A Pharmacokinetic Model for Protamine Dosing After Cardiopulmonary Bypass.

OBJECTIVE: This study investigated postoperative hemostasis of patients subjected to conventional protamine dosing compared with protamine dosing based on a pharmacokinetic (PK) model following cardiopulmonary bypass. DESIGN: Retrospective case-control study. SETTING: Tertiary university hospital. PARTICIPANTS: Patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: In 56 patients, protamine was dosed in a fixed ratio (CD), while 62 patients received protamine based on the PK model. MEASUREMENTS AND MAIN RESULTS: There was no difference in heparin administration (414±107 mg (CD) v 403±90 mg (PK); p = 0.54), whereas protamine dosing was considerably different with a protamine-to-heparin dosing ratio of 1.1±0.3 for the CD group and 0.5±0.1 for the PK group (p<0.001). The changes in activated coagulation time (ΔACT) values (ACT after protamine minus preoperative ACT;+17±77 s v+6±15 s; p = 0.31) were equal between groups. Yet, the thromboelastometric intrinsically activated coagulation test clotting time (CT; 250±76 s v 203±44 s; p<0.001) and intrinsically activated coagulation test without the heparin effect CT (275±105 v 198±32 s; p<0.001) were prolonged in the CD group. Median packed red blood cell transfusion (0 [0-2] v 0 [0-0]), fresh frozen plasma transfusion (1 [0-2] v 0 [0-0]), and platelet concentrate transfusion (0 [0-1] v 0 [0-0]) were different between the fixed ratio and PK group, respectively (all p<0.001). CONCLUSIONS: This study showed that patient-tailored protamine dosing based on a PK model was associated with a reduction in protamine dosing, with better hemostatic test results when compared with fixed-ratio protamine dosing.

[Influence of intravenous injection of fucoidan from brown seaweed Fucus evanescens by plasma rabbits anticoagulant activity and neutralisation by sulphate protamin of fucoidans antithrombin activity in vitro].

With fucoidan from Fucus evanescens dose increase from 1 to 5 mg/kg plasma coagulation time in test A(see symbol)TB increases. Sulphate protamin in final concentration 0.67-1.35 mkg/ml will neutralise antithrombin activity of fucoidans from brown seaweed Fucus evanescens and Laminaria cichorioides. The gravimetrichesky relation for the investigated samples makes an antidot/anticoagulant 1.

Reversal of heparin-induced increases in aPTT in the rat by PM102, a novel heparin antagonist.

Protamine is the only agent approved to reverse heparin-induced anticoagulation. Due to the significant adverse effects of protamine there is an important need for an alternative agent with an improved safety profile. The pharmacodynamics of PM102, a novel peptide-based heparin antagonist, was evaluated and compared to protamine in a rat model. Rats were dosed with intravenous heparin (50U/kg) and 4min later with protamine (0.25, 0.75mg/kg single intravenous bolus) or PM102 (0.1, 0.3, 1, 3, 30mg/kg single intravenous bolus). Blood samples were collected though 60min for assessment of activated partial thromboplastin time (aPTT) and plasma concentration of PM102. Both doses of protamine markedly lowered the elevated aPTT to baseline values within 1 to 5min after administration. PM102 (0.3-30mg/kg) also rapidly and completely reversed heparin-induced increases in aPTT within 1 to 5min. The effects of PM102 administered as an infusion over 10min also reversed aPTT with similar potency to that observed for bolus administration. The onset of reversal with infusion was delayed relative to the same total dose given as a bolus; however, the maximum effect was similar. PM102 rapidly (T(max) 1-2.6min) appeared in plasma after dosing. Concentrations of PM102 generally declined rapidly after reaching T(max) with a mean T(1/2) of 4 to 31min. PM102 is a novel synthetic peptide that effectively reverses the anticoagulant effect of heparin. It's utility as a bolus injection as well as infusion, its rapid efficacy and its rapid clearance make this an ideal candidate for clinical development.

[Etiopathogenic and clinical considerations on primary pulmonary hypertension]. / Considerazioni eziopatogenetiche e cliniche sull'ipertensione polmonare primitiva.

Primary pulmonary hypertension is a severe condition of unknown etiology first described by Romberg in 1891. The authors review the literature with particular emphasis on new hypotheses concerning etiopathogenesis, and recent suggestions for management. The former take into account the discovery of endothelium derived relaxing factors and the identification in pulmonary arteries of a polypeptide called endothelin. Further hypotheses contemplate 1) interaction between platelets and endothelium; 2) the role of heparin-inhibiting enzymes; 3) abnormal cellular adhesion. Heart catheterism is apt to exclude other causes of pulmonary hypertension and also permits to assess the severity of the condition and its prognosis, as well as acting as a guide to management. If venous O2 saturation is higher than 63%, calcium blocking agents and anticoagulants should be used, if it is lower than 63% long-term prostaglandin infusion should be given awaiting heart-lung transplantation unless this can be done immediately.

[The dynamics of the body distribution of heparin and its antagonist, the quaternary ammonium salt of conidine oligomer-25, when administered via the lungs]. / Issledovanie dinamiki raspredeleniia v organizme geparina i ego antagonista--chetvertichnoi ammoniinoi soli oligomera-25 konidina, vvedennykh cherez legkie.

The distribution in the organism of radioactivity after intratracheal administration of labelled heparin and its quarterly ammonium salt oligomer-25 conidine was studied. Within 25 hours the preservation of a high level of radioactivity in plasma, its decrease in other investigated organs and the accumulation in mast cells of the peritoneal cavity were observed. The involvement of the lymphatic system in heparin metabolism was shown. A positively charged oligomer conidine administered intratracheally, in contrast to heparin, was not detected in blood plasma in the studied time. The accumulation of the drug in the lung tissue, lymph nodes and excretory organs was noted.

[Heparin and its antagonist--a quaternary ammonium salt of oligomer-25-conidine: distribution in subcellular organelles, effect on DNA synthesis in the regenerating rat liver]. / Geparin i ego antagonist--chetvertichnaia ammoniinaia sol' oligomera-25-konidina: raspredelenie po subkletochnym organellam, vliianie na sintez DNK v regeneriruiushchei pecheni krys.

Dynamics of distribution in subcellular organelles as well as effects on DNA synthesis of heparin, polycanidine (ChAS oligomer of 25 canidine) and their complexes were studied in regenerating rat liver tissue after partial hepatectomy. Polycanidine and heparin penetrated from circulation into hepatocyte cells, nuclei and mitochondria. After consecutive administration of polyelectrolytes polycanidine increased 2-2.5-fold the amount of heparin entering into cells. Polycanidine formed stable complexes with DNP in nuclei. Heparin and its complexes with polycanidine decreased the DNA synthesis within first day. Heparin appears to be responsible for the inhibitory effect, whereas administration of polycanidine only into animals caused a slight increase in 3H-thymidine incorporation into DNA as compared with controls.