Pilot efficacy and tolerability: a randomized, placebo-controlled trial of levetiracetam for essential tremor.

The purpose of this pilot single-site study was to assess efficacy and safety of levetiracetam for essential tremor, using a placebo-controlled, double-blind, randomized crossover design with an interim analysis planned after completion of the first 10 to 15 subjects. The study was designed to detect a mean 30% reduction in composite tremor score, comparable to that of primidone or propranolol, which can be demonstrated with 30 or fewer subjects. Each treatment arm included baseline tremor assessments, a 4-week medication titration, 2 weeks of stable dose, and treatment tremor assessments. Levetiracetam was titrated to 3,000 mg/day or to a lower maximal tolerated dose. The median age was 72 years, with 28 years median tremor duration. There was no statistically significant difference in response between placebo and levetiracetam on any tremor rating scale or accelerometry measure. The 95% confidence interval for the true mean difference between placebo and levetiracetam treatments was +18.5 to -22.5%, which excludes the minimum 30% drop required to consider levetiracetam clinically effective to a degree comparable to primidone or propranolol. Whether levetiracetam has lesser-degree antitremor efficacy was not addressed in this pilot study.     

Additive effects of CD59 expression in Gal knockout mice in vitro but not in an ex vivo model

Abstract: Transgenic expression of the human complement regulatory molecule CD59 in mice and genetic deletion of the major xenoantigen galactose α 1,3 galactose (Gal KO) each resulted in partial protection of spleen cells from lysis by human serum. These protective effects were additive when the two genetic modifications were combined. However, when the effects of these genetic modifications were examined in an ex vivo model in which mouse hearts were perfused with human plasma, it was Gal KO which was the modification which determined protection. CD59 expression alone was not protective and CD59 expression in combination with Gal knockout did not result in a significant additional increase in protection over and above that provided by Gal knockout alone. The likely explanation for this discrepancy between the in vitro and ex vivo data is that the H2-K^b promoter used to drive CD59 expression results I in substantially less expression on endothelium than on spleen cells.     

Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium

Summary The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.C1 and milrinone at A₁ adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A₁ adenosine receptors, all compounds inhibited ³H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K_i-values, the rank order of potency was saterinone > sulmazole > UD-CG 212.C1 > milrinone. The new inotropic agents also displaced the binding of ³H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean K_i-values were considerably higher at m-cholinoceptors than at A₁ adenosine receptors. The rank order of potency was saterinone > sulmazole > UD-CG 212.Cl > milrinone. Competition of the A₁ adenosine receptor agonist R-PIA to ³H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient n_H = 0.63) and revealed two affinity states of the A₁ adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient n_H = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the superhigh affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p. Accordingly, in isolated, electrically driven human atrial trabeculae, the negative inotropic effect of adenosine was antagonized concentration-dependently by saterinone, sulmazole and UD-CG 212.Cl. Similarly the negative inotropic effect of carbachol was antagonized concentration-dependently by saterinone. It is concluded that the new inotropic agents bind to A₁ adenosine receptors and that their interaction is of antagonist nature. This mechanism might contribute to their capacity to enhance force of contraction by stimulation of cAMP-formation in addition to phosphodiesterase inhibition. The effects of saterinone may be partially due to antagonism at m-cholinoceptors. This is presumably not the case with the other inotropic agents studied given their low affinity for this receptor.Send offprint requests to M. Böhm at the above addressSupported by the Deutsche Forschungsgemeinschaft     

Small-airways dysfunction in never smoking asbestos exposed Danish plumbers

Summary Among 701 Copenhagen plumbers we examined the lung function of 23 never smokers, who had removed asbestos insulation and intermittently been exposed to high levels of asbestos for about 25 years without being exposed to welding fume. The plumbers had significantly lower TLC, MEF₂₅, MEF₅₀, closing volume and closing capacity in comparison to 23 never smoking electricians without asbestos exposure. There was no reduction in TL_CO. Pulmonary clearance of aerosolized ^99mTc-DTPA was normal indicating that the asbestos had not induced increases in pulmonary epithelial permeability. However, in 11 of the 23 plumbers the ^99m-Tc-DTPA ventilation scintigrams had a slightly irregular and spotty appearance, which together with the results of the lung function tests are suggestive of small airways' dysfunction. None of the subjects had symptoms or clinical signs of lung disease.     

Comparison of 2-drug and 3-drug immunosuppression for cadaveric renal transplantation

We compare the results in recipients of cadaveric renal allografts immunosuppressed with cyclosporine and prednisone to those who received immunosuppression with cyclosporine, azathioprine and prednisone. The 2 groups were compared relative to HLA-ABDR matching, plasma reactive antibodies, cold ischemia time, diabetes as a cause of renal failure and recipient age greater than 50 years. The incidences of clinical allograft rejection and grafts lost to rejection were not significantly different in these 2 groups evaluated at 1 year. In the 2-drug immunosuppressed group the actual 3, 6 and 12-month graft function was 87, 86 and 85%, respectively, compared to 79, 78 and 74%, respectively, in the 3-drug immunosuppressed group. A difference in graft survival was due to graft loss secondary to vascular thrombosis and patient death, and not to immunological events. No advantage was demonstrated for the use of 3-drug immunosuppression for kidney allografts over a 2-drug protocol of cyclosporine and prednisone.     

Influence of indenyl ligand substitution pattern on metallocene-catalyzed propene copolymerization with 1-octene

Copolymerization of propene with 1-octene (1 mol/1 mol) was performed in toluene at 40°C in the presence of homogeneous methylaluminoxane (MAO)-activated ansa-metallocenes in order to study the role of benzannelation and 2-methyl-substitution of the silylene-bridged bisindenyl ligand on comonomer incoporation, molecular mass, molecular mass distribution, and end groups. While 2-methyl-substitution promoted higher degree of polymerization without affecting copolymerization parameters, benzannelation improved markedly 1-octene incorporation. Only with MAO-activated rac-Me₂Si(2-MeBenz[e]Ind)₂ZrCl₂ catalysts vinylidene end groups were formed exclusively. Molecular weight distribution remains narrow in all experiments.     

Mortality patterns among hypertensives by reported level of caffeine consumption

The effect of caffeine consumption on mortality was evaluated in a historical cohort study of 10,064 diagnosed hypertensive individuals participating in the Hypertension Detection and Follow-up Program from 1973 to 1979. Total caffeine intake level from beverages (coffee and tea) and certain medications, was estimated at the 1-year visit. No evidence was found supporting an association between increased level of caffeine consumption and increased all-cause mortality or cardiovascular disease mortality during the following 4 years. Cigarette smoking was significantly associated with mortality; the association being more pronounced among non- and low-caffeine consumers for all-cause mortality and among non-caffeine consumers for all cardiovascular mortality except cerebrovascular mortality.