Pharmacokinetic-pharmacodynamic analysis of changrolin in dogs with arrhythmia

The pharmacokinetics and pharmacodynamics of changrolin (CRL) were studied in 7 dogs with arrhythmia induced by coronary artery ligature. The ECG and the percentage of reduction ratio of ventricular premature were used to evaluate the effect of CRL, and an HPLC method was used to determine the serum drug concentration. A pharmacokinetic program was used to fit concentration-time (C-T) data and a combined pharmacokinetic-pharmacodynamic model was used to analyze effect-time (E-T) data in individual dogs. After infusion with CRL 83.33 micrograms.kg-1.min-1 for 60 min, it was found that K10, T1/2, Vd, Cl and Ce were 0.0087 min-1, 78.03 min, 40.55 ml.kg-1, 0.42 ml.kg-1.min-1, and 2.01 micrograms.ml-1, respectively.     

The interference effects of hexadecylphosphocholine on proliferation and membrane phospholipid metabolism in human myeloid leukemia cell lines

Membrane phospholipids are important regulators of cellular function. The phospholipid activities, such as lipid composition and transportation, contribute to cellular homeostasis in the lifespan of cells. Alterations in phospholipids result in the movement of bilayer lipids and the initiation of coagulation, recognition and internalization. Hexadecylphosphocholine (HePC) exerts antitumor potencies and represents a new class of antitumor agents targeted to the cellular membrane. Human myeloid leukemia cell lines HL-60 and K562 employed in this study were inhibited by HePC in vitro. The results indicate that the HL-60 cell line was sensitive, while K562 was resistant to HePC. Synthetic HePC is an alkyllysophospholipid analog which interacted with the cell membrane, thereby altering lipid composition and metabolism of membrane phospholipids and modulating intracellular calcium in human myeloid leukemia HL-60 and K562 cell lines. The contents of membrane phospholipids, including phosphatidylinositol (PI), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylethanolamine (PE), were determined quantitatively with high performance liquid chromatography. The sensitivity of myeloid leukemia HL-60 and K562 cell lines to HePC probably depends on the different distribution of these four phospholipids in the cellular membrane, or on the response of these phospholipids to HePC. The cytosolic free calcium ([Ca++]i) concentration increased by HePC confirmed that [Ca++]i was released from the intracellular calcium pool and is associated with cell differentiation and apoptosis. We investigated the hypothesis that the antiproliferative effect of HePC was mediated through the interference with cellular membrane phospholipids, including choline-containing phospholipids (PC), aminophospholipids (PE and PS) and PI, in eukaryotic cells.     

Levels of thermostable direct hemolysin production by Vibrio parahaemolyticus strains carrying both tdh and trh genes

One hundred and twenty-five strains of Vibrio parahaemolyticus carrying both the tdh and trh genes were selected from the strains isolated from the travelers with diarrhea by an hybridization test using polynucleotide probes. The levels of TDH produced by these strains and the association between the TDH levels and related characteristics in these strains were analyzed. The TDH level varied greatly from strain to strain, but none of the levels was as high as that of the typical Kanagawa phenomenon-positive strains. The strains were classified into "TDH producer" (18 strains), "Low-level TDH producer" (85 strains), and "No TDH producer" (22 strains) based on the results of a modified Elek test and the hemolysis assay on Wagatsuma agar. The highest TDH level achieved by the "TDH producer" was twofold lower than that of the Kanagawa phenomenon-positive strains as assayed by the RPLA method. All strains possessed the toxR gene. The trh1 and trh2 genes were detected in, respectively, 105 and 20 strains, and no correlation existed between the type of the trh gene and the levels of TDH produced. Considerable restriction fragment length polymorphism was observed with the tdh gene-bearing HindIII DNA fragment in different strains, but it was not related with the TDH level.     

Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery

OBJECTIVE: To investigate prospectively the proportion of patients actually operated on early in units that aim at surgery in the acute phase of aneurysmal subarachnoid haemorrhage (SAH) and what is the main current determinant of poor outcome. METHODS: A prospective analysis of all SAH patients admitted during a one year period at three neurosurgical units that aim at early surgery. The following clinical details were recorded: age, sex, date of SAH, date of admission to the neurosurgical centre, whether a patient was referred by a regional hospital or a general practitioner, Glasgow coma scale and grade of SAH (World Federation of Neurological Surgeons (WFNS) score) on admission at the neurosurgical unit, results of CT and CSF examination, the presence of an aneurysm on angiography, details of treatment with nimodipine or antifibrinolytic agents, and the date of surgery to clip the aneurysm. At follow up at three months, the patients' clinical outcome was determined with the Glasgow outcome scale and in cases of poor outcome the cause for this was recorded. RESULTS: The proportion of patients that was operated on early--that is, within three days after SAH--was 55%. Thirty seven of all 102 admitted patients had a poor outcome. Rebleeding and the initial bleeding were the main causes of this in 35% and 32% respectively of all patients with poor outcome. CONCLUSIONS: In neurosurgical units with what has been termed "modern management" including early surgery, about half of the patients are operated on early. Rebleeding is still the major cause of poor outcome.