piperidines and Blood-Coagulation-Disorders

Thromboembolic diseases such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic strokes are mainly responsible for people's morbidity and mortality and have severely affected the people's quality of life all over the world. According to WHO statistics, an average of 17 million people are killed by the thromboembolic diseases each year globally. Therefore, the prevention and treatment of thromboembolic diseases have received widespread attention in recent years. Based on thrombotic mechanism, anti-thrombotic drugs are mainly divided into anticoagulants, antiplatelet agents and direct thrombolytic drugs. In particular, anticoagulants such as vitamin K antagonists (VKAs), unfractionated heparin (UFH), and low-molecular-weight heparins (LMWHs) have become the main therapies for pre-treatment of thromboembolic disorders. However, the limitations of traditional anticoagulants such as slow onset of action, dose-adjusted requirement, drug-drug and drug-food interactions have restricted their improvement in the clinical treatment. The mechanism of the thromboembolic disorders has indicated that coagulation factor Xa (fXa) plays a pivotal role in the blood coagulation cascade. Thus, selective inhibition of fXa by diminishing the amplified generation of thrombin without affecting the pre-existing thrombin levels can provide better antithrombotic effect, thereby causing less impairment of primary hemostasis. In this paper, we mainly introduce the recent advances of fXa inhibitors, with focus on their biological activity and structure-activity relationship (SAR) information. In particular, the inspirations from the structures of the fXa inhibitors and their future direction are highlighted.

Topics: Animals; Benzene Derivatives; Blood Coagulation; Blood Coagulation Disorders; Chemistry; Coumarins; Factor Xa Inhibitors; Heterocyclic Compounds; Humans; Piperidines; Pyrrolidines; Structure-Activity Relationship

Providing adequate analgesia and appropriate sedation to high-risk parturients during late second stage labour without compromising foetal safety remains a major challenge, especially in situations when neuraxial block is not applicable. Remifentanil emerged as an option for labour analgesia during the last decade but may be suitable for the facilitation of complicated vaginal deliveries as well.. A retrospective chart review of nine labouring women with significant medical and/or obstetrical risk factors was conducted. According to the assessment of an experienced obstetrician, vaginal delivery could only be achieved with profound analgesia, and neuraxial block was not possible because of contraindications, technical failure, or shortage of time. Mode of delivery, need for neonatal resuscitation, maternal and neonatal vital parameters, drug consumption, and personnel resource expenses were recorded.. Remifentanil target-controlled infusion (TCI) facilitated vaginal delivery in eight out of nine women. No serious adverse events were observed, but three newborns needed initial respiratory support for a few minutes. The total cost of remifentanil TCI administration to facilitate vaginal delivery compared with the estimated additional cost of an emergency caesarean section was negligible.. This case series suggests that remifentanil TCI may be used to facilitate vaginal delivery in high-risk parturients when other forms of analgesia are limited. However, the small number of patients studied does not allow generalisation of the results; neither can safety concerns be dispelled yet.

Topics: Adult; Analgesia, Obstetrical; Anesthesia, General; Anesthesia, Obstetrical; Blood Coagulation Disorders; Conscious Sedation; Contraindications; Delivery, Obstetric; Drug Costs; Female; Fetal Monitoring; Hospital Costs; Humans; Hypnotics and Sedatives; Infant, Newborn; Infusions, Intravenous; Labor Stage, Second; Narcotics; Nerve Block; Oxygen; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Pregnancy, High-Risk; Remifentanil; Retrospective Studies

Obstructive ileus is a life-threatening gastrointestinal condition that requires emergency operation. Patients with obstructive ileus sometimes develop coagulopathy. In such cases, central neuraxial blockade should be avoided. Rectus sheath blockade (RSB) is one of the popular methods for abdominal wall surgery. Ultrasound imaging of the rectus sheath may facilitate successful RSB by indicating the presence and location of rectus abdominis. Two patients presented with ileus secondary to rectal or sigmoid cancer and underwent emergency ileostomy. The patients had mild coagulopathy [platelet count, 77,000 microl(-1) in case 1, and platelet count, 98,000 microl(-1) in case 2]. Each patient underwent general anesthesia using propofol and remifentanil. They were given 0.5% ropivacaine 20ml for RSB under ultrasound-guidance. Their hemodynamics was stable and they did not need another muscle relaxant during operation, except succinylcholine during induction. RSB is useful for abdominal operations. In addition, ultrasonogrhaphy facilitates the prediction of depth of the posterior rectus sheath and improves the accuracy of local anesthetic placement. We conclude that RSB is effective for improving postoperative pain and intraoperative muscle relaxation of the abdominal wall. Ultrasound-guided RSB is an alternative method to central neuraxial blockade.

Topics: Aged, 80 and over; Anesthesia, General; Blood Coagulation Disorders; Emergencies; Female; Humans; Ileostomy; Ileus; Male; Nerve Block; Perioperative Care; Piperidines; Propofol; Rectal Neoplasms; Rectus Abdominis; Remifentanil; Sigmoid Neoplasms; Ultrasonography

The most potent synthetic reversible thrombin inhibitor described so far, N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide (Ki = 6 nmol/l), was studied with respect to its pharmacodynamics and pharmacokinetics in mice, rats and rabbits. In mice the LD50 was 54 mg/kg i.v. and greater than 800 mg/kg p.o. Prolongation of bleeding time in mice and reduction of mean arterial blood pressure in rats were seen only at doses above the antithrombotically effective doses. After i.v. injection in rabbits the plasma half-life was estimated to be about 9 min. Subcutaneous injection resulted in measurable inhibitor plasma levels for 4 h. Administration of high does into the duodenum did not give antithrombotically effective plasma levels. The ligature of the functional and nutritive hepatic vessels prolonged the half-life of the thrombin inhibitor, whereas renal excretion seems to be of minor importance. A dose-dependent antithrombotic effect was shown in venous stasis-induced thrombosis in rabbits.

Topics: Animals; Blood Coagulation Disorders; Dipeptides; Hypotension; Kinetics; Lethal Dose 50; Liver; Mice; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Thrombin; Thrombosis