ABSTRACT
PURPOSE: Bioavailability of clopidogrel in the form of crushed tablets administered via nasogastric tube (NGT) has not been established in patients after cardiopulmonary resuscitation. Therefore, we performed a study comparing pharmacokinetic and pharmacodynamic response to high loading dose of clopidogrel in critically ill patients after cardiopulmonary resuscitation (CPR) with patients scheduled for elective coronary angiography with stent implantation. METHODS: In the NGT group (nine patients, after cardiopulmonary resuscitation, mechanically ventilated, therapeutic hypothermia), clopidogrel was administered in the form of crushed tablets via NGT. Ten patients undergoing elective coronary artery stenting took clopidogrel per os (po) in the form of intact tablets. Pharmacokinetics of clopidogrel was measured with high-performance liquid chromatography (HPLC) before and at 0.5, 1, 6, 12, 24 h after administration of a loading dose of 600 mg. In five patients in each group, antiplatelet effect was measured with thrombelastography (TEG; Platelet Mapping) before and 24 h after administration. RESULTS: The carboxylic acid metabolite of clopidogrel was detected in all patients in the po group. In eight patients, the maximum concentration was measured in the range of 0.5-1 h after the initial dose. In four patients in the of NGT group, the carboxylic acid metabolite of clopidogrel was undetectable and in the remaining patients was significantly delayed (peak values at 12 h). All patients in the po group reached clinically relevant (>50 %) inhibition of thrombocyte adenosine diphosphate (ADP) receptor after 24 h compared with only two in the NGT group (p = 0.012). There was a close correlation between peak of inactive clopidogrel metabolite plasmatic concentration and inhibition of the ADP receptor (r = 0.79; p < 0.001). CONCLUSION: The bioavailability of clopidogrel in critically ill patients after cardiopulmonary resuscitation is significantly impaired compared with stable patients. Therefore, other drugs, preferentially administered intravenously, should be considered.
Subject(s)
Blood Platelets/drug effects , Cardiopulmonary Resuscitation , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacokinetics , Ticlopidine/analogs & derivatives , Administration, Oral , Aged , Aged, 80 and over , Biological Availability , Blood Platelets/metabolism , Chromatography, High Pressure Liquid , Clopidogrel , Critical Illness , Female , Humans , Hypothermia, Induced , Intubation, Gastrointestinal , Male , Middle Aged , Percutaneous Coronary Intervention/instrumentation , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/blood , Purinergic P2 Receptor Antagonists/administration & dosage , Purinergic P2 Receptor Antagonists/blood , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2/metabolism , Respiration, Artificial , Stents , Tablets , Thrombelastography , Ticlopidine/administration & dosage , Ticlopidine/blood , Ticlopidine/pharmacokineticsABSTRACT
The paper deals with analytical evaluation of newly prepared substances, derivatives of N-(4-alkoxy-phenyl)-2-(2-oxo-azepan-1-yl)-acetamide. The substances are a homological series (methyl- to hexyl-). The purity of the substances was verified by thin-layer adsorption chromatography, and the principal physical characteristics--melting point and solubility--were determined. Experimental determination of the partition coefficient, extraction of the substances between two liquids miscible to a limited degree (n-octanol--water), determination of RM values by means of TLC partition chromatography (glass plates DC-Fertigplatten RP-8 F254S), determination of the capacity factor by means of HPLC (column C18 Plaris), and calculation by means of computer programmes were employed to determine the lipophilicity of this series of substances. The antiradical activity of the substances was evaluated by the method of extinguishing the stable radical 2,2-diphenyl-1-picryl-hydrazyl. Ascorbic acid, in which an antiradical effect had been demonstrated, was used for the sake of comparison. The substances show a certain activity, but they do not reach the antioxidative effect of ascorbic acid.
Subject(s)
Nootropic Agents/chemistry , Chemistry, PharmaceuticalABSTRACT
The paper deals with chromatographic separations of newly prepared substances, aryloxyaminopropanol derivatives. The derivatives represent three homological series of four carbons and four groups of positional isomers (methyl- to butyl- in positions 2-, 3, and 4-). Thin-layer adsorption chromatography employed the foil Silufol UV 254 as the stationary phase and partition chromatography, commercially produced glass plates DC Fertigplatten MERCK RP-8 F254 S. High-performance liquid chromatography was used to separate positional isomers on the column Supelkosil ABZ + PLUS. The mobile phase was methanol and acetonitrile in graded rations with water and various flow rates of the mobile phase were tested. Partition chromatography, determination of partition coefficient in the system octanol-water, and the values of capacity factors k' of the substances was employed to evaluate their lipophilicity.
Subject(s)
Cardiovascular Agents/chemistry , Propanols/chemistry , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , IsomerismABSTRACT
The paper is devoted to the synthesis and study of some physico-chemical properties of a group of substances--potential antagonists of beta-adrenergic receptors. The substances are derivatives of aryloxyaminopropanol, where the basic part consists of diphenylmethylpiperazine and the aromatic part is modified with alkyl esters (methyl to butyl) of carbamic acid in positions 2-, 3-, 4-. The representation of the elements was confirmed by elemental analysis. The substances were characterized by melting point, IR and UV spectra. Their solubility and surface activity were determined. The purity of prepared substances was examined by means of TLC.
