Use of a polyvalent bacterial lysate in patients with recurrent respiratory tract infections: results of a prospective, placebo-controlled, randomized, double-blind study.

Respiratory tract infections (RTIs) are the most common infections in humans, and it is difficult to effectively treat patients with increased susceptibility to these ailments. LW 50020 (Luivac; Paspat oral), an oral immunomodulator consisting of the antigens of seven bacteria commonly involved in RTIs, has been developed for the induction of specific and nonspecific immune responses of the mucosa-associated lymphoid tissue. In this placebo-controlled study, the efficacy and safety of the tablet formulation of LW 50020 were evaluated in children and adults with recurrent RTIs. Tablets were taken once daily during two periods of 4 weeks each, interrupted by a treatment-free interval of 4 weeks. The main endpoint of the study, a clinical severity score that evaluated treatment benefits, was significantly lower in the second study period in patients treated with the bacterial lysate compared to patients given placebo. A comparison of the infection rates in the first and second study periods of patients treated with LW 50020 revealed a placebo-corrected reduction of 39% in children and a placebo-corrected reduction of 44% in adolescents and adults. The placebo-corrected duration of infections was shortened by 47% in children and by 55% in older patients. No serious drug-related side effects occurred. This study demonstrated that the oral bacterial immunomodulator LW 50020 is efficacious in treating patients with recurrent RTIs.

Effect of repeated Aprosulate and Enoxaparin administration on tissue factor pathway inhibitor antigen levels.

Tissue factor pathway inhibitor (TFPI) is a naturally occurring, Kunitz-type serine protease inhibitor whose anticoagulant activity is due to an inhibition of the extrinsic coagulation pathway. Heparin injection has previously been shown to increase the plasma levels of TFPI. In this study, plasma samples were obtained from a multiple dose phase I tolerance study with a synthetic analogue of heparin, namely Aprosulate (PALLAS). Volunteers were randomized into four treatment groups: (A) 35 mg Aprosulate b.i.d. s.c.; (B) 70 mg Aprosulate b.i.d. s.c.; (C) 70 mg Aprosulate o.d. + placebo o.d. s.c.; (D) 40 mg of a low molecular weight heparin, Enoxaparin o.d. + placebo o.d. s.c. All treatments were for 7 days, with blood samples taken periodically over this time period. TFPI antigen levels were determined using Imubind TFPI ELISA kits (American Diagnostica, Greenwich, CT). TFPI antigen levels were observed to rapidly increase to levels two- to three-fold over baseline in all groups. Aprosulate caused a slightly larger increase in TFPI antigen levels than Enoxaparin, though this may be related to the doses chosen for this study. These data indicate that plasma concentrations of TFPI are increased following Aprosulate administration. TFPI may be important in mediating the antithrombotic activity of Aprosulate.

Topical treatment of acute sprains.

In a randomised, placebo-controlled, double-blind study with parallel group comparison, the efficacy and tolerability of topical treatment with a mucopolysaccharide polysulphate/salicylic acid cream was investigated in 156 patients with acute sprains of the knee or ankle joint. There was a more rapid reduction in pain on movement (the main parameter) in the active drug group compared with the placebo group. On day 9 after randomisation the difference was highly significant. There were no adverse events in the active drug group.

Phase I--study with aprosulate, a new synthetic anticoagulant.

This paper describes the first human study with aprosulate, a new chemically synthesized anticoagulant with a defined molecular structure and a molecular weight of 2388. Twelve healthy male volunteers received subcutaneous injections of placebo on the first day followed by ascending doses of aprosulate in the range of 0.25 mg/kg to 2.0 mg/kg body weight on alternate days. Anticoagulant, pharmacokinetic and safety parameters were assessed for 48 hours after each injection. The activated partial thromboplastin time and the Heptest showed a dose-dependent increase for up to ten hours after each application. A trend towards prolongation of the bleeding time was indicated with higher doses. In general, the tolerance was good. Plasma transaminase concentrations were raised in some volunteers but returned spontaneously to normal during or after the study.

Comparison of plasma bismuth levels after oral dosing with basic bismuth carbonate or tripotassium dicitrato bismuthate.

In 20 healthy subjects plasma bismuth concentration was measured after single oral doses of basic bismuth carbonate or tripotassium dicitrato bismuthate. The drugs were administered in the fasted state or immediately after ingestion of a standard breakfast. After basic bismuth carbonate, plasma bismuth rose to concentrations between 0.7 and 2.6 micrograms/L in the fasted state, while after the meal the maximal level was only 1.3 micrograms/L. In contrast to these very low levels after basic bismuth carbonate, the administration of tripotassium dicitrato bismuthate was paralleled by an increase of plasma bismuth to concentrations between 15 and 232 micrograms/L with a mean peak value of 64 +/- 15.3 (S.E.M.) micrograms/L in the fasted state. Postprandial ingestion of tripotassium dicitrato bismuthate attenuated the peak concentrations to 10.9 +/- 6.3 micrograms/L. One subject, however, had a value of 120 micrograms/L. This study demonstrates that basic bismuth carbonate leads to very low plasma bismuth concentrations, which are far below the critical range that might eventually be associated with bismuth neurotoxicity. Therefore this compound can be considered potentially useful for bismuth therapy of gastrointestinal disorders.

Alterations in rat myocardial mechanics under Goldblatt hypertension and experimental aortic stenosis.

Left ventricular hypertrophy was induced in young male Wistar rats by unilateral renal artery constriction, either with (Goldblatt I [ = G I]) or without (Goldblatt II [ = G II]) simultaneous contralateral nephrectomy. An average increase in left ventricular weight of 55% and 18% respectively was reached within 4 weeks as compared with controls of the same age. Further increase in ventricular mass up to the 6-month stage was considerably dependent on the degree of inhibition of body growth of the experimental animals. Other rats underwent a stenosis of the Aorta ascendens (AO) with a reduction in diameter to 50%--60% of the original value, whereby a left ventricular hypertrophy of 10%--30% ensued. Isolated trabecular muscle strips of the left ventricle were examined 4, 8 and 24 weeks (G II), 4 and 8 weeks (G I), and 4 and 6 weeks (AO) after operation. Sham operations were performed for all models used.

Myocardial function in different models of cardiac hypertrophy. An attempt at correlating mechanical, biochemical, and morphological parameters.

Based on mechanical, biochemical and electron microscopic studies performed in the same stage of experimental cardiac hypertrophy, an attempt is made to define the significance of individual factors responsible for the alterations in myocardial function. Using swimming rats, it is demonstrated that a load-induced increase in cardiac mass is not necessarily connected with an impairment of contractile capability on a cellular level. Yet, also, the reduction of specific ATPase activity and unloaded shortening velocity in pressure-induced hypertrophy (goldblatt rats; aortic stenosis) seems to be the expression of adaptation rather than of cellular damage, at least in the earlier stages. Although there are distinct indications of alterations in Ca-dependent activation and deactivation, in the Goldblatt model electromechanical coupling does not seem to be the main cause of altered contraction parameters. The correlation between specific ATPase activity of actomyosin and unloaded shortening velocity as well as the persistance of decrease in shortening velocity, also under optimal electromechanical coupling conditions, point to an inner relationship between the two values. A discrepancy between unloaded shortening velocity on the one hand and developed tension on the other is mainly due to an increased content of contractile structures. In later stages, an increased connective tissue content influences both isometric and isotonic parameters.

[Maximum velocity of load-free shortening Vmax, myocardial capacity and "contractility indices" in the hypertrophic myocardium]. / Maximalgeschwindigkeit der lastfreien Verkürzung (Vmax), myokardiale Leistungsfähigkeit und "Kontraktilitätsindizes" beim hypertrophierten Myokard

Based upon literature and our own experimentation on Goldblatt rats, the significance of a decrease of the maximal shortening velocity of the myocardium at zero load (Vmax) in the hypertrophied, chronically pressure-loaded heart is discussed. In the hypertrophied myocardium with varying concentrations of the contractile structures, the developed tension under isometric conditions (sigma) and the maximum rate of tension development (d sigma/dtmax) can indicate significant deviations from the values of controls of the same age, without, however, making it possible to draw from these changes absolute conclusions about the elementary contractile process. With the enhanced concentration of contractile proteins, the mentioned isometric values, as well as the maximum instantaneous power (cross-sectionally related) of the myocardium can be increased during a stage of hypertrophy in which Vmax is already reduced. The decrease of Vmax shows a rough correlation with the reduction of the specific ATPase activity of actomyosin and is already observed at moderate degrees of hypertrophy (30 to 50%). The time course of the change of both parameters in experimental hypertrophy suggests a causal relation between the changes of those two parameters and the failure of the myocardium in later stages of a chronic overload. Under the condition of reliable estimation, Vmax allows for, also with changed actomyosin concentration, an assessment of the elementary contractile process. On the other hand, Vmax does not present a sufficient measure for the cross-sectionally related power capacity of the hypertrophied myocardium. The possible dissociation between the unloaded shortening velocity and the cross-sectionally related power capacity could, in certain cases, explain an unsatisfactory correlation between Vmax and the clinical state of the heart. The so-called empirical indices of contractility, which are not always clearly related to basic physiological characteristics of the myocardium, should be interpreted with particular reserve in relation to the hypertrophied cardiac muscle.

Mechanics of the isolated ventricular myocardium of rats conditioned by physical training.

Force-velocity relations from after-loaded contractions, from isometric and isotonic QR experiments, resting-tension curves and biochemical analyses were conducted on sixteen trabecular muscles (SH) from hearts of rats conditioned by eight weeks of swimming training (increase in heart weight 8%), and compared to a control (CH) of eighteen trabecular muscles. (SH) showed increased tension development (p less than 0.01), whereas the diastolic properties remained almost unchanged. Analysis of the amount of hydroxyproline did not prove any variation. Vmax of (SH) was only slightly increase when there was a singificnat rise in actomyosin and myosin ATPase activity, while PO of the force-velocity relations of (SH) on the x axis (tension) shifted clearly to the right (p less than 0.01). Consequently, the maximum instantaneous power of (SH), expressed by the maximum rectangular plane under the force-velocity curve, increased considerably (p less than 0.01) in comparison with (CH). The experiments show that haemodynamic load induced by training does not alter the passive properties of the myocardium, but does bring about an increase in the contractile capabiltiy.

[Influence of long-term swimming training on the structure and enzyme activity of myosin in the rat myocardium (author's transl)]. / Einfluss eines chronischen schwimmtrainings auf Struktur und Enzymaktivität von Myosin beim Rattenmyokard

Intermittent hemodynamic loading of the rat myocardium due to swimming training for several weeks leads to a significant increase in the specific ATPase activity of myosin. This enzymatic alteration of the myosin molecule is accompanied by changes in the stoichiometry of its light chains which are of great significance for the ATPase activity. The maximum shortening velocity of the unloaded myocardium (Vmax), estimated on the basis of afterloaded contractions, shows a slight increase as a result of the physical training. Since, on the other hand, the increase is not significant using the quick release technique, a close relationship between the specific ATPase activity and the augmented cross-sectional contractile capability cannot be proved in our experiments.