Pharmacokinetics of RheothRx injection in healthy male volunteers.

The objectives of this study were to evaluate the safety and tolerability of RheothRx (poloxamer 188) injection administered as an intravenous (i.v.) infusion to healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. Thirty-six healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation trial for RheothRx injection. The volunteers were randomized to three treatment groups (12 per treatment group, with eight receiving active therapy and four receiving placebo). In each treatment group, volunteers received RheothRx injection or placebo as an i.v. infusion on two occasions at least 3 weeks apart to make a total of six doses being studied (10, 30, and 45 mg/kg/h for 72 h, 60 mg/kg/h for 43.3 to 72 h, 60 and 90 mg/kg/h for 24 h). Serial plasma samples were collected during and up to 36 h after the end of the infusions; urine was collected over intervals from the start of the infusion until 36 h after the infusions were terminated. Plasma and urine samples were assayed for poloxamer 188 by gel-permeation chromatography. Pharmacokinetic parameter values were calculated by noncompartmental and compartmental methods. Poloxamer 188 was eliminated primarily by renal excretion. Estimates of clearance, elimination rate constant, and apparent volume of distribution at steady state values were independent of infusion rate. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

The effects of hormone replacement therapy on antithrombin III and protein C levels in menopausal women.

OBJECTIVE: To determine if menopausal women taking estrogen with and without progestin are at increased risk for thrombotic disease as evidenced by decreased levels of antithrombin III and protein C. DESIGN: A case controlled study. SETTING: General community in southeastern New Hampshire. PARTICIPANTS: One hundred seventy-one healthy women aged 38 to 65 years. Women were defined as premenopausal if follicle stimulating hormone levels were < 40 mIU/ml and menopausal if follicle stimulating hormone levels were > 40 mIU/ml. Menopausal women were subdivided according to hormone replacement therapy status; women not taking estrogen or progestin, and women taking estrogen with and without progestin for at least 1 year. MAIN OUTCOME MEASURES: Significant differences in antithrombin III and protein C levels. RESULTS: Premenopausal women had significantly less antithrombin III than menopausal women not taking hormone replacement therapy. Premenopausal women had significantly less protein C than menopausal women taking estrogen for at least 1 year with and without progestin. CONCLUSION: Estrogen taken for at least 1 year with and without progestin by menopausal women will not increase the risk of thrombotic disease by lowering the levels of antithrombin III or protein C. On the contrary, estrogen is associated with an increase in circulating levels of protein C in menopausal women, and could create a protective effect not seen in premenopausal women or menopausal women not taking estrogen therapy.

A study of the fibrinolytic response in healthy men and women following a brief exposure to venous occlusion.

In this study, 176 healthy men and women between the ages of 18 and 25 yrs were tested for fibrinolytic activity before and after a 5 min period of venous occlusion (VO) at 100 mm Hg. Using this protocol, 140 demonstrated an increase in fibrin plate lysis following this brief period of venous occlusion and were classified as "Responders." There were 36 individuals in the study who showed either a decrease or no change in fibrin plate lysis after 5 min of venous occlusion and they were classified as "Non-Responders." Responders showed a decrease in PAI-1 following VO. However, neither Responders nor Non-Responders demonstrated any significant differences in the levels of plasminogen, antiplasmin, protein C, free t-PA, or total t-PA following this brief exposure to venous occlusion. When comparing women and men in this study, women had significantly greater fibrin plate lysis both before and after 5 min of VO. They also demonstrated higher pre- and post-VO levels of circulating plasminogen. Also, women had less PAI-1 pre- and post-VO than men. When examining Responders and Non-Responders according to gender, women who were Responders had significantly greater fibrin plate lysis before and after VO than male Responders. Also, women Responders demonstrated a significant decrease in PAI-1 following 5 min of VO when compared to men who were Responders in this study.

Ventilatory threshold and maximal oxygen uptake during cycling and running in triathletes.

VO2max and the ventilatory threshold (Tvent) were measured during cycle ergometry (CE) and treadmill running (TR) in a group of 10 highly trained male triathletes. Tvent was indicated as the VO2 at which the ventilatory equivalent for oxygen increased without a marked rise in the ventilatory equivalent for carbon dioxide. Triathletes achieved a significantly higher VO2max for TR (75.4 +/- 7.3 ml.kg-1.min-1) than for CE (70.3 +/- 6.0 ml.kg-1.min-1). Mean CE VO2max was 93.2% of the TR value. Average VO2max values for CE and TR compared favorably with values reported for elite single-sport athletes and were greater than those previously reported for other male triathletes. CE Tvent occurred at 3.37 +/- 0.32 l.min-1 or 66.8 +/- 3.7% of CE VO2max, while TR Tvent was detected at 3.87 +/- 0.33 l.min-1 or 71.9 +/- 6.6% of TR VO2max. The VO2 (l.min-1) at which Tvent occurred for TR was significantly higher than for CE (P less than 0.001). Although the VO2 values at TR Tvent expressed as a percentage of VO2max were consistently higher than for CE, the difference between the means did not reach statistical significance (P greater than 0.05). The average Tvent for CE (as %VO2max) was nearly identical to Tvent values reported in the literature for competitive male cyclists, whereas TR Tvent was lower than recently reported values for elite distance runners and marathoners. We speculate that triathlon training results in general (cross-training) adaptations which enhance maximal oxygen uptake values, whereas anaerobic threshold adaptations occur primarily in the specific muscle groups utilized in training.

The effects of acute exercise and increased atmospheric pressure on the hemostatic mechanism and plasma catecholamine levels.

The hemostatic response to acute exercise and increased atmospheric pressure was studied in 20 healthy male subjects (18-35 yr of age) exercised to volitional exhaustion on a cycle ergometer in a hyperbaric chamber at 3 atmospheres absolute (ATA). As a means of comparison, 6 of the 20 subjects were exercised in the same manner at 1 ATA. Similar increases in fibrinolytic activity (FA), Factor VIII activity (VIII:C), von Willebrand factor antigen (vWF:Ag) and plasma catecholamine levels were observed following acute exercise at 1 ATA and at 3 ATA. There were no changes in the levels of plasminogen, antithrombin III, Protein C or Fibrinopeptide A (FPA) with exercise either at 1 ATA or at 3 ATA. In addition, there were no changes in plasma catecholamine levels or any of the hemostatic variables measured when atmospheric pressure was increased from 1 ATA to 3ATA without exercise. These findings demonstrate that increasing atmospheric pressure from 1 ATA to 3 ATA does not alter the exercise-induced changes in hemostasis. Therefore, exercise or physical exertion at 3 ATA for a time period not to exceed 30 min does not perturb the hemostatic mechanism and increase the risk of bleeding or thrombosis.