Open labeled, uncontrolled pharmacokinetic study of a single intramuscular hCG dose in healthy male volunteers.

The current study was designed to compare blood and cerebrospinal fluid (CSF) pharmacokinetic characteristics of two forms of human chorionic gonadotropin (hCG): Pregnyl(R), derived from human urine, and Ovitrelle(R) a recombinant form. Two separate groups, each with six older male human subjects, were dosed with either form of the drug at 10,000 IU intramuscularly (IM), and followed over a 36-hour period. No significant difference in the serum level of hCG was observed for either preparation of hCG (Peak serum conc.: 316 +/- 53 vs. 270 +/- 60 at 12 hours, 311 +/- 38 vs. 321 +/- 60 IU/l at 24 hours; AUC: 10,053 +/- 1,268 vs. 8,793 +/- 1,768, Pregnyl and Ovitrelle, mean +/- SD, respectively). Additionally, both forms of circulating hCG distributed to the central nervous system (CNS) as manifest by an increased number of subjects whose CSF samples showed detectable levels of hCG in their CSF over a 36-hour period. Similarly, there was no significant difference between the two forms when distribution to the CSF was compared at 36 hours (2.0 and 1.2 IU/l; range 1.9 - 2.1 and 1 - 1.4 IU/l for Pregnyl and Ovitrelle, resp.). This preliminary study in normal human volunteers suggests that the two forms of hCG tested, Ovitrelle(R) and Pregnyl(R), when administered IM, distribute in a similar fashion into the circulation and CSF. Consequently, we conclude that these two drugs demonstrate no statistical significant difference with respect to the CSF.

Congestive heart failure after myocardial infarction in the rat: cardiac force and spontaneous sarcomere activity.

The causes of reduced cardiac force development in congestive heart failure (CHF) are still uncertain. We explored the subcellular mechanisms leading to decreased force development in trabeculae from rats with a myocardial infarction. We defined CHF according to clinical and pathological criteria and compared properties of trabeculae from animals with CHF (cMI) to those of animals with a myocardial scar but without evidence of CHF (uMI), and sham-operated animals. The new findings of this study on properties of cMI trabeculae are that (1) maximal twitch force following post-extrasystolic potentiation is unchanged; (2) the sensitivity of cMI trabeculae to [Ca(2+)](o) is increased; (3) spontaneous diastolic sarcomere length (SL) fluctuations (SA) are increased in cMI at all levels of SR Ca(2+) loading; and (4) SA is accompanied by a proportional reduction of F(max). The results suggest that the probability of spontaneous diastolic opening of SR Ca(2+) channels is increased in CHF. These data provide the basis for a novel mechanism underlying systolic and diastolic dysfunction as well as arrhythmias in hearts in CHF. If SA proves to be a component of myocardial dysfunction in human CHF, our thinking about therapy of the patient with CHF may be profoundly changed.

Damage induced arrhythmias: mechanisms and implications.

Little is known about the role played by non-uniform myocardial stress and strain distributions and by non-uniform excitation contraction coupling in mechanisms underlying the premature beats that initiate an arrhythmia. We will review the evidence in support of a mechanism in which both non-uniform contraction and increased Ca2+ load of cells adjacent to acutely damaged cells are essential in the "spontaneous" generation of Ca2+ transients during the relaxation phase of the electrically driven twitch. The putative mechanism of initiation of the propagating Ca2+ waves involves feedback of rapid length (or force) changes to dissociation of Ca2+ from the contractile filaments. A novel aspect of this concept is that these mechanically elicited Ca2+ transients induce propagating Ca2+ waves that travel into the adjacent normal myocardium and cause after-depolarizations, which, in turn, may cause premature action potentials. These premature action potentials will further load the cells with Ca2+, which promotes the subsequent generation of propagating Ca2+ transients and leads to triggered arrhythmias. The damage-induced premature beats may also initiate re-entry arrhythmias in non-uniform myocardium. These observations strongly support the concept that abnormal cellular Ca2+ transport plays a crucial role in the initiation of arrhythmias in damaged and non-uniform myocardium.

Expression of platelet-derived growth factor receptor in rat heart allografts.

Growth factors may play a role in the tissue remodeling of long-surviving allografts. The aim of these experiments was to investigate the pattern of expression of platelet-derived growth factor and epidermal growth factor receptors in relation to the immunohistopathology of rat cardiac allografts. Heart grafts were transplanted between LEW and F344 and LEW.1A and LEW.1AR2 strains and removed for analysis at graft asystole or at predetermined time intervals. The grafts were studied with direct and indirect immunofluorescence and immunoperoxidase staining techniques and monoclonal antibodies against T lymphocytes, monocytes/macrophages, and endothelium. Expression of growth factor receptor was studied with the use of a monoclonal antibody against the platelet-derived growth factor-beta receptor and autoradiography with platelet-derived growth factor-BB or epidermal growth factor labeled with iodine 125. Increased expression of platelet-derived growth factor-beta receptors was observed in the media of graft arteries and in a number of myocardial cells in association with infiltration of the graft with T cells and monocytes/macrophages. Autoradiography with epidermal growth factor labeled with 125I failed to show changes in the binding pattern in relation to rejection. Upregulation of platelet-derived growth factor receptors may suggest involvement of platelet-derived growth factor in the tissue remodeling that occurs in conjunction with chronic rejection.

Xenoantibodies in the rat against guinea pig tissues.

The role of naturally occurring antibodies in discordant xenograft rejection is poorly defined. This is partly attributable to a lack of information regarding their tissue specificity and titers. Sera from different rat strains were studied for naturally occurring antibodies against guinea pig tissues using immunofluorescence and immunoperoxidase staining techniques. All sera contained IgG and IgM antibodies in low titers against erythrocytes, lymphoid cells, and a variety of tissue structures. Intentional immunizations of adult rats with guinea pig cells resulted in the production of xenoantibody specificities that were not detectable in nonimmunized animals. Immunizations of Munich-Wistar rats with guinea pig skin grafts occasionally resulted in the formation of antibodies that reacted with allogeneic and syngeneic cells of the liver, lung, and lymphoid organs. We conclude that rats have low titers of naturally occurring xenoantibodies against various tissue structures of the guinea pig, but their importance in xenograft rejection remains to be established.