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1.
Anaesthesia ; 76(10): 1377-1391, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33984872

ABSTRACT

The need to evacuate an ICU or operating theatre complex during a fire or other emergency is a rare event but one potentially fraught with difficulty: Not only is there a risk that patients may come to harm but also that staff may be injured and unable to work. Designing newly-built or refurbished ICUs and operating theatre suites is an opportunity to incorporate mandatory fire safety features and improve the management and outcomes of such emergencies: These include well-marked manual fire call points and oxygen shut off valves (area valve service units); the ability to isolate individual zones; multiple clear exit routes; small bays or side rooms; preference for ground floor ICU location and interconnecting routes with operating theatres; separate clinical and non-clinical areas. ICUs and operating theatre suites should have a bespoke emergency evacuation plan and route map that is readily available. Staff should receive practical fire and evacuation training in their clinical area of work on induction and annually as part of mandatory training, including 'walk-through practice' or simulation training and location of manual fire call points and fire extinguishers, evacuation routes and location and operation of area valve service units. The staff member in charge of each shift should be able to select and operate fire extinguishers and lead an evacuation. Following an emergency evacuation, a network-wide response should be activated, including retrieval and transport of patients to other ICUs if needed. A full investigation should take place and ongoing support and follow-up of staff provided.


Subject(s)
Disasters , Fires , Intensive Care Units , Operating Rooms , Safety Management/methods , Emergencies , Floods , Humans
2.
Mol Aspects Med ; 61: 41-49, 2018 06.
Article in English | MEDLINE | ID: mdl-29317252

ABSTRACT

The gastrointestinal (GI) tract plays a central role in the absorption, distribution, metabolism, and excretion of flavonoids, which ultimately define the health effects of these bioactives. These aspects are modulated by the interactions of flavonoids with other dietary components, environmental factors, the host, and the GI microbiota. Flavonoid can target molecules in the luminal content, the different GI tract cell types, and the microbiota. Importantly, flavonoid actions at the GI tract can have an impact systemically, e.g. on glucose homeostasis, lipid and energy metabolism, or cardiovascular risk factors. The beneficial actions of flavonoids at the GI include their capacity to: i) protect the intestinal epithelium against pharmacological insults and food toxins; ii) modulate the activity of enzymes involved in lipid and carbohydrate absorption; iii) maintain the intestinal barrier integrity; iv) modulate the secretion of gut hormones; v) modulate the GI tract immune system; vi) exert potential anti-colorectal cancer activity; and vii) shape microbiota composition and function. Further understanding of the mechanisms mediating the effects of flavonoids on the intestine (and its microbiota) is of critical importance given the relevance of the GI tract on sustaining overall health and of the widespread recommendations of increasing the intake of plant bioactives.


Subject(s)
Flavonoids/metabolism , Gastrointestinal Tract/metabolism , Gastrointestinal Diseases/metabolism , Gastrointestinal Diseases/microbiology , Gastrointestinal Diseases/pathology , Gastrointestinal Microbiome , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/pathology , Health , Humans
3.
Br J Cancer ; 102(2): 419-27, 2010 Jan 19.
Article in English | MEDLINE | ID: mdl-20051947

ABSTRACT

BACKGROUND: Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males. Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited number of genes are known to be epigenetically changed in TGCT. This report documents the genome-wide analysis of differential methylation in an in vitro model culture system. Interesting genes were validated in TGCT patient samples. METHODS: In this study, we used methylated DNA immunoprecipitation (MeDIP) and whole-genome tiling arrays to identify differentially methylated regions (DMRs). RESULTS: We identified 35 208 DMRs. However, only a small number of DMRs mapped to promoters. A genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. We identified several candidate genes, including APOLD1, PCDH10 and RGAG1, which were dysregulated in TGCT patient samples. Surprisingly, APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. We also observed aberrant methylation in the loci of some non-coding RNAs (ncRNAs). One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples, and also in our in vitro model culture system. CONCLUSION: This report is the first application of MeDIP-chip for identifying epigenetically regulated genes and ncRNAs in TGCT. We also demonstrated the function of intergenic and intronic DMRs in the regulation of ncRNAs.


Subject(s)
Neoplasms, Germ Cell and Embryonal/genetics , DNA Methylation , Epigenesis, Genetic , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genome , Genome-Wide Association Study , Humans , Immunoprecipitation , Male , RNA/genetics , Testicular Neoplasms/genetics
4.
Drug Dev Ind Pharm ; 32(8): 919-28, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16954104

ABSTRACT

PURPOSE: To study the effect of gender on the renal disposition of two organic anions, p-aminohippuric acid (PAH) and furosemide (FSM) in the isolated perfused rat kidney (IPK). METHODS: IPK experiments (3-4 per treatment group) were conducted using kidneys from male and female Sprague Dawley rats. PAH was administered as a continuous infusion (with loading dose, targeted steady-state concentration 10 ug/mL). FSM was added as a bolus dose (2.65 mg, targeted concentration 33 ug/mL). Urine was collected in 10-min. intervals and perfusate was sampled at the midpoint of each collection period. Control (drug naïve) perfusions were performed for both genders. PAH and FSM were measured by HPLC. Kidney viability (GFR [estimated using inulin clearance], sodium reabsorption, glucose reabsorption) was monitored continuously during each perfusion experiment (2-h duration). RESULTS: Good kidney function was maintained across all study groups, and lower GFR estimates in female kidneys were due to differences in kidney weight. For PAH, kidney weight corrected renal clearance (0.88 +/- 0.37 mL/min/g vs. 0.59 +/- 0.19 mL/min/g) and excretion ratio (3.8 +/- 1.7 vs. 2.2 +/- 0.72) were significantly higher in male kidneys. For FSM, renal clearance was significantly lower in female (0.10 +/- 0.05 mL/min/g) compared to male kidneys (0.15 +/- 0.07 mL/min/g). Mass balance analysis showed that FSM cumulative urinary excretion was significantly higher and kidney accumulation was significantly lower in experiments with male kidneys. CONCLUSIONS: The study demonstrates that the IPK is a useful model to assess gender effects on renal drug disposition. The renal excretion of organic anions is reduced in female rats, possibly due to gender differences in expression and/or activity of membrane transporters (both basolateral and luminal) in the kidney.


Subject(s)
Kidney/metabolism , Animals , Female , Furosemide/metabolism , Glomerular Filtration Rate , Male , Organic Anion Transport Protein 1/physiology , Organic Anion Transporters, Sodium-Independent/physiology , Perfusion , Rats , Rats, Sprague-Dawley , Sex Characteristics , p-Aminohippuric Acid/metabolism
5.
J Pharm Biomed Anal ; 26(5-6): 687-99, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11600282

ABSTRACT

Para-aminohippuric acid (PAH), an indicator of renal plasma flow, is a commonly used marker of organic anion transport by the kidney. An analytical method for PAH using HPLC was developed. The method is simple, fast and requires a minimum amount of organic solvent. Sample preparation involved protein precipitation with zinc sulfate. Para-amino benzoic acid was utilized as an internal standard (IS). Chromatography was performed using a reversed-phase phenyl column with UV detection at a wavelength of 254 nm. Mobile phase consisted of 0.1 M acetic acid and acetonitrile (99:1) at a flow rate of 1 ml/min. The assay was validated over a standard concentration range from 1 to 25 microg/ml. Accuracy, precision, reproducibility and specificity of the method was established with coefficients of variation <10%. The method was sensitive and showed linear response in peak height ratio (analyte:IS) over the concentration range studied (r(2)>0.99). The assay was used to study the effect of aging on PAH excretion in the isolated perfused rat kidney model. Experiments were conducted in kidneys from young (2-3 months, n=6), adult (6-9 months, n=5) and aged (12-16 months, n=3) male Sprague-Dawley rats at an initial drug concentration of 20 microg/ml. Significant differences in kidney function (e.g. glomerular filtration rate and glucose reabsorption) were observed in aged kidneys. Despite a 5-fold reduction in glomerular filtration rate, PAH renal clearance (kidney weight-corrected) decreased by only 2-fold in aged (2.2+/-0.42 ml/min per gram) compared to young (4.6+/-0.70 ml/min per gram, P<0.05) rats. Furthermore, renal excretion ratio was significantly higher in aged rats (27+/-8.0 vs. 15+/-5.0, P<0.05). These preliminary findings challenge the 'Whole Nephron Hypothesis' that assumes parallel reductions in renal filtration and secretory capacity secondary to disease or aging.


Subject(s)
Aging/metabolism , Kidney/growth & development , p-Aminohippuric Acid/urine , Animals , Calibration , Chromatography, High Pressure Liquid , In Vitro Techniques , Kidney/physiology , Kidney Function Tests , Male , Perfusion , Rats , Rats, Sprague-Dawley , Reference Standards , Reproducibility of Results , Solutions
6.
J Pharmacokinet Biopharm ; 27(1): 45-66, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10533697

ABSTRACT

The rate and extent of binding of methazolamide to human erythrocytes was studied in vitro. All experiments were carried out at physiological temperature (37 C) and pH (7.4). Methazolamide (MTZ) buffer concentrations were analyzed by HPLC. Distributional equilibrium between buffer and washed red blood cells was achieved after 1 hr. Results of equilibrium studies were consistent with two classes of binding sites for MTZ within the erythrocyte: a low affinity, high capacity site (CA-I) and a high affinity, low capacity site (CA-II). A two-binding site model was fitted to experimental data generating estimates for binding parameters Ka1 (0.0017 +/- 0.00022 microM-1) nM1 (636 +/- 5.23 microM), Ka2(0.46 +/- 0.0083 microM-1), and nM2(80.9 +/- 0.389 microM). Based upon these findings, kinetic studies were performed in order to characterize the rate of drug distribution. The rate of erythrocyte uptake of MTZ was mathematically modeled using a series of differential equations describing drug diffusion across the red blood cell membrane and subsequent complexation with intracellular binding sites. The model assumed that penetration of MTZ into the red blood cells was passive but drug binding to the carbonic anhydrase isozymes was not instantaneous. Using a novel curve fitting technique, parameter estimates of RBC membrane permeability (0.0102 +/- 0.000618 cm/min), and binding rate constants k-1(0.254 +/- 0.0213 min-1), k1 (0.0022 +/- 0.00020 ml/microgram-min), k-2(1.59 +/- 0.0358 min-1), and k2(3.1 +/- 0.035 ml/microgram-min) were obtained. The model characterized the observed biphasic decline of MTZ buffer concentrations over time and may help explain the prolonged residence of MTZ in vivo.


Subject(s)
Carbonic Anhydrase Inhibitors/blood , Erythrocytes/metabolism , Methazolamide/blood , Models, Biological , Models, Chemical , Binding Sites , Biological Transport , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrase Inhibitors/pharmacokinetics , Humans , Kinetics , Mathematical Computing , Methazolamide/metabolism , Methazolamide/pharmacokinetics
7.
Genomics ; 62(3): 477-82, 1999 Dec 15.
Article in English | MEDLINE | ID: mdl-10644446

ABSTRACT

Based on searches of EST databases for signal sequences and amphipathic helices, we have identified and cloned an angiopoietin-like gene, ANGPTL3. Multiple tissue Northern blots show that ANGPTL3 is expressed principally in the liver. ANGPTL3 is expressed early during liver development, and expression is maintained in adult liver. Human ANGPTL3 is a 460-amino-acid polypeptide with the characteristic structure of angiopoietins: a signal peptide, an extended helical domain predicted to form dimeric or trimeric coiled-coils, a short linker peptide, and a globular fibrinogen homology domain (FHD). Murine ANGPTL3 is a 455-acid polypeptide encoded by seven exons on mouse chromosome 4, spanning about 11 kb of DNA. ANGPTL3 contains the four conserved cysteines implicated in the intramolecular disulfide bonds within the FHD, but it does not contain two other cysteines that are found within the FHD of angiopoietins 1, 2, and 4. ANGPTL3 also does not contain the characteristic calcium binding motif found in the other angiopoietins. By radiation hybrid mapping and the use of surrounding genes, human ANGPTL3 maps to the 1p31 region.


Subject(s)
Angiopoietins , Growth Substances/genetics , Intercellular Signaling Peptides and Proteins , Liver/metabolism , Membrane Glycoproteins/genetics , Proteins/genetics , Amino Acid Motifs/genetics , Amino Acid Sequence , Angiopoietin-1 , Angiopoietin-2 , Angiopoietin-Like Protein 3 , Angiopoietin-like Proteins , Animals , Base Sequence , Binding Sites/genetics , Blotting, Northern , Chromosomes, Human, Pair 1/genetics , Glycosylation , Growth Substances/biosynthesis , Humans , Mice , Molecular Sequence Data , Organ Specificity , Physical Chromosome Mapping , RNA, Messenger/biosynthesis , Sequence Analysis, DNA , Sequence Homology, Amino Acid
8.
Biopharm Drug Dispos ; 19(6): 373-80, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9737818

ABSTRACT

The pharmacokinetic disposition of methazolamide (MTZ) was studied in five healthy volunteers following administration of a single oral dose. Drug concentrations in blood, plasma, and urine were measured by HPLC. Over the range of plasma concentrations observed in vivo, MTZ free fraction (measured by ultrafiltration) was 0.28. Being a carbonic anhydrase inhibitor, MTZ would be expected to distribute into, and be sequestered by, red blood cells. For this reason, MTZ disposition was characterized utilizing blood concentrations as the reference. Using a two-compartment model, a series of differential equations were simultaneously fitted to blood concentrations and urinary excretion data generating estimates for k10 (0.035 +/- 0.019 h(-1)), k12 (0.200 +/- 0.036 h(-1)), k21 (0.077 +/- 0.046 h(-1)), k(a) (0.304 +/- 0.064 h(-1)), Vc (1.1 +/- 0.18 L) and f(r) (fraction excreted renally, 0.61 +/- 0.14). Total blood clearance was 0.037 +/- 0.020 L h(-1). The model estimate of elimination half-life (126 +/- 61 h) was consistent with drug binding to a high affinity carbonic anhydrase isozyme in the erythocyte. Estimates of MTZ renal clearance and renal excretion ratio were 0.021 +/- 0.010 L h(-1) and 0.16 +/- 0.06, respectively. Overall, the prolonged elimination of MTZ from the blood is the result of extensive erythrocyte distribution and tubular reabsorption by the kidney.


Subject(s)
Carbonic Anhydrase Inhibitors/blood , Carbonic Anhydrase Inhibitors/urine , Erythrocytes/metabolism , Methazolamide/blood , Methazolamide/urine , Administration, Oral , Adult , Area Under Curve , Carbonic Anhydrase Inhibitors/administration & dosage , Cohort Studies , Female , Half-Life , Humans , Male , Methazolamide/administration & dosage , Models, Biological , Prospective Studies
9.
J Pharm Biomed Anal ; 16(6): 1021-7, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9547705

ABSTRACT

Methazolamide is a carbonic anhydrase inhibitor used to treat glaucoma. In vivo, methazolamide readily distributes into red blood cells. Therefore, both blood and plasma concentration data are needed in order to characterize the pharmacokinetics of methazolamide. In the present study, an analytical method using high performance liquid chromatography was validated for determination of methazolamide concentrations in several biological fluids. Through slight modification of a previously reported method for acetazolamide, another carbonic anhydrase inhibitor, methazolamide was readily quantitated in whole blood, plasma and urine. Sample preparation involved liquid-liquid extraction with ethyl acetate followed by a washing step using phosphate buffer (pH 8.0). After back extraction into glycine buffer (pH 10.0), samples were then washed with ether and injected onto the chromatograph. Chromatography was performed using a C-18, 5 microns reverse-phase column with UV detection at a wavelength of 285 nm. Mobile phase consisted of 0.05 M sodium acetate (pH 4.0) and acetonitrile (20%). The assay was validated over two standard concentration ranges from 1 to 100 micrograms ml-1, concentrations reflective of those expected in vivo, Calibration curves were linear for all biological fluids and coefficients of variation for interday and intraday reproducibility studies were less than 8% (range 3.1-7.9%). The method was used to measure methazolamide concentrations in blood, plasma and urine following oral administration to five human subjects.


Subject(s)
Carbonic Anhydrase Inhibitors/analysis , Methazolamide/analysis , Acetazolamide/chemistry , Calibration , Carbonic Anhydrase Inhibitors/pharmacokinetics , Chromatography, High Pressure Liquid , Humans , Indicators and Reagents , Methazolamide/pharmacokinetics , Quality Control , Reference Standards , Reproducibility of Results , Spectrophotometry, Ultraviolet
10.
Drug Metab Dispos ; 25(10): 1215-8, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9321527

ABSTRACT

Venlafaxine (VEN), a drug used in the treatment of depression, undergoes significant first-pass metabolism after oral dosing to O-desmethylvenlafaxine (ODV), a metabolite with comparable therapeutic activity to that of parent drug. The pharmacokinetic disposition of VEN was characterized using a "first-pass" model that incorporates a presystemic compartment (liver) to account for the first-pass metabolism of VEN to ODV. A series of differential equations were simultaneously fitted to plasma concentrations of parent and metabolite. A good fit of the model to observed data was demonstrated, generating estimates for the following parameters: ka (1.31 +/- 0.009 hr-1), VVEN (252 +/- 87.6 liters), CLint (65.8 +/- 39.7 liters/hr), RL (liver:plasma partition coefficient, 29.6 +/- 18. 3), VODV (181 +/- 84.1 liters), and CLODV (23.5 +/- 12.5 liters/hr). Parameter estimates correlated closely with those obtained through noncompartmental methods. These results indicate that the time-course disposition of a compound undergoing first-pass hepatic metabolism after oral dosing can be successfully modeled.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacokinetics , Cyclohexanols/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Biological Availability , Humans , Male , Metabolic Clearance Rate , Venlafaxine Hydrochloride
11.
Nutrition ; 13(9): 774-7, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9290089

ABSTRACT

The electrolyte composition of breast milk beyond 6 months postpartum has not been extensively examined, particularly chloride concentrations. A total of 140 samples of breast milk from 30 breast-feeding mothers were collected and analyzed. Mean mother's values +/- standard error of sodium (141 +/- 17 mg/L), potassium (480 +/- 11 mg/L), and chloride (452 +/- 32 mg/L) were found to be stable after 4 months postpartum until weaning commenced. Considerable variability was found for each constituent, equally divided between intra-individual and inter-individual for chloride and potassium, and predominantly intra-individual for sodium and lactose. In light of reported nutritional deficiency states involving electrolytes in exclusively breast-fed infants, it is possible that the variability of breast milk electrolyte concentrations may adversely affect infant nutrition in selected cases of older exclusively breast-fed infants.


Subject(s)
Chlorides/analysis , Milk, Human/chemistry , Postpartum Period/metabolism , Potassium/analysis , Sodium/analysis , Chlorides/metabolism , Chromatography, High Pressure Liquid/methods , Female , Humans , Infant Nutritional Physiological Phenomena , Infant, Newborn , Lactose/analysis , Lactose/metabolism , Milk, Human/metabolism , Postpartum Period/physiology , Potassium/metabolism , Regression Analysis , Sodium/metabolism , Spectrophotometry
12.
Biochem Pharmacol ; 52(4): 535-41, 1996 Aug 23.
Article in English | MEDLINE | ID: mdl-8759025

ABSTRACT

The residence of morphine in the systemic circulation is prolonged despite a high systemic clearance, suggestive of significant extravascular sequestration. The present study was conducted to test the hypothesis that morphine binds significantly in tissues, and that the liver plays an important role in morphine binding. [14C]Morphine was administered to male Sprague-Dawley rats 55 min before unlabeled morphine or saline. Blood 14C increased immediately after injection of unlabeled morphine; the area under the blood concentration-time curve (AUC) for 14C increased approximately 2-fold after morphine compared with saline injection. Residual radioactivity in the liver was lower in morphine-treated rats than in controls, suggesting that unlabeled drug displaced [14C]morphine (or a metabolite) from binding sites. To examine this phenomenon more directly, a recirculating isolated perfused liver system was employed. [14C]Morphine was added to the perfusate reservoir 15 min before unlabeled morphine or saline; perfusate and bile samples were collected for 120 min. Upon termination of perfusion, the liver was fractionated to identify the hepatic subcellular fraction(s) in which morphine was sequestered. The perfusate AUC for [14C]morphine was increased approximately 2-fold in response to unlabeled drug, consistent with the in vivo experiment. Morphine was associated preferentially with the cytosolic fraction, and [14C]morphine in all relevant fractions was reduced after administration of unlabeled morphine. In contrast, unlabeled drug had no influence on derived [14C]morphine-3-beta,D-glucuronide. These data are consistent with significant, reversible binding of morphine in hepatic tissue.


Subject(s)
Liver/metabolism , Morphine/metabolism , Animals , Male , Rats , Rats, Sprague-Dawley
13.
Drug Metab Dispos ; 24(4): 456-61, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8801061

ABSTRACT

An isolated perfused rat kidney (IPK) technique was used to study the effect of salicylic acid (SA) on the excretion of acetazolamide (AZ). Initial experiments were conducted in the absence of interactants at three nominal AZ concentrations (50, 100, and 250 micrograms/ml). Over the concentration range studied, AZ demonstrated net tubular secretion in the IPK. Significant decreases in excretion ratio (4.97 +/- 0.79-2.66 +/- 1.1) and secretory clearance (0.809 +/- 0.23-0.541 +/- 0.28) were observed with increasing AZ concentration, consistent with saturation of tubular secretion. Using a facilitated model for renal secretion, values of tubular transport parameters were obtained from a plot of excretion ratio vs. unbound AZ concentration: tmax = 118 +/- 29.4 micrograms/min, KM = 53.4 +/- 22.4 micrograms/ml, and tmax(A) = 6.31 +/- 2.82 micrograms/min. In the presence of SA (200 micrograms/ml), renal secretion of AZ was inhibited, as demonstrated by significant decreases in renal clearance (0.731 +/- 0.21-0.147 +/- 0.03) and excretion ratio (3.77 +/- 0.82-0.378 +/- 0.07). Although these findings were indicative of a reabsorption component to AZ excretion in the IPK that had not been previously proposed, the results were consistent with a previous investigation of concomitant administration of AZ and SA in humans (Br. J. Clin. Pharmacol. 27, 866, 1989), thereby endorsing utilization of the IPK as a screening tool for renal clearance mechanisms in humans.


Subject(s)
Acetazolamide/metabolism , Diuretics/metabolism , Kidney/drug effects , Kidney/metabolism , Salicylates/pharmacology , Acetazolamide/pharmacology , Albumins/metabolism , Animals , Diuretics/pharmacology , Drug Interactions , In Vitro Techniques , Kidney Tubules/metabolism , Male , Perfusion/methods , Protein Binding , Rats , Salicylic Acid
14.
Pharm Res ; 12(12): 1958-63, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8786973

ABSTRACT

PURPOSE: Dideoxynucleoside bases are used for the treatment of acquired immune deficiency syndrome (AIDS), acting by inhibiting reverse transcriptase and preventing human immunodeficiency virus (HIV) replication. Currently, AZT (zidovudine), ddC (zalcitibine), and ddI (didanosine) are available to the medical community to prevent the onset of AIDS in HIV-infected individuals. 3TC (-)-2'-deoxy-3'-thiacytidine, lamivudine), a new dideoxynucleoside base, is currently undergoing Phase II/III trials, and has exhibited anti-HIV replication activity, a favorable adverse event safety profile, and is eliminated via renal mechanisms. Concomitantly administered drugs could potentiate the effects of 3TC due to interaction in the kidney. METHODS: An isolated perfused rat kidney (IPK) technique was used to screen several clinically relevant drugs for potential interaction with 3TC. The following perfusions were performed: baseline 3TC; and 500 ng/mL 3TC with clinically relevant concentrations of AZT, ddC, ddI, probenecid, trimethoprim, sulfamethoxazole, ranitidine, and cimetidine. RESULTS: Renal clearance of 3TC was nonlinear between 500 and 5000 ng/mL, decreasing from 3.06 to 1.74 mL/min. Excretion ratio also decreased, from 3.67 (500 ng/mL) to 2.49 (5000 ng/mL), consistent with a decrease in 3TC secretion. AZT, ddI, and ddC elicited no or minimal effects on 3TC elimination at the concentrations studied. However, trimethoprim caused significant reductions in 3TC elimination parameters: clearance and excretion ratio decreased to 1.25 mL/min and 1.43, respectively. CONCLUSIONS: These results indicate that caution should be exercised when the combination of 3TC and trimethoprim are administered to AIDS patients.


Subject(s)
Antiviral Agents/pharmacokinetics , Kidney/metabolism , Zalcitabine/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Drug Interactions , Lamivudine , Male , Rats , Rats, Sprague-Dawley , Zalcitabine/pharmacokinetics
15.
J Pharmacol Exp Ther ; 274(2): 752-60, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7636739

ABSTRACT

The impact of albumin on the renal elimination of acetazolamide, a low extraction ratio compound, was investigated in the isolated perfused rat kidney. Perfusion studies were conducted over a wide range of protein concentrations (0.25, 0.5, 0.75, 1.0, 4.0 and 6.0 g/100 ml) and an initial drug concentration of 100 micrograms/ml. Kidney viability was within normal limits among all treatment groups. Over the range of albumin levels studied, an approximate 3.4-fold increase in drug-free fraction effected a 2.8-fold increase in renal clearance. Although this finding contradicted conventional wisdom regarding extraction ratio and renal elimination, the results were consistent with a proposed ancillary role of albumin in renal tubular transport processes. An alternative clearance model was developed, analogous to earlier models of hepatic elimination. The facilitated renal clearance model utilized and validated in this investigation represents a composite of previously proposed theories, modified to account for albumin-mediated tubular secretion.


Subject(s)
Acetazolamide/pharmacokinetics , Kidney Tubules/metabolism , Kidney/metabolism , Serum Albumin/metabolism , Animals , Biological Transport , Male , Metabolic Clearance Rate , Perfusion , Protein Binding , Rats , Rats, Sprague-Dawley
16.
Am J Epidemiol ; 120(4): 542-9, 1984 Oct.
Article in English | MEDLINE | ID: mdl-6475924

ABSTRACT

An automatic blood pressure apparatus was devised for use in an epidemiological study that required self-administered measurements of blood pressure for up to 200 students each week over a school year. A Dinamap device was used to determine systolic and diastolic blood pressures by the oscillometric method. An Apple II Plus computer with one disc drive was used for control of the device and storage of data. Two such apparatuses were assembled and used to make more than 6,000 recordings of blood pressure over a six-month period. Except for some initial problems with a computer component, the apparatuses performed well; successful blood pressure recordings were obtained 99% of the time. Use of the automatic devices proved to be very acceptable to students. It is concluded that the use of such devices offers a reasonable means for obtaining accurate measurements of blood pressure and may be applicable for many epidemiologic studies.


Subject(s)
Blood Pressure Determination/instrumentation , Computers , Epidemiologic Methods , Female , Humans , Male , Self Care
17.
Am J Surg ; 148(1): 7-13, 1984 Jul.
Article in English | MEDLINE | ID: mdl-6742331

ABSTRACT

Ectopically located parathyroid adenomas may be difficult to find during initial neck exploration. They account for over 70 percent of missed adenomas found at reexploration. Preoperative localization of parathyroid adenomas would reduce unnecessary dissection and possibly reduce the number of negative results of initial neck exploration. Before reoperative parathyroid surgery is performed, some means of localization is mandatory to detect ectopic adenomas in the neck and mediastinum. Computed tomography and ultrasonography cannot effectively evaluate the mediastinum. Angiography and venous parathyroid hormone sampling are invasive, costly, and tedious to perform. We have shown that thallium-201 will accurately localize ectopic parathyroid adenomas. All 10 adenomas found in positions not immediately adjacent to the thyroid gland were detected by thallium-201 scintigraphy. One was a mediastinal adenoma resected with a median sternotomy. Our results suggest that thallium-201 scintigraphy should be the initial localization procedure of choice before all reexplorations. Its use before initial explorations, as well, will enable the surgeon to immediately direct attention to the area of the localized adenoma. If mediastinal uptake is found to be present, then median sternotomy may be performed during initial surgery provided a thorough neck exploration is performed first.


Subject(s)
Adenoma/diagnostic imaging , Choristoma/diagnostic imaging , Parathyroid Neoplasms/diagnostic imaging , Radioisotopes , Thallium , Adenoma/complications , Adenoma/surgery , Adult , Aged , Female , Humans , Hyperparathyroidism/etiology , Male , Mediastinal Neoplasms/diagnostic imaging , Middle Aged , Neck/diagnostic imaging , Parathyroid Glands , Parathyroid Neoplasms/complications , Parathyroid Neoplasms/surgery , Radionuclide Imaging , Technetium
18.
Am J Surg ; 142(1): 30-5, 1981 Jul.
Article in English | MEDLINE | ID: mdl-7258512

ABSTRACT

Ten cystadenomas and cystadenocarcinomas of the pancreas are presented. We believe that the strong recommendations of the pathologists who feel that all cystic neoplasms of this type have malignant potential or contain malignant elements emphasizes the need for total excision if at all possible in these patients. It is conceivable that the reason for the high incidence of cystadenocarcinomas in our small series may be the meticulous searching of the cellular elements for evidence of malignancy. It strongly militates against anything less than total excision as treatment for these curable lesions. The correct preoperative diagnosis is mandatory for a logical plan for surgical intervention. All cysts, whether deemed benign or malignant, should be aggressively attacked surgically unless there is distant metastasis. The very high rate of malignant potential of benign cystadenomas coupled with the relatively indolent growth pattern of malignant cystadenocarcinomas combine to give a high rate of surgical cure.


Subject(s)
Cystadenocarcinoma/surgery , Cystadenoma/surgery , Pancreatic Neoplasms/surgery , Adult , Aged , Cystadenocarcinoma/diagnostic imaging , Cystadenocarcinoma/pathology , Cystadenoma/diagnostic imaging , Cystadenoma/pathology , Female , Humans , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/pathology , Radiography
19.
Otolaryngol Clin North Am ; 12(2): 253-63, 1979 May.
Article in English | MEDLINE | ID: mdl-460873

ABSTRACT

The management of trauma patients requires organization and the cooperation of trained health personnel, beginning at the site of injury and continuing until the patient is discharged from the hospital. Treatment guidelines and priorities must be well outlined in advance to provide optimal care and minimize delay prior to definitive therapy. Resuscitation and treatment must begin immediately and simultaneously following well established principles. These guidelines and the general care of the patient with multiple trauma are discussed in this article.


Subject(s)
Emergencies , Wounds and Injuries/diagnosis , Abdominal Injuries/diagnosis , Clinical Laboratory Techniques , Emergency Medical Services , Hemodynamics , Humans , Patient Care Planning , Physical Examination , Respiration , Resuscitation , Thoracic Injuries/diagnosis , Tracheotomy , Wounds and Injuries/therapy , Wounds, Nonpenetrating/diagnosis
20.
AJR Am J Roentgenol ; 131(5): 795-802, 1978 Nov.
Article in English | MEDLINE | ID: mdl-101030

ABSTRACT

Cystic neoplasms of the pancreas (cystadenoma, cystadenocarcinoma) are rare tumors. Early diagnosis and differentiation from other pancreatic lesions are essential for appropriate management. Pancreatic angiography and gray scale ultrasonography facilitate rapid, accurate diagnosis and proper surgical therapy. In a 7 year period, eight patients were studied (one cystadenoma, seven cystadenocarcinoma); five had selective visceral angiography and six underwent abdominal ultrasonography. The ultrasonographic characteristics of these neoplasms and some new angiographic findings are presented. The sonographic findings for cystadenocarcinoma were similar to those of cystadenoma.


Subject(s)
Cystadenocarcinoma/diagnosis , Cystadenoma/diagnosis , Pancreatic Neoplasms/diagnosis , Ultrasonography , Adult , Aged , Cystadenocarcinoma/blood supply , Cystadenocarcinoma/diagnostic imaging , Cystadenoma/blood supply , Cystadenoma/diagnostic imaging , Evaluation Studies as Topic , Female , Humans , Male , Middle Aged , Pancreas/blood supply , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/diagnostic imaging , Radiography , Time Factors
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