Pharmacokinetics of Amitriptyline Demethylation;A Crossover Study with Single Doses of Amitriptyline and Nortriptyline

A single dose crossover pharmacokinetic study of amitriptyline and nortriptyline was done to find out the extent of first-pass metabolism to nortriptyline after amitripyline administration, and the contribution of nortriptyline during amitriptyline therapy. Six healthy male volunteers took part in this study and were given single doses (50 mg) of amitriptyline and nortriptyline at more than three-week intervals. Plasma concentrations of the drugs were measured up to 48 hours. Total area under the plasma concentration-time curve (AUe) of amitriptyline (744.6±258.4 ng/ml·hl was smaller than that of nortriptyline (l497.3±589.8 ng/ml'h), and the mean terminal half-life of amitriptyline (21.8±3.9 hr) was shorter than that of nortriptyline (36.8±5.9 h). The total area under the plasma concentration-time curve of nortriptyline produced by amitriptyline administration was 498.1 ±274.5 ng/ml·h, and the fraction produced by the first-pass of amitriptyline was 33.7 ± 10.5%. From this data, it can be estimated that the average nortriptyline concentration could be about 40% of the total tricyclic antidepressants present in the plasma of patients taking multiple amitriptyline therapy at steady state. About 34% of nortriptyline is produced by first- pass effect during gastrointestinal absorption of amitriptyline to systemic circulation resulting from N-demethylation of amitriptyline in the liver. Then, the rest of the nortriptyline is formed continuously at a rate proportional to the rate of amitriptyline elimination

Bone regeneration potential of sub-microfibrous membranes with osteogenic induction of rBMSC for tissue engineering

Purpose: To examine the biocompatibility and osteoinductive potential of  sub-microfibrous membranes with cells in vitro and in vivo.Methods: Polylactic acid (PLA) and poly-ε-caprolactone (PCL) were blended at various volume ratios (PLA:PCL = 100:0, 70:30, 50:50, 30:70 and 0:100) and each membrane form was prepared by electrospinning. Cell viability,  biocompatibility, and bone regeneration were measured.Results: The membranes from the PLA/PCL blends prepared by an electrospinning process showed a range of diameter distribution ranging from 1,580 to 550 nm. The cells of 100 % PCL membrane (smallest diameter) exhibited significantly higher adhesion and proliferation than those of the other membranes. Among the  membranes from PLA/PCL blends, PCL membrane showed weak inflammatory changes in the early stages of implantation without acute or chronic inflammation. PCL membranes with osteogenically-induced cells successfully stimulated new bone formation in a rate calvarial defect model.Conclusion: The results indicate that biodegradable PCL sub-microfibrous membrane produced by electrospinning process seems to have excellent biocompatibility, and may be used as a scaffold for bone tissue engineering.Keywords: Biocompatibility, Hard tissue, Biomaterial availability, Bone remodeling, Polylactic acid, Poly-ε-caprolactone, Osteoinductive potential, Sub-microfibrous membrane

Cerebral Artery Dissection: Spectrum of Clinical Presentations Related to Angiographic Findings

PurposeCerebral arterial dissections are recognized as a common cause of stroke. However, few studies have reported on the distribution of cerebral arterial dissection and angiographic pattern related to the presenting clinical symptom pattern. We analyzed the distribution of cerebral artery dissection along with angiographic and clinical presenting a pattern as depicted on angiograms.Materials and MethodsFrom January 2000 to January 2007, 133 arterial dissection patients admitted to our institutes were retrospectively reviewed. The characteristic angiographic findings of all cerebral arteries were carefully evaluated on 4-vessel angiograms. The male-female ratio was 77: 56 and the mean age was 51 years. According to the angiographic finding depicting the location of the dissection plane in the arterial wall, we categorized to steno-occlusive, aneurysmal, combined and unclassifiable pattern. In each dissection pattern, we evaluated presenting symptoms and presence of infarction or hemorrhage.ResultsThe most common symptom on presentation was headache (47%), followed by motor weakness of arm or leg (31%), dysarthria/aphasia (19%) and vertigo (16%). The most common angiographic pattern was steno-occlusive (46%), followed by combined (steno-occlusive and aneurismal) (27%) and aneurysmal (22%) patterns. Steno-occlusive pattern was most commonly related to infarction (33/61, 54%) in contrast that aneurysmal pattern was most frequently related to subarachnoid hemorrhage (SAH) (7/29, 24%). The most frequent abnormality in patients with dissection of the intradural vertebral arteries including posterior cerebral artery (PCA) was SAH (23/70, 33%), followed by infarction. Infarction was the most common abnormality in patients with the extradural and intradural carotid arteries, and the extradural vertebral artery.ConclusionIn contrast that the extradural arterial dissections tended to result in ischemia with steno-occlusive pattern, the intradural arterial dissections tended to result in SAH with aneurysmal type, especially in the vertebral artery. Dissection requires combined analysis of angiographic pattern and type of stroke depending on the location

Early Growth Response Factor-1 Is Associated With Intraluminal Thrombus Formation in Human Abdominal Aortic Aneurysm

ObjectivesThe goal of this study was to investigate the expression of early growth response-1 (Egr-1), a vascular pathogenic transcription factor, and its potential relationship with tissue factor (TF), a key player during the thrombus formation in the abdominal aortic aneurysm (AAA) wall.BackgroundAlthough intraluminal thrombus is a common finding in human AAA, the molecular mechanism of the thrombus formation has not been studied.MethodsDuring the elective AAA repair, specimens were taken from the thrombus-covered and thrombus-free portions of the aneurysmal wall in each of 16 patients with AAA and analyzed to assess the differential expression of Egr-1 and TF. The proinflammatory and prothrombogenic activities of Egr-1 in vasculature were evaluated in vitro and in vivo by overexpressing it using adenovirus.ResultsThe expression of both Egr-1 and TF was significantly increased in the thrombus-covered wall compared with the thrombus-free wall, in which their up-regulation in the thrombus-covered wall was strongly correlated with each other (p < 0.005, r = 0.717). Adenoviral overexpression of Egr-1 in human vascular smooth muscle and endothelial cells was found to up-regulate the expression of TF and inflammation-related genes. Moreover, Egr-1 overexpression in endothelial cells increased their adhesiveness to monocytes and also substantially promoted the intravascular thrombus formation in vivo, as shown in the inferior vena cava ligation experiment of the rat.ConclusionsThe present study demonstrates the differential up-regulation of Egr-1 in the thrombus-covered wall of human AAA and also suggests its possible contribution to the thrombogenic and inflammatory pathogenesis in human AAA

Leukotactin-1/CCL15-induced chemotaxis signaling through CCR1 in HOS cells

AbstractLeukotactin-1 (Lkn-1)/CCL15 is a recently cloned CC-chemokine that binds to the CCR1 and CCR3. Although Lkn-1 has been known to function as a chemoattractant for neutrophils, monocytes and lymphocytes, its cellular mechanism remains unclear. To understand the mechanism of Lkn-1-induced chemotaxis signaling, we examined the chemotactic activities of human osteogenic sarcoma cells expressing CCR1 in response to Lkn-1 using inhibitors of signaling molecules. Inhibitors of Gi/Go protein, phospholipase C (PLC) and protein kinase Cδ (PKCδ) inhibited the chemotactic activity of Lkn-1 indicating that Lkn-1-induced chemotaxis signal is transduced through Gi/Go protein, PLC and PKCδ. The activities of PLC and PKCδ were also enhanced by Lkn-1 stimulation. Chemotactic activity of Lkn-1 was inhibited by the treatment of cycloheximide and actinomycin D suggesting that newly synthesized proteins are needed for chemotaxis. Nuclear factor-κB (NF-κB) inhibitor reduced chemotactic activity of Lkn-1. DNA binding activity of NF-κB was also enhanced by Lkn-1 stimulation. These results suggest that Lkn-1 transduces the signal through Gi/Go protein, PLC, PKCδ, NF-κB and newly synthesized proteins for chemotaxis

Primary Pulmonary Plasmacytoma Presenting as Multiple Lung Nodules

Extramedullary plasmacytoma is a plasma cell tumor arising outside the bone marrow and usually occurs as a solitary tumor in the upper respiratory tract, such as the pharynx, paranasal sinuses, nasal cavity, or oral cavity [1]. Other cases develop in the lymph nodes, skin, gastrointestinal tract, genitourinary tract, and other regions. Primary pulmonary plasmacytomas are very rare and usually present as solitary lung nodules or masses [2]. Unusual cases manifest as diffuse pulmonary infiltration [3,4]. We describe here a unique case of primary pulmonary plasmacytoma, which presented as multiple lung nodules during regular screening in a patient with systemic lupus erythematosus

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

<p>Abstract</p> <p>Background</p> <p>The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food.</p> <p>Methods</p> <p>Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates.</p> <p>Results</p> <p>A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h^-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction.</p> <p>Conclusions</p> <p>A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.</p