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2.
ACS Appl Mater Interfaces ; 6(9): 6786-9, 2014 May 14.
Article in English | MEDLINE | ID: mdl-24694204

ABSTRACT

Using first-principles calculation based on density functional theory, diffusion of Mg atom into α- and ß-Sn was investigated. The diffusion barriers are 0.395 and 0.435 eV for an isolated Mg atom in the α- and ß-Sn, respectively. However, the diffusion barriers of the Mg atom decrease in the α-Sn, whereas they increase in the ß-Sn, when an additional Mg atom was inserted near the original diffusing Mg atom, which is mainly due to strong binding of Mg-Mg atoms in the ß-Sn. Therefore, it is better to use the α-Sn, rather than the ß-Sn, as an anode material for Mg ion batteries.

3.
Cancer Gene Ther ; 16(6): 516-31, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19165234

ABSTRACT

Coexpression of multiple shRNAs can simultaneously inhibit multiple genes or target multiple sites on a single gene. These approaches can be used for dissecting complex signaling pathways and even be applied to targeting multiple genes in cancer therapy. Here we established a simple and efficient multiple shRNAs expression system based on pSUPER, the most popular expression vector in mammalian cells. A series of head-to-tail tandem array multiple shRNAs expression vectors were constructed containing different combinations of six shRNA expression cassettes targeting genes involved in cell proliferation and survival pathways: Bcl-2, Survivin, Akt1, Erk2, CyclinE and NFkappaB. In HeLa and HEK293 cells, the multiple shRNAs expression constructs could efficiently and simultaneously induce inhibition of all six genes. We further evaluated the inhibition effects of the multiple shRNAs expression vectors on the human prostate cancer cell line PC3, which contains different cell variants with distinct oncogenic signaling alterations. The results revealed that the multiple shRNAs expression system could inhibit all six genes and was much more efficient in inducing apoptosis in the PC3 cells. Our results suggest that the multitarget shRNAs expression system could be an effective strategy in cancer therapy and be applied to any other DNA vector-based shRNA expression system.


Subject(s)
Neoplasms/therapy , RNA Interference , RNA, Untranslated/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Survival , Cells, Cultured , Genetic Vectors , HeLa Cells , Humans , Male , Models, Genetic , Neoplasms/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , RNA, Small Interfering/genetics , RNA, Untranslated/chemistry , Transfection
4.
J Thromb Haemost ; 6(11): 1953-61, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18761727

ABSTRACT

BACKGROUND: Angiostatin, a circulating angiogenic inhibitor, is an internal fragment of plasminogen and consists of several isoforms, K1-3 included. We previously showed that K1-3 was the most potent angiostatin to induce E-selectin mRNA expression. The purpose of this study was to identify the mechanism responsible for K1-3-induced E-selectin expression and investigate the role of E-selectin in the anti-angiogenic action of K1-3. METHODS AND RESULTS: Quantitative real time RT-PCR and Western blotting analyses confirmed a time-dependent increase of E-selectin mRNA and protein induced by K1-3. Subcellular fractionation and immunofluorescence microscopy showed the co-localization of K1-3-induced E-selectin with caveolin 1 (Cav1) in lipid rafts in which E-selectin may behave as a signaling receptor. Promoter-driven reporter assays and site-directed mutagenesis showed that K1-3 induced E-selectin expression via promoter activation and AP1 and Ets-1 binding sites in the proximal E-selectin promoter were required for E-selectin induction. The in vivo binding of both protein complexes to the proximal promoter was confirmed by chromatin immunoprecipitation (ChIP). Although K1-3 induced the activation of ERK1/2 and JNK, only repression of JNK activation attenuated the induction of E-selectin by K1-3. A modulatory role of E-selectin in the anti-angiogenic action of K1-3 was manifested by both overexpression and knockdown of E-selectin followed by cell proliferation assay. CONCLUSIONS: We show that K1-3 induced E-selectin expression via AP1 and Ets-1 binding to the proximal E-selectin promoter (-356/+1), which was positively mediated by JNK activation. Our findings also demonstrate E-selectin as a novel target for the anti-angiogenic therapy.


Subject(s)
Angiostatins/physiology , E-Selectin/genetics , Proto-Oncogene Protein c-ets-1/physiology , Transcription Factor AP-1/physiology , Transcriptional Activation , Binding Sites , Caveolin 1/metabolism , Cell Line , Cell Line, Tumor , E-Selectin/metabolism , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Kinetics , Membrane Microdomains/chemistry , Promoter Regions, Genetic , Protein Binding , Protein Isoforms/physiology , RNA, Messenger
5.
J Am Assoc Gynecol Laparosc ; 8(1): 61-7, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11172116

ABSTRACT

STUDY OBJECTIVE: To describe our experience with major complications in gynecologic laparoscopy compared with literature reports. DESIGN: Retrospective study (Canadian Task Force classification II-3). SETTING: Two regional teaching hospitals in southern Taiwan. Patients. One thousand five hundred seven women. INTERVENTION: Gynecologic laparoscopy. MEASUREMENTS AND MAIN RESULTS: The overall number of major complications in 1507 laparoscopies was 24 (1.6%): 6 bladder injuries, 5 bowel injuries, 4 ureteral injuries, 3 cases of delayed vaginal stump bleeding, 2 cases of postoperative ileus, 2 abscesses, 1 vessel injury, and 1 umbilical hernia. Complication rates were analyzed by type of surgery-laparoscopic-assisted vaginal hysterectomy (LAVH) versus non-LAVH. We correlated clinical outcome with time of recognition and treatment of complications. Our complication rates were similar to those reported in the literature and were not significantly different between LAVH and non-LAVH. CONCLUSION: Early recognition of injuries, preferably intraoperatively, with immediate appropriate treatment is crucial. It is also important to be alert to early manifestations of complications in the postoperative observation period. (J Am Assoc Gynecol Laparosc 8(1):61-67, 2001)


Subject(s)
Gynecologic Surgical Procedures/adverse effects , Laparoscopy/adverse effects , Adolescent , Adult , Aged , Child , Female , Gynecologic Surgical Procedures/methods , Humans , Intestine, Small/injuries , Middle Aged , Retrospective Studies , Taiwan , Ureter/injuries , Urinary Bladder/injuries
6.
Yao Xue Xue Bao ; 36(2): 108-11, 2001 Feb.
Article in Chinese | MEDLINE | ID: mdl-12579875

ABSTRACT

AIM: To determine the effects of glycoconjugates and their glycans from Lycium barbarum L. on inhibiting low density lipoprotein (LDL) peroxidation. METHODS: Using Cu(2+)-induced oxidation as a model, the oxidative production of thiobarbituric acid-reactive substances (TBARS) and the LDL electrophoresis migration on agarose gel were measured. RESULTS: The effects of glycoconjugates and their glycans from Lycium barbarum L. on inhibiting LDL peroxidation were different, among them, glycoconjugate LbGp5 showed the best effect on inhibiting LDL peroxidation. CONCLUSION: The glycoconjugates can inhibit LDL peroxidatin while their glycans showed no effects on inhibiting LDL peroxidation.


Subject(s)
Glycoconjugates/pharmacology , Lipid Peroxidation/drug effects , Lipoproteins, LDL/metabolism , Lycium/chemistry , Fruit/chemistry , Glycoconjugates/isolation & purification , Humans , Polysaccharides/isolation & purification , Polysaccharides/pharmacology
7.
Am J Surg ; 179(1): 67-73, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10737583

ABSTRACT

BACKGROUND: Electrosurgery is one of the most commonly used energy systems in laparoscopic surgery. Two major categories of potential complications related to electrosurgery in laparoscopy are mechanical trauma and electrothermal injury. The latter can result from unrecognized energy transfer in the operational field or, less commonly, to unnoticed stray current outside the laparoscopic field of view. Stray current can result from insulation failure, direct coupling, or capacitive coupling. METHODS: We reviewed the literature concerning essential biophysics of electrosurgery, including electrosurgical waveform differentiation, tissue effect, and variables that determine tissue effect. The incidence of electrosurgical injuries and possible mechanisms responsible for the injuries are discussed. Different types of injuries may result in different clinical manifestations and histopathological findings. Gross and microscopic pathological check-ups of the injury sites may distinguish between different mechanisms, and thus provide further clues postoperatively. RESULTS: Several recommended practices are proposed to avoid electrosurgical injury laparoscopically. To achieve electrosurgical safety and to prevent electrosurgical injuries, the surgical team should have a good understanding of the biophysics of electrosurgery, the basis of equipment and general tissue effects, as well as the surgeon's spatial orientation and hand-eye coordination. Some intraoperative adjuvant procedures and newly developed safety devices have become available may aid to improve electrosurgical safety. CONCLUSIONS: Knowledge of the biophysics of electrosurgery and the mechanisms of electrosurgical injury is important in recognizing potential complications of electrosurgery in laparoscopy. Procedures for prevention, intraoperative adjuvant maneuvers, early recognition of the injury with in-time salvage treatment, and alertness to postoperative warning signs can help reduce such complications.


Subject(s)
Burns, Electric , Electrosurgery , Intraoperative Complications , Laparoscopy , Burns, Electric/etiology , Burns, Electric/prevention & control , Electrosurgery/adverse effects , Humans , Intraoperative Complications/epidemiology , Intraoperative Complications/prevention & control , Laparoscopy/adverse effects
8.
J Am Assoc Gynecol Laparosc ; 6(4): 509-11, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10548715

ABSTRACT

Almost all operations that were traditionally performed by open laparotomy operations can be done laparoscopically; however, surgeons may experience several negative health effects. A 37-year-old gynecologic laparoscopist had a herniated intervertebral disk at C5-6 level. Due to a negative trauma history, a possible explanation may be the nonergonomic posture that he held while performing laparoscopic surgery for many hours. To reduce the risk of this complication, we recommend that surgeons' spatial orientation and hand-eye coordination for laparoscopy be improved by sequential phases of training.


Subject(s)
Cervical Vertebrae , Cumulative Trauma Disorders/etiology , Gynecology , Intervertebral Disc Displacement/etiology , Laparoscopy , Occupational Diseases/etiology , Adult , Cumulative Trauma Disorders/diagnosis , Cumulative Trauma Disorders/surgery , Humans , Intervertebral Disc Displacement/diagnosis , Intervertebral Disc Displacement/surgery , Male , Occupational Diseases/diagnosis , Occupational Diseases/surgery
9.
J Formos Med Assoc ; 98(10): 678-82, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10575837

ABSTRACT

To assess the clinical features of Taiwanese patients with tuberculous pleurisy and their response to treatment, we analyzed the records of patients treated for this condition from December 1990 through November 1995, at a regional 100-bed referral center for tuberculosis care. Diagnosis of tuberculous pleurisy was based on histologic evidence of caseating granulomatous inflammation in the pleural biopsy specimen, or evidence of mycobacteria in pleural fluid. Patients were also stratified on the basis of parenchymal involvement. Ninety-seven patients (79 men, 18 women) with a mean age of 47.5 (range, 15-90) years were included in the analysis. The two major symptoms were cough (69%) and shortness of breath (57%). Chest roentgenographs showed that the pleural effusion was unilateral in 88 (91%) patients, and small to moderate in amount in 74 (76%). Laboratory analysis of the pleural fluid showed moderate levels of glucose (4.6 mmol/L), with no significant difference between patients with and without parenchymal involvement. The levels of lactate dehydrogenase and triglycerides were significantly higher in patients with parenchymal involvement (172 vs 240.5 IU and 0.36 vs 0.45 mmol/L, respectively). In 85 of 93 patients (91%) with available data, lymphocytes were predominant in the differential count. All patients had received short-course chemotherapy for at least 6 months. After excluding the defaulters and patients receiving subsequent management in other hospitals, the overall rate of successful treatment was 97% (72/74). There was no significant difference in the treatment outcome between patients with parenchymal involvement and those without. None of the successfully treated patients had a relapse within a mean follow-up period of 31.7 +/- 18.4 months. We conclude that current patients with tuberculous pleurisy in Taiwan are not young, and short-course chemotherapy with isoniazid, ethambutol, rifampicin, and pyrazinamide is an effective treatment. The presence of parenchymal tuberculous lesions does not appear to influence the treatment outcome.


Subject(s)
Pleural Effusion/drug therapy , Tuberculosis, Pleural/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , L-Lactate Dehydrogenase/metabolism , Male , Middle Aged , Triglycerides/analysis
10.
J Clin Ultrasound ; 27(9): 541-3, 1999.
Article in English | MEDLINE | ID: mdl-10525218

ABSTRACT

Large pelvic cysts are commonly seen in gynecologic practice; their heterogeneous origin is reflected in their pleomorphic clinical features. We report the case of a 64-year-old multiparous postmenopausal woman with an unusual manifestation of endometrial adenocarcinoma that presented as hematometra mimicking a large pelvic cyst. In this case, hematometra was well demonstrated by transabdominal sonography, but transvaginal sonography allowed better visualization of the endometrial lining and suggested the correct diagnosis of endometrial cancer. Abnormal vaginal bleeding or hematometra in postmenopausal women should lead to assessment of the endometrial mucosa. Transvaginal sonography can be used to visualize neoplastic lesions in the endometrium when hematometra is detected through transabdominal sonography.


Subject(s)
Adenocarcinoma/diagnostic imaging , Adnexal Diseases/diagnostic imaging , Cysts/diagnostic imaging , Endometrial Neoplasms/diagnostic imaging , Hematometra/diagnostic imaging , Pelvis/diagnostic imaging , Adenocarcinoma/complications , Diagnosis, Differential , Endometrial Neoplasms/complications , Endosonography , Female , Hematometra/etiology , Humans , Middle Aged , Tomography, X-Ray Computed , Vagina/diagnostic imaging
11.
J Formos Med Assoc ; 97(8): 581-3, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9747072

ABSTRACT

To evaluate the patterns of drug resistance of Mycobacterium tuberculosis in Taiwan, a total of 1,091 isolates collected from patients from January 1996 through December 1996 were tested for drug susceptibility using the absolute concentration method at the Taiwan Provincial Chronic Disease Control Bureau. The overall drug rate of resistance to at least one drug was 35.5%. Among the 249 isolates from patients who had never been treated for tuberculosis, 16.1% were resistant to one or more drugs; 1.6% were resistant to at least isoniazid and rifampin. Of 200 patients with prior antituberculosis treatment, 67.0% had isolates resistant to one or more drugs and 46.0% had isolates resistant to at least isoniazid and rifampin. We conclude that drug-resistant M. tuberculosis is an important issue in tuberculosis treatment in Taiwan, especially when dealing with patients with a prior history of antituberculosis treatment. More aggressive interventions, such as directly observed therapy, short-course, are needed to improve the cure rate of pulmonary tuberculosis and to decrease resistance rates.


Subject(s)
Tuberculosis/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Drug Resistance, Microbial , Female , Humans , Male , Middle Aged
12.
Aviat Space Environ Med ; 69(6): 577-82, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9641404

ABSTRACT

BACKGROUND: Both ethanol ingestion and hyperthermia contribute to orthostatic intolerance (OI). HYPOTHESIS: Since ethanol has been cited as a major risk factor for hyperthermia-related deaths, we hypothesized that ethanol exacerbates OI induced by hyperthermia. METHODS: There were seven subjects (four males, three females) rendered hyperthermic (esophageal temperature = 39 degrees C) in a 40 degrees C water bath on two separate days: Condition 1) Control (juice ingestion); and Condition 2) Ethanol [ethanol (1 ml x kg(-1) body mass) and juice ingestion]. To test for OI, 5-min supine periods were followed by 5-min 63 degrees head-up tilts prior to and following immersion. BPs, heart rate and esophageal temperatures were monitored throughout the experiments. RESULTS: For first and second post-immersion tilts, mean arterial BP (MAP) during tilting increased by 5.9 +/- 3.6 (SE) and 9.8 +/- 2.6 mm Hg in the control condition, while it decreased by 7.9 +/- 5.8 and 0.6 +/- 4.3 mm Hg in the ethanol condition. This gave significantly lower MAP (ethanol vs. control) of 63.6 +/- 3.1 vs. 71.8 +/- 4.5 mm Hg (p < 0.05) for the first and 79.6 +/- 2.3 vs. 86.7 +/- 4.4 mm Hg (p < 0.05) for the second post-immersion tilts. These values were all significantly less (p < 0.05) than normothermic tilted values of 94.7 +/- 4.7 mm Hg in the ethanol and 93.6 +/- 2.9 mm Hg in the control condition. Prior to warm water immersion, subjects tolerated all head-up tilts. In the control condition, only one subject experienced orthostatic intolerance following the first post-heating tilt and no intolerance was experienced following 30 min post-heating. However, during the ethanol condition, 4 subjects experienced orthostatic intolerance following the first tilt with episodes of intolerance lasting as long as 80 min (8 supine/tilt cycles). CONCLUSION: Ethanol ingestion prolonged and increased the magnitude of OI in hyperthermic subjects. This may at least partly explain why ethanol is a major risk factor in hyperthermia-related deaths.


Subject(s)
Ethanol/adverse effects , Fever/physiopathology , Posture , Adult , Alcohol Drinking/adverse effects , Blood Pressure , Ethanol/blood , Female , Humans , Male , Risk Factors
14.
Aviat Space Environ Med ; 66(10): 968-75, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8526834

ABSTRACT

BACKGROUND: Whole body cooling impairs manual arm performance. The independent contributions of local (peripheral) and/or whole body (central) cooling are not known. Therefore, a protocol was developed in which the arm and the rest of the body could be independently cooled. METHODS: Biceps temperature (Tmus), at a depth of 20 mm, and esophageal temperature (Tes) were measured. Six subjects were immersed to the clavicles in a tank (body tank) of water under 3 conditions: 1) cold body-cold arm (CB-CA); 2) warm body-cold arm (WB-CA); and 3) cold body-warm arm (CB-WA). In the latter two conditions, subjects placed their dominant arm in a separate (arm) tank. Water temperature (Tw) in each tank was independently controlled. In conditions requiring cold body and/or cold arm, Tw in the appropriate tanks was 8 degrees C. In conditions requiring warm body and/or warm arm, Tw in the appropriate tanks was adjusted between 29 and 38 degrees C to maintain body/arm temperature at baseline values. A battery of 6 tests, requiring fine or gross motor movements, were performed immediately before immersion and after 15, 45, and 70 minutes of immersion. RESULTS: In CB-CA, Tes decreased from an average of 37.2 to 35.6 degrees C and Tmus decreased from 34.6 to 22.0 degrees C. In WB-CA, Tmus decreased to 18.1 degrees C (Tes = 37.1 degrees C), and in CB-WA, Tes decreased to 35.8 degrees C (Tmus = 34.5 degrees C). By the end of immersion, there were significant decrements (43-85%) in the performance of all tests in CB-CA and WB-CA (p < 0.0002); scores for each test were similar in these two conditions. There was no significant change in scores throughout the CB-WA condition. In both conditions with arm cooling (i.e., WB-CA and CB-CA), Tmus accounted for 85-98% of the variance in all tests. When the core was cooled in the CB-WA condition, Tes was significantly correlated to scores in only two tests (accounted for 90 and 93% of the variance) although the actual effect was small. In the CB-CA condition, partial correlations indicated that Tes accounted for 4-10% of the variance in scores of 4 tests. CONCLUSIONS: We conclude that cooling of the body and/or the arm elicits large decrements in finger, hand and arm performance. The decrements are due almost entirely to the local effects of arm tissue cooling.


Subject(s)
Arm/physiology , Hypothermia, Induced/adverse effects , Motor Skills/physiology , Adult , Analysis of Variance , Body Temperature , Esophagus/physiology , Functional Laterality , Hand Strength , Humans , Hypothermia, Induced/methods , Immersion , Movement , Range of Motion, Articular
15.
Int J Gynaecol Obstet ; 48(3): 295-8, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7781873

ABSTRACT

We present a case of prenatally diagnosed mediastinal cystic hygroma with spontaneous resolution. To our knowledge, this is only the second case report of mediastinal cystic hygroma diagnosed prenatally, and the first one with spontaneous resolution perinatally. Our case shows that, in the absence of hydrops fetalis, mediastinal cystic hygroma in a fetus with normal karyotype can be associated with a normal outcome. Therefore we recommend fetal karyotyping, a careful search for other anomalies and close sonographic follow-up in such cases.


Subject(s)
Fetal Diseases , Lymphangioma, Cystic , Mediastinal Neoplasms , Neoplasm Regression, Spontaneous , Adult , Female , Fetal Diseases/diagnostic imaging , Fetal Diseases/genetics , Humans , Karyotyping , Lymphangioma, Cystic/diagnostic imaging , Lymphangioma, Cystic/genetics , Mediastinal Neoplasms/diagnostic imaging , Mediastinal Neoplasms/genetics , Pregnancy , Ultrasonography, Prenatal
17.
J Biomed Mater Res ; 28(3): 387-95, 1994 Mar.
Article in English | MEDLINE | ID: mdl-8077254

ABSTRACT

Intracranial studies to analyze the degradation kinetics of the bioerodible polymer poly[bis(p-carboxyphenoxy)propane-sebacic acid] [p(CPP-SA) 20:80] copolymer wafers were conducted in a rat model. Rats were separated into four groups: those receiving 1) polymer, 2) polymer loaded with the chemotherapeutic agent BCNU, 3) drug-loaded polymer with previous tumor implantation, and 4) polymer and an absorbable hemostatic material. A polymer wafer was surgically implanted into the brain of each animal. Residual polymer was harvested at varying times for chromatographic analysis. In vitro effects of pH, mixing, and water availability on degradation were also studied. The results of in vitro and in vivo studies were compared to understand the behavior of polymers in a clinical setting. We found that degradation of p(CPP-SA) initially occurred more slowly in vivo than in vitro. The presence of BCNU, tumor, and absorbable hemostatic material did not affect the ultimate time of polymer degradation in vivo, and the intrinsic polymer degradation time of 1 mm thick p(CPP-SA) 20:80 disks in vivo was 6-8 weeks.


Subject(s)
Brain Neoplasms/drug therapy , Decanoic Acids/pharmacokinetics , Drug Carriers/pharmacokinetics , Gliosarcoma/drug therapy , Polyesters/pharmacokinetics , Animals , Biodegradation, Environmental , Carmustine/administration & dosage , Carmustine/therapeutic use , Cellulose, Oxidized , Delayed-Action Preparations , Drug Evaluation, Preclinical , Drug Implants , Foreign-Body Reaction/etiology , Inflammation , Male , Rats , Rats, Inbred F344
18.
Cell Mol Biol Res ; 40(4): 351-7, 1994.
Article in English | MEDLINE | ID: mdl-7866435

ABSTRACT

Platelet actin binding protein (ABP) as isolated from human platelets exists in at least four phosphorylated forms which we have designated ABP-0, ABP-1, ABP-2, and ABP-3 whose phosphate content ranges from 18 (ABP-0) to 40 (ABP-3) moles Pi/mole ABP. These forms differ in their resistance to calpain cleavage and ability to cross-link F-actin with ABP-3 being the best in each of these properties. Attempts to phosphorylate ABP-1, two or three with protein kinase C (PKC) were unsuccessful except if the proteins were pretreated with Escherichia coli alkaline phosphatase. All of the forms could be phosphorylated with cAMP-dependent kinase (PKA) and subsequent resistance to calpain cleavage conferred. Phosphorylation/dephosphorylation of ABP may be an important regulatory mechanism by which the cytoskeletal architecture is stabilized or transformed.


Subject(s)
Actins/metabolism , Blood Platelets/enzymology , Microfilament Proteins/metabolism , Calpain , Cyclic AMP-Dependent Protein Kinases/metabolism , Humans , Phosphorylation , Protein Kinase C/metabolism
19.
Clin Pharmacokinet ; 25(4): 342-50, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8261716

ABSTRACT

By what mechanism do nonsteroidal anti-inflammatory drugs (NSAIDs) move from plasma into synovial fluid and back, and how does binding to plasma albumin in vitro relate to articular transport in vivo? To evaluate these issues, concurrent plasma and synovial fluid data of 8 different NSAIDs from 10 single-dose trials were analysed by a simple compartmental model incorporating intra-articular volume, synovial plasma flow rates and protein transport. All pharmacological and physiological data were taken from published studies of chronic knee effusions in patients with rheumatoid arthritis. The analysis shows that these protein-bound NSAIDs readily leave the vasculature and enter synovial fluid during each transit of synovial microvessels. The mean rate of transport, 0.23 min-1, is consistent with passive diffusion at rates far in excess of those attributable to movement of albumin-bound drug or of the small, free-drug fraction found by equilibrium dialysis. These findings are explained by association and dissociation of NSAIDs and albumin that occur far more rapidly than vascular transit. Ongoing dissociation makes bound drug available for transvascular exchange and thereby diminishes the pharmacokinetic significance of binding data obtained in vitro.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Cartilage, Articular/metabolism , Rheumatic Diseases/metabolism , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Humans , Models, Biological , Protein Binding , Rheumatic Diseases/drug therapy
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