Polymerization of lactams, 88. Copolymers poly(ϵ-caprolactam)-block-polybutadiene prepared by anionic polymerization,part III. Model polymerizations initiated with potassium salt of ϵ-caprolactam and accelerated with isocyanates and their derivatives

Anionic polymerization of ?-caprolactam was initiated with the potassium salt of ?-caprolactam and accelerated with phenyl isocyanate, toluylene diisocyanate, 4,4′-diphenylmethane diisocyanate, some derivatives of these isocyanates (urethanes, ureas, and allophanates), or combinations of phenyl isocyanate with its derivatives at 150°C. The effect of individual structures on the polymerization kinetics and their contribution to the preparation of block copolymers of ?-caprolactam with hydroxy-terminated prepolymers, in-situ functionalized with diisocyanates, are discussed on the basis of a detailed analysis of time functions of polymer yield and degree of polymerization.     

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Objective: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. Methods: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined␣with positron emission tomography (PET) with [¹¹C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of binding of [¹¹C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. Conclusion: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals. Received: 21 August 1996 / Accepted in revised form: 22 November 1996     

Oral administration of methylergometrine shows a late and unpredictable effect on the non-pregnant human menstruating uterus

Objective: To study the pharmacodynamic and pharmacokinetic properties of oral and intravenous methylergometrine upon uterine motility during menstruation. Study-design: Intra-uterine pressure was measured in six volunteers with a fluid-filled sponge-tipped catheter during menstruation. Methylergometrine was given orally (0.5 mg) or intravenously (0.2 mg) in a cross-over design. Results: After intravenous administration, a fast increase of the frequency of uterine contractions and basal tone occurred with a decrease of amplitude, lasting at least 30 min. Oral administration had a late and less marked effect on uterine motility. An intravenous dose administered 24 h after an oral dose had no effect on uterine motility. Pharmacokinetic data, such as the maximum plasma concentration (C_max), the time at which C_max is reached (t_max) and the half-life of absorption (t_1/2abs) also demonstrated large individual variations after oral administration. Conclusion: Oral administration of methylergometrine had an unpredictable and late effect on uterine motility on the menstruating uterus, probably due to an unpredictable bioavailability, in contrast with the fast and predictable effect after intravenous administration.     

Prospective study of antigenemia,plasma viremia and lymphocytic viremia in HIV-infected hemophiliacs

A total of 186 blood samples from 24 HIV-1 seropositive hemophiliac patients, monitored every four months for 29 months, were investigated for the presence of viral antigen in plasma. In addition, peripheral blood mononuclear cells (PBMC) were cultured for HIV-1, using normal PBMC as a target for replication. Antigenemia was detected in 51 % of the patients and from PBMC in 87.5 % of the patients. The incidence of HIV isolation in asymptomatic patients (42.8 %) was similar to that found in symptomatic patients (51.4 %). Patients with opportunistic infections had a higher incidence of lymphocytic viremia (p<0.05). Plasma viremia was closely associated (p<0.05) with low CD4+ counts and infection progression. The persistence of antigenemia was also a marker of a poor clinical course. In treated patients, plasma viremia was the marker that better correlated with the clinical course, and it did not appear during the first nine months of therapy. Zidovudine doses of >500 mg/day significantly lowered the appearance of antigenemia and lymphocytic viremia (p<0.05).     

Static stabilizers of the shoulder joint

Anatomic dissection of 220 cadaver shoulders was performed to find out more about the static stabilizers of the shoulder joint. The static stabilizers, i.e. the glenohumeral ligaments, were always found to be present and strong in healthy shoulders. It was revealed that in anatomic preparations with all the organs removal except the synovial capsule, the capsule ligaments completely stabilized the joint. Anterior dislocation at 45 degrees of abduction was prevented by the superior and medial glenohumeral ligaments, while at 90 degrees of abduction the inferior glenohumeral ligament prevented dislocation. When anterior dislocation has occurred even the coracohumeral ligament must be ruptured. A new finding recorded is that the glenoid labrum is the origin of the inferior glenohumeral ligament and not a triangular static organ enlarging the socket and having a similar function to the menisci in the knee. This ligament is the most important ventral stabilizer of the humeral joint. With the conventional arthrotomy technique the medial and inferior ligaments are immediately cut through and therefore cannot be seen. The inferior glenohumeral ligament must be reconstructed in cases of anterior recurrent dislocation.     

Synthesis of N-(phosphonoacetyl)-dipeptide derivatives and evaluation of their antihypertensive activity

A series of N-(phosphonoacetyl)-dipeptide derivatives was synthesized for pharmacological testing as antihypertensive compounds. Several of these compounds demonstrated a moderate antihypertensive effect in Wistar spontaneous hypertensive rats (SHR) with p.o. dosing. ACE inhibition by the compounds was studied using ACE from rat plasma and lung. Inhibitors containing esterified C-termini are pro-drugs and showed activity only for plasma ACE.