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1.
Biochem Pharmacol ; 71(10): 1422-34, 2006 May 14.
Article in English | MEDLINE | ID: mdl-16522318

ABSTRACT

The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.


Subject(s)
Enzyme Inhibitors/pharmacokinetics , ErbB Receptors/antagonists & inhibitors , Protein Tyrosine Phosphatases/antagonists & inhibitors , Tyrphostins/pharmacokinetics , Animals , Area Under Curve , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Injections, Intravenous , Injections, Subcutaneous , Mice , Molecular Structure , Quinazolines , Rats , Thymidine/metabolism , Tyrphostins/chemistry , Tyrphostins/pharmacology , Xenograft Model Antitumor Assays
2.
J Clin Oncol ; 23(1): 205-29, 2005 Jan 01.
Article in English | MEDLINE | ID: mdl-15625375

ABSTRACT

Drug-metabolizing enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics, including antineoplastics, resulting in either their activation or detoxification. Many studies have reported the presence of DME in tumors; however, heterogeneous detection methodology and patient cohorts have not generated consistent, firm data. Nevertheless, various gene therapy approaches and oral prodrugs have been devised, taking advantage of tumoral DME. With the need to target and individualize anticancer therapies, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses cytotoxic drug metabolism by tumors, through addressing the classes of the individual DME, their relevant substrates, and their distribution in specific malignancies. The limitations of preclinical models relative to the clinical setting and lack of data on the changes of DME with disease progression and host response will be discussed. The therapeutic implications of tumoral drug metabolism will be addressed-in particular, the role of DME in predicting therapeutic response, the activation of prodrugs, and the potential for modulation of their activity for gain are considered, with relevant clinical examples. The contribution of tumoral drug metabolism to cancer therapy can only be truly ascertained through large-scale prospective studies and supported by new technologies for tumor sampling and genetic analysis such as microarrays. Only then can efforts be concentrated in the design of better prodrugs or combination therapy to improve drug efficacy and individualize therapy.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Neoplasms/enzymology , Animals , Biotransformation/physiology , Drug Design , Humans , Neoplasms/drug therapy , Neoplasms/metabolism
3.
Curr Drug Metab ; 4(2): 131-49, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12678692

ABSTRACT

Drug metabolising enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics. Over a long period of time, many studies have reported the presence of DME in tumors, however quantitation and sampling techniques and heterogeneous patient populations have resulted in many generalisations, provoking more questions than they answer. In addition, many of the studies have focussed on a potential role of DME in procarcinogenesis rather than for modulation for therapeutic advantage. With the need to target anticancer therapies to tumor cells to avoid undesirable systemic effects, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses drug metabolism by tumors by firstly addressing the level and activity of individual DME in the common cancers: breast, gastrointestinal, brain, lung and haematological malignancies in comparison to peritumoral and nontumoral tissue. This is then put into perspective through consideration of the therapeutic implications of tumoral drug metabolism especially with regard to the new anticancer agents. The contribution of tumoral metabolism and its significance in cancer therapy must be ascertained through prospective studies. Only then can efforts be concentrated in the design of better prodrugs or combinations of therapy to improve intracellular drug concentrations. Various gene therapy approaches have been attempted experimentally with promising results. However, there are major gaps in understanding the implications of tumoral DME in disease progression (including metastasized tissue) and relapse.


Subject(s)
Antineoplastic Agents/metabolism , Neoplasms/enzymology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Gene Expression , Humans , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Transplantation , Neoplasms/drug therapy , Neoplasms/metabolism , Transplantation, Heterologous , Tumor Cells, Cultured
4.
Pharm Res ; 17(3): 291-8, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10801217

ABSTRACT

PURPOSE: 1. To compare the disposition of tracer morphine ([3H]M) following systemic and intraduodenal administration in the recirculating, rat small intestine preparation in absence or presence of verapamil (V), an inhibitor of P-glycoprotein. 2. To develop a physiological model to explain the observations. METHODS: A bolus dose of [3H]M was added to the reservoir or injected into the duodenum of the rat small intestine preparation. V (200 microM in reservoir) was either absent (control studies) or present. Intestinal microsomal, incubation studies were performed to evaluate the effect of V on morphine glucuronidation. RESULTS: After systemic administration, [3H]M was not metabolized but was exsorbed into lumen. By contrast, both [3H]M and the 3beta-glucuronide metabolite, [3H]M3G, appeared in reservoir and lumen after intraduodenal administration. A physiologically-based model that encompassed absorption, metabolism and secretion was able to describe the route-dependent glucuronidation of M. The presence of V resulted in diminished levels of M3G in perfusate and lumen and mirrored the observation of decreased glucuronidation in microsomal incubations. Verapamil appeared to be an inhibitor of glucuronidation and not secretion of M. CONCLUSIONS: M was secreted and absorbed by the rat small intestine. Route-dependent glucuronidation of M was explained by physiological modeling when M was poorly partitioned in intestinal tissue, with a low influx clearance from blood and a even poorer efflux clearance from tissue. The poor efflux rendered a much greater metabolism of M that was initially absorbed from the lumen. V increased the extent of M absorption through inhibition of M glucuronidation.


Subject(s)
Duodenum/metabolism , Intestinal Absorption/physiology , Morphine/pharmacokinetics , Narcotics/pharmacokinetics , Animals , Calcium Channel Blockers/pharmacology , Injections, Intra-Arterial , Intestinal Absorption/drug effects , Male , Microsomes/metabolism , Models, Biological , Organ Culture Techniques , Perfusion , Rats , Rats, Sprague-Dawley , Tritium , Verapamil/pharmacology
5.
Drug Chem Toxicol ; 20(4): 329-44, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9433662

ABSTRACT

The occurrence of low systemic availability due to significant metabolism or poor absorption of orally administered drugs has been well recognized. Three rate controlling factors affecting the oral absorption: unstirred water layer, membrane limitation, or flow limitation, have been identified. These are much affected by the physicochemical properties of the drug: pKA, water/lipid solubility, structural mimicry to endogenous substrates for transport proteins, and the physiology of the GI tract. Drug metabolizing enzymes are found to be present in the intestine, albeit the content is lower than that found in liver. The presence of pre-absorptive versus post-absorptive intestinal metabolism is presently discussed in experimental sets of data with luminal and systemic administration of the drugs in the vascularly perfused rat small intestine preparation. The effect of the anterior anatomical placement of the intestine and its contribution to metabolism, in relation to that for the liver, has been examined in our laboratory by the perfused intestine-liver preparation. The effect of concentration and flow have been studied and general principles governing drug absorption and metabolism in the intestine and the subsequent effects on the liver have been discussed.


Subject(s)
Intestine, Small/metabolism , Liver/metabolism , Pharmaceutical Preparations/metabolism , Toxicity Tests/methods , Animals , Intestinal Absorption , Kinetics , Pharmaceutical Preparations/administration & dosage
6.
Anesth Analg ; 83(6): 1244-50, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8942594

ABSTRACT

Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulation of epidurally administered local anesthetics.


Subject(s)
Anesthesia, Epidural , Anesthetics, Local/pharmacokinetics , Hyaluronic Acid/pharmacokinetics , Lidocaine/pharmacokinetics , Nerve Block , Absorption , Anesthesia, Intravenous , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacology , Animals , Cross-Over Studies , Delayed-Action Preparations , Dogs , Drug Combinations , Drug Interactions , Epidural Space/metabolism , Female , Hyaluronic Acid/administration & dosage , Hyaluronic Acid/pharmacology , Lidocaine/administration & dosage , Lidocaine/blood , Lidocaine/pharmacology , Molecular Weight , Random Allocation , Time Factors , Weight-Bearing
7.
Am J Respir Cell Mol Biol ; 14(2): 146-54, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8630264

ABSTRACT

An airway epithelial mucous goblet cell line would be useful towards understanding mechanisms underlying the common problem of respiratory mucus hypersecretion. SPOC1 is a novel rat tracheal epithelial (RTE) cell line that developed cytologic features suggestive of mucous goblet cells when grown in tracheal grafts in vivo (Am. J. Respir. Cell Mol. Biol. 1995; 12:385-395). Our aims were to determine whether SPOC1 cells were capable of mucin synthesis and to directly compare mucin production by SPOC1 cells and RTE cells. Towards this end, we validated the use of monoclonal antibody (mAb) RTE11 (Exp. Lung Res. 1992; 18:323-342) as an immunologic probe for rat airway secretory mucin. Our results strongly suggest that mAb RTE11 detects a carbohydrate antigen that is a sensitive and specific marker for rat tracheobronchial secretory mucin. SPOC1 cells in tracheal grafts in vivo contained granules with ultrastructural features similar to mucous granules in normal rat airway goblet cells and they were strongly stained by mAb RTE11. Retinoic acid (RA) and culture on porous supports are known to profoundly modify airway epithelial cell phenotype in vitro. Expression of several retinoid-responsive proteins was similar in cultured SPOC1 and primary RTE cells, but major differences in mucin production were noted. Primary RTE cells in vitro only made mucin when grown on porous supports in the presence of RA, whereas SPOC1 cells produced mucin when grown on plastic or glass surfaces and even in the absence of RA. Interestingly, RA enhanced mucin secretion by SPOC1 cells during the early plateau stage of culture but there were no differences due to RA late in the culture period. SPOC1 cells are capable of mucin production and will be a useful tool for studying select aspects of airway secretory cell differentiation and function.


Subject(s)
Mucins/biosynthesis , Trachea/cytology , Animals , Antibodies, Monoclonal , Antibody Specificity , Cell Differentiation/physiology , Cell Line, Transformed/cytology , Cell Line, Transformed/metabolism , Cell Line, Transformed/ultrastructure , Epithelial Cells , Epithelium/metabolism , Epithelium/ultrastructure , Histocytochemistry , Immunohistochemistry , Microscopy, Electron , Mucins/immunology , Mucins/metabolism , Rats
8.
Anesth Analg ; 80(4): 740-6, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7893028

ABSTRACT

We evaluated the utility of medium molecular weight hyaluronic acid for prolonging the local anesthetic activity of lidocaine in a rabbit model of epidural analgesia. Equiviscous formulations were prepared as either a physical mixture of lidocaine hydrochloride and sodium hyaluronate (where drug release occurred via diffusion) or as a lidocaine-hyaluronate complex (where drug release occurred via diffusional and electrostatic processes). The novel hyaluronic acid formulations were functionally evaluated, relative to lidocaine solution, in an intact, conscious rabbit model. The hyaluronate formulations were well tolerated. The duration of sensory block and loss of weight-bearing was prolonged twofold by the lidocaine-hyaluronate complex relative to the solution (P < 0.05). In terms of motor block, flaccid paresis occurred after administration of the solution formulation, whereas only partial motor block was evident after administration of the viscous formulations. Pharmacokinetic modeling of the lidocaine plasma concentration-time data indicated that the rate of drug absorption from the lidocaine-hyaluronate complex was decreased fourfold relative to the solution (P < 0.05). These observations indicate that ionic complexes of local anesthetics with medium molecular weight hyaluronic acid may offer advantages for the prolongation of epidural analgesia.


Subject(s)
Anesthesia, Epidural , Hyaluronic Acid/administration & dosage , Lidocaine/administration & dosage , Animals , Cross-Over Studies , Hyaluronic Acid/pharmacology , Lidocaine/pharmacokinetics , Molecular Weight , Rabbits , Time Factors
9.
Am J Respir Cell Mol Biol ; 12(4): 385-95, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7535063

ABSTRACT

In this report we described the establishment and characterization of a continuous rat tracheal epithelial (RTE) cell line spontaneously derived from secondary RTE cell cultures. Designated SPOC1, this cell line is nontumorigenic and maintains a diploid karyotype with specific, nonrandom chromosomal alterations involving chromosomes 1, 3, and 6. SPOC1 cells demonstrate decreased requirements for peptide growth factors, compared with primary RTE cells. Upon inoculation into denuded rat tracheas, which are then implanted into syngeneic hosts, SPOC1 cells initially form a stratified squamous epithelium, which becomes less stratified with time and forms glandlike invaginations into the surrounding lamina propria. No evidence of ciliated cell differentiation is detected. The epithelium formed by SPOC1 cells in tracheal grafts reacts with antibodies specific for keratin 14, 13, and 19 (but not keratin 18) at both early and late time points, although the localization of antibody staining changes as the epithelium becomes less stratified with time. The suprabasal epithelial cells become positive for alcian blue-periodic acid-Schiff staining at later time points. The near-normal karyotype and differentiation potential of SPOC1 cells make this cell line a unique window into early changes occurring during immortalization of airway epithelial cells and will allow studies of relationships between differentiation state and neoplastic transformation.


Subject(s)
Trachea/cytology , Animals , Cell Differentiation , Cell Division/drug effects , Electrophysiology , Epithelial Cells , Fibronectins/genetics , Gene Expression , Growth Substances/pharmacology , Immunoenzyme Techniques , Karyotyping , Keratins/metabolism , Male , Microscopy, Electron , Neoplasms, Experimental/pathology , Rats , Rats, Inbred F344
10.
Exp Cell Res ; 212(1): 141-50, 1994 May.
Article in English | MEDLINE | ID: mdl-8174636

ABSTRACT

Structural glycoproteins and cytoskeletal proteins play a major role in the regulation of cellular organization and function. Changes in the structure and function of these proteins are involved in the cascade of events which lead to neoplastic transformation. We evaluated RNA levels, protein localization, and organization of selected proteins in an in vitro model system of respiratory carcinogenesis to examine alterations in cell architecture. Localization of fibronectin (Fn), thrombospondin (Tsp), and F-actin was examined in (1) primary rat tracheal epithelial (RTE) cells; (2) spontaneously immortalized nonneoplastic cells (SPOC-1); and (3) neoplastic cells (EGV5T) derived from tumors arising following transplantation of an N-methyl-N'-nitro-N-nitrosoguanidine-transformed RTE cell line into nude mice. Proteins were stained with fluorescein-labeled antibodies or phalloidin compound and analysis was performed with a confocal laser scanning microscope. Primary RTE cells display organized F-actin stress fibers, perinuclear Fn and Tsp, and pericellular Fn in fibrillar arrays. In larger colonies, Tsp occurs between cells and occasionally in fibrillar arrays. SPOC-1 cells, unlike primary RTE cells and neoplastic EGV5T cells, seldom form junctions and exhibit few cell surface extensions. F-actin stress fibers are reduced in these immortalized cells. F-actin in SPOC-1 cells occurs in the perinuclear region, scattered diffusely throughout the cell and in punctate adhesions. Fn and Tsp are localized to the perinuclear region with Fn staining more intensely. EGV5T neoplastic cells also display a dramatic loss of stress fibers and F-actin is concentrated mainly near the cell periphery. Perinuclear staining of Fn and Tsp occurs in some cells within the colony. Levels of Tsp RNA and Fn RNA and protein are significantly reduced in both cell lines compared to primary RTE cells. We conclude that structural protein disruptions are early events in the transformation of these respiratory epithelial cells.


Subject(s)
Actins/isolation & purification , Cell Transformation, Neoplastic , Fibronectins/isolation & purification , Membrane Glycoproteins/isolation & purification , Trachea/cytology , Animals , Cell Compartmentation , Cell Division , Cells, Cultured , Epithelial Cells , Fibronectins/genetics , Fluorescent Antibody Technique , Membrane Glycoproteins/genetics , RNA, Messenger/analysis , Rats , Thrombospondins
11.
Anaesth Intensive Care ; 21(3): 298-303, 1993 Jun.
Article in English | MEDLINE | ID: mdl-8342758

ABSTRACT

A rabbit model is described for the evaluation of epidurally administered local anaesthetic agents. The technique involves a single injection via the readily identified lumbosacral space in conscious rabbits, with the epidural space being identified by a modified loss-of-resistance technique. The endpoints used to assess pharmacodynamic responses of the rabbit model were (1) sensory loss, (2) loss of weight-bearing ability, and (3) flaccid paresis. The model was further characterised by investigation of endpoint responses to changes in injection volume (0.1-0.25 ml/kg) and concentration of administered lignocaine solutions (0.5 to 2%). From these studies, a volume of 0.2 ml/kg was chosen as a standard dose and a subsequent comparison between different agents undertaken. The rank order for the onset of action, duration of effect and the observed pharmacokinetic profiles after epidural administration of 2% lignocaine, 2% lignocaine with adrenaline (1:200,000) or 0.5% bupivacaine solutions are broadly consistent with human clinical data. These data indicate that the rabbit is a simple (albeit limited) model for the screening evaluation of epidurally administered local anaesthetic agents.


Subject(s)
Anesthetics, Local/pharmacology , Injections, Epidural/methods , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacokinetics , Animals , Bupivacaine/administration & dosage , Bupivacaine/pharmacokinetics , Bupivacaine/pharmacology , Evaluation Studies as Topic , Lidocaine/administration & dosage , Lidocaine/pharmacokinetics , Lidocaine/pharmacology , Rabbits
13.
Radiology ; 187(2): 413-20, 1993 May.
Article in English | MEDLINE | ID: mdl-8475283

ABSTRACT

One hundred patients underwent transjugular intrahepatic portosystemic shunt (TIPS) creation for variceal bleeding (n = 94), intractable ascites (n = 3), hepatorenal syndrome (n = 2), and preoperative portal decompression (n = 1). Shunts were completed in 96 patients. Portal vein pressure was reduced from 34.5 mm Hg +/- 7.6 (standard deviation) to 24.5 mm Hg +/- 6.2; the residual portal vein-hepatic vein gradient was 10.4 mm Hg +/- 0.9. Acute variceal bleeding was controlled in 29 of 30 patients. Of the 96 patients who underwent successful TIPS creation, 26 have died and 22 have undergone liver transplantation; the remaining 48 patients have survived an average of 7.6 months. Variceal bleeding recurred in 10 patients. Fifteen patients developed shunt stenosis (n = 6) or occlusion (n = 9). Patency was reestablished in eight of the nine occluded shunts. Seventeen patients developed new or worsened encephalopathy. The authors conclude that TIPS creation is an effective and reliable means of lowering portal pressure and controlling variceal bleeding, particularly in patients with acute variceal bleeding unresponsive to sclerotherapy and patients with chronic variceal bleeding before liver transplantation.


Subject(s)
Esophageal and Gastric Varices/surgery , Portasystemic Shunt, Surgical , Stents , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Esophageal and Gastric Varices/diagnostic imaging , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/surgery , Hepatic Veins/diagnostic imaging , Hepatic Veins/surgery , Humans , Male , Middle Aged , Portal Vein/diagnostic imaging , Portal Vein/surgery , Postoperative Complications , Radiography, Interventional , Vascular Patency
15.
Radiology ; 186(2): 523-7, 1993 Feb.
Article in English | MEDLINE | ID: mdl-8421759

ABSTRACT

The feasibility and efficacy of transjugular intrahepatic portosystemic shunts (TIPS) were evaluated in 10 patients with preexisting portal vein occlusions. A standard transjugular approach was used in six of the 10 patients for both portal vein recanalization and TIPS placement. The protal veins were successfully recanalized and TIPS were established in three of the six patients. TIPS placement was unsuccessful in the other three patients because the catheters could not be advanced through the occluded segments. A transhepatic approach was used in four of the 10 patients for portal vein recanalization before transjugular catheterization and TIPS placement were attempted. Both portal vein recanalization and TIPS placement were technically successful in all four patients. Bleeding stopped in all patients after successful shunt placement. TIPS can be used to control variceal bleeding in some patients, despite preexisting portal vein occlusion. Preliminary recanalization of the occluded portal segment by means of the transhepatic approach may facilitate TIPS placement.


Subject(s)
Arterial Occlusive Diseases/surgery , Portal Vein/surgery , Portasystemic Shunt, Surgical , Adult , Aged , Arterial Occlusive Diseases/diagnostic imaging , Humans , Male , Middle Aged , Portal Vein/diagnostic imaging , Radiography
16.
Radiology ; 185(3): 813-7, 1992 Dec.
Article in English | MEDLINE | ID: mdl-1438768

ABSTRACT

Transjugular intrahepatic portosystemic shunts (TIPS) were placed in 93 patients between June 1990 and January 1992 for treatment of variceal hemorrhage. In each case, a Wallstent (Schneider USA, Minneapolis) was used to support the hepatic parenchymal tract between the hepatic and portal veins. Currently, these stents have a maximal diameter of 10 mm. In eight of 93 patients, major portal hypertension persisted after placement of a 10-mm-diameter shunt, manifested by continued rapid variceal filling and elevated portosystemic gradients. A second TIPS was placed parallel to the first in these patients to allow further portal decompression. In two other patients, a second TIPS was placed because the initial shunt functioned suboptimally. The mean postprocedural portosystemic gradient in the patients who received one TIPS was 10.2 mm Hg +/- 3.7. In patients who received two TIPS, the mean postprocedural gradient was 19.1 mm Hg +/- 3.8 after placement of the first TIPS and 12.5 mm Hg +/- 3.5 after placement of the second. Two patients developed their first episode of encephalopathy after placement of two TIPS. The methods and indications for placing two TIPS in this select population are discussed.


Subject(s)
Hypertension, Portal/surgery , Portasystemic Shunt, Surgical , Radiography, Interventional , Adult , Esophageal and Gastric Varices/complications , Female , Gastrointestinal Hemorrhage/etiology , Humans , Hypertension, Portal/complications , Hypertension, Portal/diagnostic imaging , Male , Middle Aged , Portasystemic Shunt, Surgical/instrumentation , Stents
17.
J Vasc Surg ; 16(2): 258-67, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1495151

ABSTRACT

A retrospective study of transjugular intrahepatic shunts performed between June 1990 and June 1991 is reported. Twelve patients were actively bleeding at the time of the procedure; 12 other patients had had one to five bleeding episodes within the previous 2 weeks, and one patient had massive ascites from Budd-Chiari syndrome. Most patients had severe liver disease: 21 Child's class C, three Child's class B, and one Child's class A. Transjugular intrahepatic shunting was technically successful in all cases. Portal vein pressures were reduced on average from 36 +/- 7 cm H2O to 22 +/- 6 cm H2O. Variceal bleeding ceased after transjugular intrahepatic shunting in all patients who were actively bleeding. Five patients died (30-day mortality, 20%), and eight patients subsequently underwent elective liver transplantation. The transjugular intrahepatic shunts in the 12 other patients have remained patent an average of 5.5 months. Shunt occlusion occurred in three patients at 21, 24, and 102 days, respectively. All three occlusions were successfully reopened with percutaneous techniques, yielding a primary shunt patency of 88% and secondary shunt patency of 100%. Complications included new onset encephalopathy in one patient, which cleared with medical therapy and transient renal failure in one patient. These preliminary data suggest that transjugular intrahepatic shunting is a safe and effective therapy for the short-term treatment of patients with variceal hemorrhage, particularly in patients with severe liver disease awaiting transplantation. The long-term benefit of transjugular intrahepatic shunting awaits further follow-up.


Subject(s)
Esophageal and Gastric Varices/surgery , Gastrointestinal Hemorrhage/surgery , Portasystemic Shunt, Surgical/methods , Adolescent , Adult , Child , Esophageal and Gastric Varices/etiology , Female , Gastrointestinal Hemorrhage/etiology , Hepatic Veins , Humans , Hypertension, Portal/complications , Hypertension, Portal/etiology , Male , Middle Aged , Portasystemic Shunt, Surgical/adverse effects , Portasystemic Shunt, Surgical/instrumentation , Retrospective Studies , Stents , Treatment Outcome
18.
Radiology ; 182(3): 697-701, 1992 Mar.
Article in English | MEDLINE | ID: mdl-1371362

ABSTRACT

A consecutive series of 50 patients with malignant biliary obstruction were treated by means of palliative drainage with a metallic expandable stent. Stent placement was successful in all patients. The patients were followed up prospectively at 2-month intervals over a period of 9-22 months. Forty-one patients (82%) died; nine (18%) are still living. The overall patency and survival rates for the 50 patients were 5.8 months and 7.5 months, respectively. The 30-day mortality rate was 8% (n = 4), the minor complication rate was 18% (n = 9), and the major complication rate was 8% (n = 4). One patient (2%) had intrahepatic arterial bleeding that required embolization, one (2%) had a right subphrenic abscess, and two patients (4%) had transient septic events. Stent occlusion requiring a second intervention occurred in 24% of patients (n = 12). Excellent palliation was achieved in most patients. No stent migration occurred. No great clinical advantages in prolonged patency compared with those of other published series involving the use of plastic stents were demonstrated. Ease of placement and versatility may offset the high cost of the stent.


Subject(s)
Biliary Tract Neoplasms/complications , Cholestasis/therapy , Palliative Care/methods , Pancreatic Neoplasms/complications , Stents , Aged , Cholestasis/etiology , Cholestasis/mortality , Drainage/instrumentation , Female , Follow-Up Studies , Humans , Male , Prospective Studies , Stainless Steel , Survival Rate , Time Factors
19.
Psychopharmacology (Berl) ; 107(2-3): 175-9, 1992.
Article in English | MEDLINE | ID: mdl-1352050

ABSTRACT

Sixty-two DSM III chronic schizophrenic inpatients were selected for a double-blind, placebo controlled, multi-centre, relapse prevention study of remoxipride, a selective dopamine (D2)-receptor antagonist. After a 1 month placebo washout, 23 patients had relapsed and were withdrawn. Of the remaining patients 19 were randomised to remoxipride (150-300 mg daily) and 20 to placebo. Their median age was 58 years, 26 were male, and the median duration of illness was 33 years. After 24 weeks a further total of 8 remoxipride and 17 placebo patients had been withdrawn. Excluding three patients withdrawn for reasons other than relapse, the comparative relapse rates were 37% and 75%, respectively (P = 0.015). Efficacy analyses using clinical global impression (P = 0.04) and change in BPRS scores (P = 0.016) were in favour of remoxipride. Extrapyramidal symptoms were minimal in both groups. Treatment emergent adverse events were similar in the two groups. Remoxipride is therefore of potential value as a safe drug which is both effective and well tolerated in the long term management of chronic schizophrenic patients.


Subject(s)
Antipsychotic Agents/therapeutic use , Benzamides/therapeutic use , Schizophrenia/prevention & control , Adult , Aged , Antipsychotic Agents/adverse effects , Benzamides/adverse effects , Chronic Disease , Double-Blind Method , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Recurrence , Remoxipride
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