep Research Society

In recent years, sleep medicine has evolved into a full-grown discipline, featuring a multidisciplinary approach to diagnosis and treatment of patients with sleep disorders. Sleep medicine cuts across the boundaries of different conventional disciplines and is therefore open to medical and non-medical professionals with different specialty backgrounds. The aim of the current paper is to introduce a qualification for those professionals whose main occupation is to practice sleep medicine in the setting of a sleep medicine centre. The drafting of guidelines dealing with requirements for such qualification was entrusted to a task force by the European Sleep Research Society. The guidelines are the result of a progressive consensus procedure in which standards were defined for education, training, and evaluation. The final step along this pathway is a theoretical and practical examination, providing proof of proficiency in the field of sleep medicine. This paper describes the object of specific competences, the scope of sleep medicine, and the qualification procedures that pertain to three professional categories: medical specialists, non-medical professionals with a university master degree (such as psychologists and biologists), and nurses and technologists. Indices of preceding practical experience and theoretical knowledge are presented in Appendices 1 and 2 . These guidelines are a European standard. They may be adapted in the future according to new scientific insights. National certification programs that comply with these guidelines may be subject to homologation by the ESRS.     

Association between Cardiac Autonomic Function and Coping Style in Healthy Subjects

The link between personality and cardiac function is insufficiently characterized. We postulated that in a healthy population, cardiac autonomic function is linked to coping style. In 276 healthy volunteers, between the ages of 18 and 71, the Utrecht Coping List was used to evaluate different coping strategies. Trait anxiety was scored by the Spielberger State Trait Anxiety Inventory. A 24-hour Holter recording was used to calculate heart rate variability (HRV). For HRV parameters and coping mechanisms this study demonstrated gender-specific differences and correlations with age. In men (n = 141) higher active coping was associated with less global autonomic activity or SDANN (r_s=−0.27, P < 0.001). This relationship was most prevalent in young (18–30 years) men (r_s=−0.45, P < 0.005). Higher expression of negative emotions or anger was related to both higher vagal (r_s= 0.23 for rMSSD, P < 0.01) tone and higher LF power (r_s= 0.23, P < 0.01). In young men expression of negative emotions or anger was associated with LF power (r_s= 0.37, P < 0.01) and in middle-aged (31–50 years) men with vagal tone (r_s= 0.43 for rMSSD, P < 0.005) and heart rate (r_s=−0.41, P < 0.005). Higher comforting ideas was related to higher LF power (r_s= 0.23 for LF power, P < 0.005), and this especially in middle-aged men (r_s= 0.37, P < 0.01). In women (n = 135), no significant correlations between coping style and HRV indices were found. We conclude that in normal individuals, at least in men, our findings suggest a relationship between coping style and cardiac autonomic function.