Value of ambulatory electrocardiographic monitoring to identify increased risk of sudden death in patients with left ventricular dysfunction and heart failure

To examine the predictive value of ventricular arrhythmias onambulatory electrocardiographic (ECG) monitoring, 211 patientswith left ventricular dysfunction and congestive heart failure(76% men, age 63±4 years, left ventricular ejection fraction0.26 ± 0.10) were studied. During a follow-up of 21 ±11 months, there were 45 cardiac deaths: 22 were due to progressivepump failure and 23 were sudden. Patients with a low left ventricularejection fraction ( 0.27) and ventricular tachycardia on 24h ECG were at higher risk of dying suddenly and from progressivepump failure (both P<0.0001). Patients who died suddenlywere found to have significantly longer (P=0.003) and faster(P=0.029) ventricular tachycardias on their baseline ambulatoryECG, than survivors. This association was not observed in patientswho died of progressive pump failure. Therefore, low left ventricularejection fraction and ventricular tachycardia on 24 h ECG recordingpredict an increased risk of cardiac mortality. Our resultsalso suggest that longer and faster ventricular tachycardiarecorded by 24 h ECG may identify patients at risk of suddendeath, a finding which has not been described before.     

EARLY AGALACTOSYLATION OF IgG IS ASSOCIATED WITH A MORE PROGRESSIVE DISEASE COURSE IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS OF A FOLLOW-UP STUDY

The clinical significance of the percentage agalactosyl IgGoligosaccharides [%G(O)] was investigated in serum of a well-characterizedcohort of 127 female RA patients who were followed for a meanduration of 6 yr. The %G(O) was determined in the first availableserum sample which was obtained at a mean of 3.4 yr after symptomonset. It could be shown that patients with a %G(O) more than2 S.D. above the mean level of controls (n = 34), had significantlymore erosions, disease activity, and were treated with moresecond-line drugs, than patients without an increased %G(O)(n = 93), both at the time the serum sample was obtained, andduring follow-up. These findings suggest that G(O) may serveas an indicator for the disease course in patients with RA. KEY WORDS: Agalactosyl IgG, Prognosis, Outcome     

FATAL CHOLESTATIC HEPATITIS CAUSED BY D-PENICILLAMINE

A 37-yr-old woman with RF-positive RA developed cholestatichepatitis after 10 days of D-penicillamine therapy. This wasdiscontinued immediately. The cholestasis persisted for theremaining 14 months of her life. Severe hypercholesterolemiadeveloped with xanthelasmata and eventually pancytopenia, whichwas caused by a massive infiltration of the bone marrow by lipidcontaining foam cells. The patient died of sepsis. Review ofthe literature shows intrahepatic cholestasis to be a rare andidiosyncratic complication of D-penicillamine therapy. To ourknowledge, ours is the first documented case of persistent cholestaticicterus. KEY WORDS: Cholestatic hepatitis, Jaundice, Adverse reactions, Drug-allergy, D-Penicillamine     

Determination of left ventricular volume by two-dimensional echocardiography: comparison with magnetic resonance imaging

Left ventricular volume was determined in 12 healthy volunteersusing a newly developed two-dimensional echocardio-graphic delineationmethod. The results were compared with those of magnetic resonanceimaging, which served as the method of reference. Left ventricularend-diastolic volume was 123 ± 12 ml, echocardiographicallydefined, and 121 ± 12 ml calculated with magnetic resonanceimaging. End-systolic volume was 41 ± 7 ml on echocardiographyand 37±6 ml on magnetic resonance imaging. Left ventricularejection fraction was 67 ± 4%, echocardiographicallydefined, and 70 ± 5%, calculated with magnetic resonanceimaging. There was no statistical difference for any of themeasured parameters. Interstudy and inter-observer variabilitywas minimal. In conclusion, in healthy volunteers left ventricularvolume was accurately defined, using this newly developed two-dimensionalechocardiographic delineation method. During endocardial delineationa dynamic display is continuously available on a second window,allowing precise visual edge-detection. Moreover, correctionscan be made easily and quickly. These two advantages enhancethe accuracy of the method, even in cases of poor echogenicity.     

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.     

Induction of Cytochrome P450 Isoenzymes after Toxicokinetic Interactions between 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-Hexachlorobiphenyl in the Liver of the Mouse

One group of male C57BL/6J mice received a single oral doseof 1 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg. Sixother groups received single oral doses of 100, 300, or 1000µmol2,2',4,4',5,5'-hexachlorobiphenyl (HxCB)/kg, alone or in combinationwith 1 nmol/kg TCDD. Liver deposition of both compounds wasstudied at Day 3 after dosage. Hepatic CYP1A1 and CYP1A2 proteinlevels and related 7-ethoxyres-orufin-O-deethylation (EROD)and acetanilide 4-hydroxylation (ACOH) activities were alsostudied. A significant increase in the hepatic deposition ofTCDD was observed in all three mixed dose groups but TCDD didnot influence hepatic HxCB deposition. TCDD did increase bothCYP1A1 and CYP1A2 protein levels. In the HxCB-treated groups,CYP1A2 levels were also increased in a dose-dependent way butCYP1A1 levels were not increased. CYP1A2 activities (ACOH),but not protein levels, in the TCDD groups cotreated with HxCBwere higher than those in the group treated with TCDD alone.CYP1A1-dependent EROD activity and CYPlA2-dependent ACOH activitywere induced in all treated dose groups. It is concluded thatthe present results do not confirm a direct role of CYP1A2 inductionin the increase of hepatic TCDD levels by HxCB cotreatment inthe mixed HxCB/TCDD dose groups. However, in this aspect, thediscrepancy between CYP1A2 activities and protein levels remainsto be explained.     

Perinatal epidemiology in Belgium

Data on the civil registration of all births and deaths recordedin 1987 in Belgium were analysed following WHO rules. The followingstatistics with significant regional variations were recorded:2.5% of teenage pregnancies, 7% of late pregnancies (35 years),6.1% of low birth weights and 5.3% of preterm deliveries. Pretermbirth rates did not improve during the last decade and are higherthan in neighbouring countries. Infant mortality rate is 9.74per 1000. This rate has remained unchanged since the early 1980sbut the relative importance of post-neonatal mortality is increasing.Congenital anomalies account for 26% of all infant deaths followedby the sudden infant death syndrome (17%). Maternal conditionssuch as eclampsia are related to 29% of the infants' deaths.     

Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response

1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite >6 months of SASP treatment.
2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two- compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis.
3. Pharmacokinetics of MTX without vs with SASP, means±s.d. were as follows: AUC: 673±179 vs 628±210 (95% confidence interval [CI] of the difference was −71 to 159) ng ml⁻¹ h, MRT: 5.2±1.3 vs 5.2±1.1 (95% CI −0.4 to 0.4) h, t½,z: 4.3±1.1 vs 4.2±1.1 (95% CI −0.3 to 0.5) h, V /F: 59.3 ±29.3 vs 65.5±25.3 (95% -23.8 to 11.4) l, CL/F: 12.3±5.0 vs 13.5±4.8 (95% CI −4.5 to 2.3) l h⁻¹. CL_R/F: 6.2±1.3 vs 6.3±2.1 (95% CI −1.3 to 1.1) l h⁻¹. All P values were ≥0.3.
4. A weak correlation existed between the change of ESR and the MRT, the t½,z and the V /F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05<P<0.1).
5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables of MTX.

     

A PHARMACODYNAMIC MODEL FOR PANCURONIUM

It has been demonstrated that a simple two-compartment kineticmodel may account for the changes in plasma concentration ofpancuronium after i.v. administration. However, it can be shownthat this simple model does not account satisfactorily for theobserved changes in muscle twitch response. By the additionof a receptor (biophase) compartment, twitch response can bereconciled with model behaviour and the characteristics resemblethose predicted by animal studies. The complete model is appliedto the problem of total renal failure, and shows that patientswith this condition are likely to be marginally resistant tosmall doses of pancuronium, with a normal rate of recovery.However, larger doses are likely to result in delayed recovery,the duration of effect increasing in a dose-dependent manner. Communications to C. J. Hull.     

EVALUATION OF THE SELECTIVITY OF α-ADRENORECEPTOR BLOCKING DRUGS FOR POSTSYNAPTIC α1- AND α2-ADRENORECEPTORS IN A SIMPLE ANIMAL MODEL

• 1 The increase in diastolic pressure of pithed, normotensive rats was determined after i.v. administration of the α-adrenoreceptor agonists L-phenylephrine and B-HT 933.
• 2 α-Adrenoreceptor antagonists varied widely in their relative inhibitory effects towards either L-phenylephrine- or B-HT 933-induced vasoconstrictor responses. Prazosin displayed the highest affinity for the postsynaptic α-adrenoreceptor triggered by L-phenylephrine. The rank order of potency was further: phentolamine > dihydroergotamine > clozapine > corynanthine > azapetine > yohimbine > piperoxan > tolazoline > mianserin > rauwolscine. On the other hand, the rank order of potency towards B-HT 933 was: dihydroergotamine > rauwolscine > yohimbine > phentolamine > piperoxan > prazosin > tolazoline > mianserin > corynanthine > azapetine > clozapine. These data are in general agreement with the classification for α1-(triggered by L-phenylephrine) and α2-(triggered by B-HT 933) adrenoreceptors. Both populations are present postsynaptically in vascular smooth muscle of the pithed rat and are involved in vasoconstriction.
• 3 The ratio of K_B post α2/K_B post α1 was calculated as a measure of selectivity for either α-adrenoreceptor site. The α-adrenoreceptor antagonists used cover a 20,000-fold range of activity ratios. The antagonists most selective for either type were prazosin (α1) and rauwolscine (α2). The selectivity of the α-adrenoreceptor antagonists for postsynaptic α1- and α2-adrenoreceptors in the intact circulatory system of the pithed rat is comparable with the reported selectivity of these blocking agents for α1 (postsynaptic)- and α2 (presynaptic)-adrenoreceptors in the rabbit isolated pulmonary artery.
• 4 It is concluded that two distinct types of postsynaptic α-adrenoreceptors participate in vasoconstriction in the pithed rat. Apart from the classical α1-adrenoreceptor, vascular smooth muscle of the pithed rat contains postsynaptic α2-adrenoreceptors resembling those previously found mainly presynaptically. The presence of separate classes of postsynaptic α1- and α2-adrenoreceptors in the intact circulatory system of the pithed rat offers the possibility to use this relatively simple animal model as an in vivo test system for the pharmacological characterization of α-adrenoreceptor agonists and antagonists.