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Zusammenfassung: Hintergrund. Reboxetin ist ein selektiver NARI (Noradrenalin reuptake inhibitor). Da Noradrenalin eine relevante Rolle bei antinozizeptiven Mechanismen spielt, sollte in dieser Studie die Hypothese untersucht werden, ob Reboxetin analgetisch wirksam ist. Methodik. Es wurden 24 gesunde Probanden in einem Cross-over-Design untersucht. Reboxetin (2×2 mg) oder Plazebo wurden über 5 Tage verabreicht. Der Therapiewechsel erfolgte nach einem Wash-out von einem Tag. Der primäre Endpunkt waren die N1- und P2-Amplituden von laserevozierten, somatosensorischen Potenzialen (Laser-SEPs) aus dem Vertex-EEG. Zusätzlich wurden visuelle Analogskalen (VAS, 100 mm) verwendet. Ergebnisse. Reboxetin zeigte eine bessere analgetische Wirkung als Plazebo mit statistisch signifikanter Überlegenheit bei mit Capsaicin gereizter Haut – sowohl bei der objektiven (Laser-SEPs; p<0,0001 für die N1- und p=0,0002 für die P2-Komponente), wie auch der subjektiven (VAS, p<0,0003) Schmerzmessung. Neben dem Schmerz war auch das subjektive Jucken und Brennen nach Capsaicin unter Reboxetin deutlich niedriger als unter Plazebo. Schlussfolgerung. Die theoretische Vorstellung, dass eine selektiv noradrenerge Substanz analgetisch effektiv sein kann, wurde erstmals experimentell bestätigt. Reboxetin reduzierte die N1- und P2-Komponenten der Laser-SEPs, was für einen zentralen und peripheren Angriffspunkt spricht.

Summary K12.148 (INN: lifibrol), a new cholesterol synthesis inhibitor, was studied in healthy volunteers to evaluate tolerance/safety, the effects on lipids, and pharmacokinetics. In a sequential block design the doses of 150, 300, 600, or 900 mg, given once daily in the morning for 14 consecutive days, were examined in 40 healthy young males (8 active drug and 2 placebo per group, randomized) under well-controlled conditions. Total and LDL cholesterol serum levels decreased significantly in the 300, 600, and 900 mg groups ( -13.4% , - 23.8%, -25.6%, and -14.7%, -33.3%, -34.8% respectively), whereas no significant change was seen with placebo and 150 mg. The antiatherogenic index Apo A-I/B increased in a dose-dependent manner between 300 and 900 mg. Changes in HDL cholesterol and triglycerides were not statistically significant. The study compound was tolerated well, and safety laboratory parameters did not show any relevant alterations. K 12.148 might be a very effective drug for the treatment of hypercholesterolemia.

Summary: K 12.148 (INN: lifibrol), a new cholesterol synthesis inhibitor, was studied in healthy volunteers to evaluate tolerance/safety, the effects on lipids, and pharmacokinetics. In a sequential block design the doses of 150, 300, 600, or 900 mg, given once daily in the morning for 14 consecutive days, were examined in 40 healthy young males (8 active drug and 2 placebo per group, randomized) under well-controlled conditions. Total and LDL cholesterol serum levels decreased significantly in the 300, 600, and 900 mg groups (−13.4%, −23.8%, −25.6%, and −14.7%, −33.3%, −34.8% respectively), whereas no significant change was seen with placebo and 150 mg. The antiatherogenic index Apo A-I/B increased in a dose-dependent manner between 300 and 900 mg. Changes in HDL cholesterol and triglycerides were not statistically significant. The study compound was tolerated well, and safety laboratory parameters did not show any relevant alterations. K 12.148 might be a very effective drug for the treatment of hypercholesterolemia.

1.Guinea-pig papillary muscles contracting at frequencies of 0.25 to 1 Hz after rest periods long enough to be followed by a rested-state contraction showed a biphasic staircase phenomenon. An initial phase was completed within about 6 beats (fast phase of the staircase). Then a slow phase followed reaching a steady state after about 4 min only. The effect on this slow phase exerted by drugs known to influence transmembrane Na-flux was investigated.2.Dihydroouabain in concentrations (1.5–5×10-5 mol/l), causing no increase in the rested-state contraction considerably augmented the slow phase of the staircase thereby prolonging the time from the onset to the steady state by severalfold. The fast phase, however, remained unchanged as far as the steepening slow phase did not influence it.3.The rest decline of force of contraction, measured by repeated interruption of stimulation, was considerbly prolonged by dihydroouabain (to about sixfold the control value by 5×10-5 mol/l).4.However, dihydroouabain did not influence the time course by which the force of contraction decreased after lowering the [Ca]0 from 3.2 to 0.8 mmol/l.5.Stimulation of the muscles in Ca-free medium produced a transient increase in force of contraction as visualized by test contractions after addition of Ca. This positive inotropic aftereffect which depended on the frequency of stimulation in the Ca free solution was augmented severalfold by 1.5 to 3×10-5 mol/l dihydroouabain.6.Tetrodotoxin in a concentration (10-5 mol/l) inhibiting the fast initial Na-current of excitation, as shown by a lowering of the depolarization velocity of the action potential, diminished the slow phase of the staircase without altering its time course.7.Veratridine (1.6×10-6 mol/l) considerably augmented the slow phase of the staircase without markedly influencing its time course. Likewise veratridine did not influence the time course of the rest decay of force of contraction.8.The effect of veratridine on the slow phase of the staircase was suppressed by tetrodotoxin.9.It may be concluded that the slow phase of the staircase and the subsequent rest decline of force of contraction reflect the time course by which the intracellular Na activity changes as a result of the interaction of passive Na influx and active Na extrusion. The effects of veratridine and tetrodotoxin are interpreted as a consequence of their effect on the Na-uptake occurring with the action potential. The cardioactive steroid influences the time course as well as the height of the slow phase of the staircase by inhibition of cellular Na-extrusion.

1.In isolated guinea-pig papillary muscles, noradrenaline (10-7–10-4 M) augmented the peak force of contraction after rest periods of 10–15 min (rested-state contractions) to the same extent as during continued stimulation at rates of 0.2–1 Hz. However, there were great differences in the shape of the isometric contraction curves dependent upon the two experimental conditions.2.The rested-state contractions developed with a latency of about 100 ms and reached peak force more than 200 ms after the stimulus. Noradrenaline increased this late contraction manyfold without a shortening of the latency period.3.In addition to the late contraction peak, an early contraction component developed at 0.2 Hz frequency. It reached its maximal force within the first 100 ms after the stimulus. Noradrenaline, in the same concentration range, increased the force and steepness of the early component of contraction to about the same extent as of the late component, i.e., the rested-state contraction.4.Increasing the frequency of contraction up to 1 Hz augmented the early component of contraction and diminished the late component, concomitantly with a shortening of the action potential and the total contraction time.5.In regard to the influence on the two components of contraction, dibutyryl-cyclic-adenosine-monophosphate (1–4 mM) resembled that of noradrenaline.6.In contrast to the rested-state contractions as influenced by noradrenaline or dibutyryl-cyclic-AMP, rested-state contractions, increased either by a high concentration (2×10-4 M) of dihydro-ouabain or by a reduction of the external sodium concentration (to 40 mM), showed a steep rise early after the stimulus and reached peak force within 125 ms.7.It is concluded that, in the resting muscle, noradrenaline augments Ca accumulation by a cellular store (store II), probably the sarcoplasmic reticulum. Ca ions, released from this store with a latency during a long lasting action potential, cause the late appearing rested-state contraction. After its release, part of the Ca may be bound by another store (store I, located probably at the sarcolemma); from this it is set free during subsequent excitations, thereby causing an additional early component of contraction.

1.Contractures of guinea-pig papillary muscles, induced either by potassium withdrawal or by high potassium concentrations, were investigated under the influence of noradrenaline and dihydro-ouabain, respectively.2.Noradrenaline in concentrations between 10-7 M and 10-5 M enhances contractures induced by high [K+]0. There is a parallel shift of the relation between contracture force and [K+]0 towards lower potassium concentrations. The effect of noradrenaline on the time course of contracture equals the effect of a rise in [Ca2+]0. The contracture-enhancing effect of noradrenaline is not accompanied by an influence on potassium-dependent depolarization.3.Even at high concentrations (3.5×10-5 M), noradrenaline does not increase contractures induced by potassium withdrawal.4.In concentrations which increase the force of contraction (10-5–4×10-5M) dihydro-ouabain, in contrast to noradrenaline, enhances potassium-withdrawal contractures. Dihydro-ouabain does not change the hyperpolarization of the cardiac cells elicited by potassium withdrawal.5.There is no noteworthy contracture after potassium withdrawal and simultaneous reduction of [Na+]0 to 25 mM, if [Ca2+]0 is only 1.6 mM. However, contracture develops under these conditions after a brief transitory rise of [Na+]0 to 140 mM. This contracture is increased and prolonged by dihydro-ouabain.6.Contractures induced by elevation of [K+]0 can be enhanced by high concentrations of dihydro-ouabain (6×10-5–2×10-4 M). The maximal effect of dihydroouabain on potassium contracture is greater than that on potassium-withdrawal contracture.7.It is concluded that noradrenaline enhances contractures of papillary muscles by an influence on a steady Ca entry from the extracellular solution in dependence upon [K+]0 and membrane depolarization, respectively. On the other hand, dihydroouabain increases contracture force by the same mechanism as potassium with-drawal, i.e., by an inhibition of the sodium pump with consequent increase in exchange of intracellular sodium against extracellular calcium.

The efficacy and safety of lifibrol, a novel cholesterol-lowering drug, was investigated in a double-blind clinical study in 168 patients with primary hypercholesterolaemia. Placebo and four lifibrol dose groups (150, 300, 450 and 600 mg/day) were tested over a period of 4 weeks.

Summary An increase in extracellular potassium concentration from 4 to 16 mmol/l caused a decrease in membrane potential from −92 to −59 mV and selectively diminished the earlier of two contraction components of guinea-pig papillary muscles at 0.2 Hz stimulation frequency in the presence of noradrenaline. The influence on the early contraction component had a threshold of 8 mmol/l K+, corresponding to a membrane potential of −77 mV. However, test contractions elicited 800 ms after the 5 s stimulation interval exhibited an unimpaired early component. Since the activator calcium responsible for the early contraction component is derived, in mammalian ventricular muscle, from the junctional sarcoplasmic reticulum (20), it is assumed that the release site of the reticulum was filled with calcium shortly (800 ms) after a regular contraction, and lost its calcium at 16 mmol/l extracellular K+ during the 5 s stimulation interval. The potassium-induced depolarization determined the rate of calcium leakage during rest from the intracellular store. The depolarization-induced decline of the early contraction component was equally well antagonized by Mg2+ or Ca2+ without influencing the measured transmembrane potential. Both divalent cations shifted the relation between potassium concentration or membrane potential and the strength of the early contraction component to less negative membrane potentials. In order to reduce the early contraction component by 25% in the presence of 9.6 instead of 1.2 mmol/l Mg2+, the potassium concentration had to be increased from 9.6 to 22.0 mmol/l, with a respective decrease in resting membrane potential from −72.6 to −51.1 mV. The antagonistic effect of both divalent cations is thought to result from the neutralization of negative charges outside the sarcolemma with a respective decrease in the outside surface potential.

Summary Under normal experimental conditions, the force of rested-state contractions (i.e., contractions after a rest period of 15 min or longer) of mammalian ventricular myocardium is insignificant. In Mg2+-free solution, in low sodium solution or in the presence of a cardioactive steroid, a strong “early” restedstate contraction develops without delay after stimulation, indicating the accumulation during rest of intracellularly stored activator calcium. By contrast, catecholamines cause a “late” rested-state contraction with a characteristic latent period of about 100 ms between stimulation and onset of contraction.

Summary

Summary Different types of rested-state contractions were examined under the influence of various inotropic agents. In magnesium-free solution, in low sodium (40 mmol/l) solution or in the presence of dihydroouabain, an “early” rested-state contraction developed without delay after stimulation. A distinctive “late” rested-state contraction was observed under the influence of noradrenaline. It is characterized by a latent period of about 100 ms between stimulation and onset of contraction. This latency was not reduced by increasing the catecholamine concentration, despite a concentration-dependent increase in the hight of the “late” rested-state contraction. The late rested-state contraction under the influence of noradrenaline was suppressed by the slow inward current inhibitor nifedipine whether or not the nifedipine-dependent shortening of the action potential duration was prevented by caesium.

Zusammenfassung Bei 36 Patienten wurden mittels der Elektrostimulation bei Lage einer Schrittmachersonde im rechten Ventrikel Refraktärzeitbestimmungen der Kammermuskulatur vorgenommen. In einem Teil der Fälle wurde eine Parasystolie ausgewertet, die entweder experimentell erzeugt wurde oder nach der Schrittmacherimplantation spontan auftrat; in einem anderen Teil wurde die gekoppelte und gepaarte Stimulation zur Refraktärzeitbestimmung herangezogen. Unabhängig von der jeweils verwendeten Methode zeigen die Ergebnisse eine annähernd lineare Beziehung zwischen dem vorausgehenden RR-Intervall im EKG und der Refraktärzeit.

Summary The positive inotropic effect of noradrenaline on the guinea-pig papillary muscle is potentiated in the presence of 1×10−5 M tyramine, the concentration of noradrenaline that is necessary to produce a half maximal increase in force of contraction being reduced to about one third. There is no alteration of the maximal inotropic effect since the concentration-effect curve of noradrenaline is simply shifted to the left.

Summary Tachyphylaxis and susceptibility to pretreatment with reserpine demonstrate that tyramine increases contractility of the guinea-pig papillary muscle in concentrations up to 10−4 M by means of an indirect sympathomimetic effect.

Zusammenfassung Es wird über den Fall einer primären Oxalose einer 44jährigen Frau berichtet. Hervorzuheben ist neben einem Raynaudschen Syndrom die Manifestation der Erkrankung am Herzen in Form von Calciumoxalatablagerungen mit ausgeprägter granulomatöser fibroplastischer Myokarditis, Herzmuskelnekrosen und entsprechenden Funktions-störungen des Herzens. Eine Zusammenstellung der Literatur über die primäre Oxalose aus kardiologischer Sicht wird gegeben.

Summary The positive inotropic effect of a reduction of [K+]e from 5.9 mM to 1.2 mM or less depends on the extracellular concentration of sodium. The increase in contractility is greatly reduced or prevented if [Na+]e has been diminished from 140 mM to 70 mM (with the addition of sucrose).

1.Contractures of guinea-pig papillary muscles were induced at reduced (Na+]0 by means of potassium elevation, potassium withdrawal and electrical stimulation, respectively.2.The force development of the contractures is biphasic. After a period of several minutes, a small initial force development (first-phase contracture) is followed by the main part of force development (second-phase contracture). The time course of the biphasic contracture is reproducible and it is unaltered in papillary muscles depleted of noradrenaline by pretreatment of the animals with reserpine, 5 mg/kg.3.In contrast to the contracture induced by an elevation of [K+]0, the membrane depolarization develops monophasically. 88% of the depolarization is reached 75 sec after the elevation of [K+]0. At 40 mM Na+ and 5.2 mM Ca2+, the potassium-induced contracture has its threshold at a membrane potential (MP) of -53 mV which is obtained by an increase in [K+]0 to 22.5 mM. With higher [K+]0, the magnitude of force development during both contracture phases increases and the duration of the first-phase contracture decreases. Maximal contracture force is reached at 55 mM K+ which corresponds to a MP of about -30 mV.4.Changes in [Na+]0 and [Ca2+]0 do not influence time course or degree of the potassium-induced membrane depolarization. However, an increase of [Ca2+]0 from 2.0 mM to 7.8 mM or a decrease of [Na+]0 in the range between 74 mM and 32.5 mM have a contracture-enhancing effect similar to that of a variation in [K+]0 between 22.5 mM and 55 mM at constant [Na+]0 and [Ca2+]0.5.During the hyperpolarization following a reduction of [K+]0 to zero, a biphasic contracture develops after [Na+]0 is reduced to 25 mM. The contracture is enhanced if the reduction of sodium is preceded by a period during which the muscle is kept in a solution with 140 mM Na+ without K+. This indicates the importance of sodium ions for the mechanism of contractures produced by potassium withdrawal.6.If a papillary muscle, in a solution containing 25 mM Na+ and 5.9 mM K+, is electrically stimulated, single contractions are followed by aftercontractions. The muscle oscillates during the intervals between the stimulation-induced conctractions about a “diastolic” resting force which increases biphasically as in the other contracture experiments. With increasing “diastolic” force, the height of the single contraction declines.7.During oxygen deficiency, produced by replacement of oxygen by nitrogen in the gas mixture, the force of the second-phase contracture increases, while the duration of the first-phase contracture decreases. This indicates that an energy requiring process antagonizes foree development during the contracture of guinea-pig cardiac ventricular muscle, thereby determining its time course and magnitude.