Population pharmacokinetics of didanosine in patients with human immunodeficiency virus infection.
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Antiviral Agents↗
Biomedical subjects
T Delahunty
Publications and source records attributed to T Delahunty.
The hydroxylamine of sulfamethoxazole and adverse reactions in patients with acquired immunodeficiency syndrome.
We measured the urine concentrations of sulfamethoxazole, sulfamethoxazole hydroxylamine, and N-sulfamethoxazole on days 3 and 10 in 15 patients with acquired immunodeficiency syndrome treated with a combination product of trimethoprim (15 mg/kg/day) and sulfamethoxazole (75 mg/kg/day). The percentage of sulfamethoxazole and metabolites excreted on days 3 and 10, respectively, were sulfamethoxazole 17.2% +/- 11.3% versus 15.6% +/- 8.2%; sulfamethoxazole hydroxylamine 2.6% +/- 2.0% versus 5.0% +/- 5.2% (p < 0.05); N-acetylsulfamethoxazole 80.0% +/- 12.9% versus 79.8% +/- 11.8%. The percentage of sulfamethoxazole hydroxylamine excreted was similar between the eight patients who discontinued therapy because of toxicity and the seven patients who did not (2.9% +/- 2.3% versus 2.3% +/- 2.0%, p = 0.7). In two patients who had major liver toxicity the percentage of sulfamethoxazole hydroxylamine excreted was significantly lower than that of the 13 patients who did not (0.8% +/- 0.1% versus 2.9% +/- 2.0%, p < 0.05). This is the first report of the formation and excretion of sulfamethoxazole hydroxylamine in patients with acquired immunodeficiency syndrome. With 15 patients we were unable to show a significant correlation between the percentage of sulfamethoxazole hydroxylamine excreted and adverse reactions. However, patients with liver toxicity excreted less sulfamethoxazole hydroxylamine.
AIDS-Related Opportunistic Infections↗
Hemoglobin variants.
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Chromatography, High Pressure Liquid↗
Convenient screening for hemoglobin variants by using the Diamat HPLC system.
Hemolysates from 102 different patients previously assessed for the presence of hemoglobin variants by cellulose acetate electrophoresis were reanalyzed with the Diamat, a microprocessor-controlled step-gradient HPLC technique designed to determine glycohemoglobin (Hgb A1c). This pool contained 81 abnormal specimens, each with one of seven different variant abnormalities. In all cases the HPLC technique correctly detected the presence or absence of a variant. The common S trait gave a large peak immediately after Hgb A, and the SS and SC variants gave clearly abnormal patterns, caused in part by the absence of Hgb A. The pattern from EE variants was distinguished by the appearance of the glycated fraction Hgb E1c, which is eluted at 4.7 instead of 4.2 min, whereas the AE pattern had two glycated peaks. Hemoglobins F, "fast", S, and C were discerned by the presence of a major peak at 3, 5.2, 6.5, and 7.5 min, respectively. The findings suggest that the Diamat is a convenient tool to detect and help diagnose variants in a screening pool.
Analysis of Variance↗
Intestinal permeability in patients with Crohn's disease and their healthy relatives.
The healthy relatives of patients with Crohn's disease were previously found to have increased intestinal permeability to polyethylene glycol 400. To determine whether the abnormal permeability is uniquely detectable by polyethylene glycol 400, we studied the intestinal permeability of three new probes (lactulose, rhamnose, and mannitol) in 25 patients with Crohn's disease, 41 of their healthy relatives, and 29 normal controls without a family history of inflammatory bowel disease. Patients with Crohn's disease had increased lactulose permeability when compared with relatives or controls. Lactulose absorption by patients with Crohn's disease was 0.41% +/- 0.07% (mean +/- SE), whereas that of their relatives and unrelated controls was 0.28% +/- 0.03% and 0.26% +/- 0.03%, respectively. There was no significant difference between the relatives and controls, but both groups differed from the patients (p less than 0.05 and p less than 0.025, respectively). The patients' lactulose/rhamnose ratio was 70.5% +/- 9.2% vs. 37.2% +/- 3.3% in relatives and 40.6% +/- 5.7% in unrelated controls (p less than 0.0005 and p less than 0.0025, respectively). The two intermediate-sized probes, rhamnose and mannitol, did not detect permeability differences among the three groups. The inability of lactulose, rhamnose, or mannitol to detect permeability abnormalities in healthy relatives of patients with Crohn's disease suggests that these probes penetrate the intestinal barrier by routes or mechanisms that are different from those of polyethylene glycol 400. Lactulose, in particular, detects permeability changes in patients with intestinal inflammation, and polyethylene glycol 400 is able to detect permeability changes in the health relatives of our patients. These data indicate that permeability may be abnormal as a secondary result of inflammation, or as a result of a primary genetic abnormality.
Adult↗
Intestinal permeability changes in rodents: a possible mechanism for degraded carrageenan-induced colitis.
Rats and guinea-pigs were treated with degraded carrageenan (50 g/litre in the drinking-water) and their intestinal permeability was studied at weekly intervals over the last 4 wk of the test period by determining the recovery of orally administered tracer doses of [3H]polyethylene glycol (PEG-900) or D-[3H]mannitol in 16-hr urine collections. A freely diffusible dye, Azure A, was administered simultaneously to compensate for non-intestinal factors that could modify renal excretion. Animals were killed after a total treatment period of 5 months for rats and 6 wk for guinea-pigs. After 3 wk of carrageenan treatment, excretion of PEG-900 (expressed as a ratio of the Azure A excretion) in guinea-pigs showed a statistically significant increase over that in the control group. At autopsy, the caeca showed numerous macroscopically visible erosions of the entire mucosal surface and histological examination showed ulcerations largely in the mucosa with abscesses in the crypts. Although no such histological changes were seen in the intestines of the treated rats, even after 5 months, a statistically significant increase in PEG-900 excretion was again found compared with the control group. This increase did not occur when deoxycholate was administered with the carrageenan solution. No effect of carrageenan treatment on mucosal permeability to D-[3H]mannitol was demonstrated in either species. The results suggest that degraded carrageenan-induced colitis could be a result of increased intestinal permeability, since ingestion of this polysaccharide by rats increased PEG-900 absorption without causing mucosal damage.
Animals↗
A comparison of intestinal permeability between humans and three common laboratory animals.
Intestinal permeability of humans and three species of experimental animals was assessed by the oral administration of the three non-metabolizable sugars: lactulose, rhamnose and mannitol and collecting all the urine produced in a specified time. The total percentage recovery of the permeability markers was determined by high performance liquid chromatographic assays of urinary aliquots. The permeability of the human gut to mannitol was substantially greater than that of rats, guinea pigs, or hamsters (18-, 6- and 29-fold increases, respectively). The permeability to lactulose in humans was somewhat less than that found in guinea pigs (P less than 0.05), but three times greater than that found in rats or hamsters (P less than 0.001). Human rhamnose permeability was substantially greater than that of rats, guinea pigs or hamsters (6-, 2.5-, and 7-fold increases, respectively). The results suggest that the permeability of the human gut to probe molecules is considerably different from that of three common laboratory rodents, but is closest to that of guinea pigs. Possible species differences in the physiological factors which control permeability are discussed.
Adult↗
Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor.
The cause of Crohn's disease is unknown, although alterations in intestinal permeability may play a primary role. Because we were interested in permeability changes that occur before the onset of intestinal inflammation, we took advantage of the known genetic predisposition to this disease and studied not only patients with Crohn's disease, but their clinically unaffected relatives as well. Intestinal permeability was assessed using the marker polyethylene glycol-400 ingested with a standard meal. We found that 17 normal volunteers absorbed 215 +/- 29.6 mg (mean +/- SE), whereas 11 patients with Crohn's disease absorbed 514 +/- 94.7 mg and their 32 healthy relatives absorbed 566 +/- 62.4 mg. The twofold increase in permeability of patients and their relatives (p less than 0.005 compared with controls) indicates that the intestinal defect in the ability to exclude larger sized molecules is not secondary to clinically recognized intestinal inflammation, but is a primary defect that may be an etiologic factor in this disease.
Adolescent↗
Liquid-chromatographic method for estimating urinary sugars: applicability to studies of intestinal permeability.
Sugars of exogenous origin excreted in the urine can be rapidly quantified by "high-pressure" liquid chromatography. A simple extraction with an ion-exchange resin is used to prepare the sample for analysis. Aliquots (20 microL) are chromatographed on a cation-exchange column at 85 degrees C, with water as the mobile phase. Sugars are detected with a refractive index detector. Lactulose, rhamnose, and mannitol all give discrete peaks and a linear response up to 5 g/L, with analytical recoveries from urine of 80, 62, and 80%, respectively. Precision is good, the CVs for lactulose, rhamnose, and mannitol being 2.9, 4.0, and 5.6%, respectively. The only endogenous compound consistently present in the chromatograms is urea, which does not interfere. However, glucosuria, if present, could interfere with the lactulose estimation. This method may be a simple, labor-saving means of quantifying urinary sugars in the clinical laboratory.
Carbohydrates↗
New liquid-chromatographic method for measuring polyethylene glycol in urine.
The various Mr fractions of polyethylene glycol (PEG) in human urine are quantified by "high-pressure" liquid chromatography. A simple preparation step involving lyophilization and chloroform extraction of the sample is required. Aliquots (10 microL) are chromatographed isocratically in equivolume mixtures of methanol and water on a column of styrene divinylbenzene and the refractive index of the effluent is measured. The results vary linearly with the concentrations of standards up to at least 10 g/L, and the six major fractions are clearly identifiable in injected samples containing 2 g or more of total PEG per liter. As little as 4 g/L can be precisely quantified, but for assessing the individual fractions, we recommend a minimum sample concentration of 7 g/L. Analytical recovery of PEG added to urine controls was 90%. Urines collected during 6 h from 11 human subjects after each had ingested 5.6 g of PEG showed no interference from endogenous compounds. We find this method to be a simple, labor-saving means of quantifying urinary PEG in the clinical laboratory.
Adult↗
Atypical CK and cardiac surgery: further comments.
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Cardiac Surgical Procedures↗
Creatine kinase-BB isoenzyme in rat plasma after chronic lead intoxication.
Creatine kinase (CK) activity in plasma obtained non-invasively from adult healthy, Sprague-Dawley, male rats was found to be 528 +/- 270 U/L (N = 17), a value which was 7 times that obtained in human specimens. Agarose gel electrophoresis revealed that the only detectable CK isoenzyme present was CK-BB, in contrast to the human serum isoenzyme which was CK-MM. Furthermore, it was found that the rat CK-BB could be detected using an RIA technique designed to quantitate human CK-BB occasionally present in blood after brain injury (rat CK-BB = 84.5 +/- 55.2 micrograms/L, N = 17, human CK-BB: Not detectable). It was thus possible to calculate the CK-BB specific activity (SA) in rat plasma using total CK assay and RIA (rat CK-BB SA = 6.25 +/- 3.87 U/micrograms, N = 17). When six rats (156 +/- 23 g) were treated with lead acetate in the drinking water (26 mM) for 3 weeks, the CK-BB SA rose to 18 +/- 5.8 U/micrograms (P less than .02). At this point the electrophoresis pattern of the CK-BB showed a transient change from a single band to a doublet. The dose was then increased to 52 mM for 6 weeks, during which time the CK-BB SA declined steadily to 1.6 +/- 0.6, a level significantly less than that of the untreated animals (p less than .02). The results suggest that chronic lead treatment evokes a biphasic response in CK-BB SA with the initial release of enzyme of high SA from tissues. Further treatment apparently results in an inactivation of the enzyme within lead sensitive tissues.
Animals↗
A new technique for studying the relationship between maternal diabetes and the sialic acid content of fetal pulmonary surfactant.
By adapting a standard method for precipitation of high-density lipoprotein cholesterol with phosphotungstic acid (PTA) and Mg2+, fetal pulmonary surfactant can be rapidly isolated from human amniotic fluid, 97% of the total disaturated phosphatidylcholine being precipitated from the sample. The lecithin/sphingomyelin ratio for 17 separate specimens correlated reasonably well (r = 0.76) with the concentration of disaturated phosphatidylcholine in the PTA precipitate. Using thiobarbituric acid as the chromophore, I measured sialic acid in the PTA precipitate after overnight treatment with neuraminidase. The sialic acid/protein ratio for the PTA precipitate was identical to that for the surfactant, as isolated by ultracentrifugation. The concentrations of insulin and C-peptide were significantly greater in specimens of amniotic fluid from mothers with diabetes than from non-diabetic mothers (p less than 0.001). When the specimens were segregated according to a C-peptide cutoff value of 4 micrograms/L, there was a small, significant decrease in PTA-precipitated concentrations of sialic acid in the samples with C-peptide greater than 4 micrograms/L. The results suggest a possible mechanism for the increased incidence of respiratory distress among infants born to diabetic mothers.
Amniotic Fluid↗
Estimation of creatine kinase isoenzyme CK-MB by immunoinhibition and by ion-exchange chromatography compared.
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Chromatography, Ion Exchange↗
A study of endogenous N-cholylglycine distribution among serum proteins using radioimmunoassay.
The amount of N-cholylglycine endogenously associated with the various protein fractions was assessed in serum of patients with hepatobiliary obstruction using a sensitive radioimmunoassay. In contrast to evidence obtained with cholate, the albumin fraction separated by electrophoresis was found to contain only 2.6% of the total N-cholylglycine, while the alpha 2 region had 64% associated with it. The serum beta-lipoprotein isolated by anionic precipitation also contained significant quantities of the conjugated bile acid, the amount in this fraction being greater in the serum of hyperlipidemic subjects. The results suggest that despite accounting for some 63% of the total serum protein, albumin is not the major carrier of endogenous N-cholylglycine in the circulation.
Biological Transport, Active↗
The primary structure of human plasma high density apolipoprotein glutamine I (ApoA-I). I. The amino acid sequence of cyanogen bromide fragment II.
Apolipoprotein glutamine I (apoLP-Gln-I or apoA-I) is one of the major protein constituents of human plasma high density lipoproteins. The protein has 245 amino acid residues, including 3 residues of methionine, and is lacking isoleucine, cystine, and cysteine. Cleavage of apoLP-Gln-I with cyanogen bromide yields four fragments, designated in their order of elution from Bio-Gel P-30 as CNBr I, II, III, and IV. In the present study, we report the complete amino acid sequence of the NH2-terminal fragment, CNBr II, a peptide that contains 90 amino acid residues.
Amino Acid Sequence↗
The primary structure of high density apolipoprotein-glutamine-I.
The major protein constituent of human plasma high density lipoproteins has been isolated and its complete amino-acid sequence determined. The protein, designated apolipoprotein-glutamine-I by the presence of carboxyl-terminal glutamine, is a single polypeptide chain of 245 amino-acid residues, including three residues of methionine. The protein is devoid of cysteine, cystine, and isoleucine. Cleavage of apolipoprotein-glutamine-I with cyanogen bromide yields four fragments with 94, 90, 36, and 25 amino acids. The amino-acid sequence of each fragment was determined by conventional methods, with proteolytic digestion with trypsin, chymotrypsin, and thermolysin. The alignment of the cyanogen bromide fragments was determined by the isolation of the methionine-containing tryptic peptides from apolipoprotein-glutamine-I. Inspection of the sequence of apolipoprotein-glutamine-I suggests an interesting distribution of amino acids that may account for its helical structure and its ability to bind and transport lipid.
Amino Acid Sequence↗
Glycosylation of beta-lipoprotein and the possible role of choline derivatives.
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Animals↗