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1.
Clin Toxicol (Phila) ; 52(9): 976-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25211007

ABSTRACT

CONTEXT: Methemoglobinemia (MetHb) after exposure to benzocaine (BZC) has been reported for more than 50 years, however the pathophysiologic mechanism has not been previously established. Direct administration of BZC to blood does not produce MetHb. After topical use, due to the lipophilicity and rapid acetylation in the tissue, little BZC reaches the liver for hepatic biotransformation. However, isolated human livers have been shown to produce MetHb forming N-hydroxyl metabolites from BZC. We report a case of BZC-induced MetHb with the first identification and quantification of the reactive metabolite responsible for the oxidative stress: N-Hydroxy-Para-amino benzoic acid (N-OH-PABA). CASE DETAILS: An 8 year old male was admitted to a hospital for an appendectomy. Several applications of BZC spray were used during multiple attempts at nasogastric tube placement. In various attempts to achieve local anesthesia, benzocaine spray was used in both nares and through the mouth aimed at the posterior oropharynx. The patient subsequently became cyanotic with an initial MetHb level of 32.9 %. Methylene blue was administered and the patient promptly responded with resolution of cyanosis. Blood taken within 20 min of the initial symptoms contained benzocaine (5.2ug/mL), bupivacaine (740ng/mL), lidocaine (530ng/mL), acetaminophen (12ug/mL), midazolam (60ng/mL), PABA and N-OH-PABA (35ng/mL). Serum was analyzed using Liquid Chromatography- Quadrupole Time-of-Flight Mass Spectrometry. Mass spectrometry was done using an electrospray ionization source run in negative and positive polarities. A reference standard for N-OH-PABA was synthesized for confirmation and quantification. DISCUSSION: The rare and idiopathic nature of methemoglobinemia after benzocaine use has made study of the pathophysiologic mechanism in humans difficult. Lack of understanding has brought calls for restriction of use of the widely used medication that may not be based on evidence. Our case presents several unique features: 1) benzocaine absorption after topical administration was documented with serum concentrations 2) confirmation of an in vivo formation of MetHb-forming n-hydroxyl-metabolite after benzocaine use and 3) the documentation of N-OH-PABA in humans within 20 min of MetHb post-benzocaine administration.


Subject(s)
4-Aminobenzoic Acid/blood , Benzocaine/toxicity , Cyanosis/blood , Hydroxylamines/blood , para-Aminobenzoates/blood , Acetaminophen/blood , Administration, Topical , Bupivacaine/blood , Child , Cyanosis/drug therapy , Dose-Response Relationship, Drug , Humans , Lidocaine/blood , Male , Methemoglobinemia/chemically induced , Methemoglobinemia/drug therapy , Methemoglobinemia/pathology , Methylene Blue/administration & dosage , Midazolam/blood
2.
J Anim Physiol Anim Nutr (Berl) ; 92(3): 399-404, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18477323

ABSTRACT

The NBT-PABA test is an established method for diagnosis of pancreatic exocrine insufficiency. In the present study the NBT-PABA test was used to test and compare the efficacy of two multienzyme preparations (product A and B) differing in galenic preparation in minipigs in which pancreatic exocrine insufficiency (PEI) was induced by pancreatic duct ligation. Without enzyme substitution no distinct increase in PABA was found in blood after oral administration of NBT-PABA. Administration of both enzyme preparations led to a clear dose dependent rise in PABA-concentrations in blood. Interestingly, the two preparations showed different time curves of serum PABA concentration, indicating differences in the kinetic of proteolytic enzyme action. It is concluded that the NBT-PABA test can be a very useful test for indirectly evaluating proteolytic enzyme efficacy in vivo, and also gives information about the kinetics of enzyme action, not only the end-result of enzyme action (like digestibility trials which were used traditionally). A single test is performed in a few hours and there is no need for fistulated animals.


Subject(s)
4-Aminobenzoic Acid/pharmacokinetics , Exocrine Pancreatic Insufficiency/veterinary , Pancreatic Ducts/enzymology , Swine, Miniature , Vitamin B Complex/pharmacokinetics , 4-Aminobenzoic Acid/blood , Administration, Oral , Animals , Area Under Curve , Dose-Response Relationship, Drug , Exocrine Pancreatic Insufficiency/diagnosis , Ligation/veterinary , Pancreatic Ducts/surgery , Pancreatic Function Tests/methods , Pancreatic Function Tests/veterinary , Swine/metabolism , Swine, Miniature/metabolism , Vitamin B Complex/blood
4.
J Nutr ; 131(7): 1928-37, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11435509

ABSTRACT

To investigate the effects of pregnancy on folate metabolism, we conducted an 84-d study in second-trimester (gestational wk 14-25) pregnant women (n = 6) and nonpregnant controls (n = 6) with stable-isotopic tracer methods. All subjects were fed a diet containing approximately 272 nmol/d (120 microg/d) folate from food, along with supplemental folic acid that contained 15% [3',5'-(2)H(2)] folic acid ([(2)H(2)]folic acid) during d 1--41 and that was unlabeled during d 42--84 to yield a constant total folate intake of 1.02 or 1.93 micromol/d (450 or 850 microg/d). Isotopic enrichment of plasma folate, urinary folate and the urinary folate catabolites para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (ApABG) was determined at intervals throughout the study. The labeling of pABG and ApABG reflected that of tissue folate pools from which the catabolites originate. After the intake of labeled folic acid was terminated on d 41, labeling of urinary folate exhibited a biphasic exponential decline with distinct fast and slow components. In contrast, during d 42--84, the enrichment of urinary pABG and ApABG exhibited primarily monophasic exponential decline, and plasma folate underwent little decline of labeling during this period. Pregnant women and controls did not differ in estimates of body folate pool size and most aspects of the excretion of labeled urinary folate and catabolites, rates of decline of excretion, and areas under the curves for folate and catabolite excretion. Pregnant women, however, tended to have a slower rate of decline of pABG than ApABG and higher enrichment at d 42 of ApABG and pABG. These data support and extend our previous findings indicating that pregnancy (gestational wk 14--26) causes subtle changes in folate metabolism but does not elicit substantial increases in the rate or extent of folate turnover at these moderately high folate intakes.


Subject(s)
Folic Acid/administration & dosage , Folic Acid/pharmacokinetics , Pregnancy/metabolism , para-Aminobenzoates , 4-Aminobenzoic Acid/blood , 4-Aminobenzoic Acid/metabolism , 4-Aminobenzoic Acid/urine , Adolescent , Adult , Case-Control Studies , Diet , Female , Folic Acid/analysis , Folic Acid/metabolism , Gas Chromatography-Mass Spectrometry , Glutamates/blood , Glutamates/metabolism , Glutamates/urine , Humans , Isotope Labeling , Kinetics , Metabolic Clearance Rate , Nutritional Status , Pregnancy Trimester, Second , Tissue Distribution
5.
Forensic Sci Int ; 116(1): 9-14, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11118747

ABSTRACT

Blood concentrations of tetracaine and its metabolite, p-butylaminobenzoic acid, were measured after spinal anesthesia with tetracaine which had been administered to patients under going orthopedic surgery. Tetracaine, an ester anesthetic, was given to 10 patients, the dose was 8-14mg, and blood samples were collected 1, 2 and 6h after the injection of tetracaine. We used gas chromatography/mass spectrometry for purposes of analysis. Tetracaine was not detected in any blood sample, but the metabolite was detected in each sample with the mean concentrations of 126.5, 97.9 and 43.3ng/ml at 1, 2 and 6h, respectively. This data will be useful in determination of the cause of death after spinal anesthesia with tetracaine.


Subject(s)
4-Aminobenzoic Acid/blood , Anesthesia, Spinal , Anesthetics, Local/blood , Anesthetics, Local/metabolism , Tetracaine/blood , Tetracaine/metabolism , para-Aminobenzoates , 4-Aminobenzoic Acid/metabolism , Adult , Aged , Anesthesia, Spinal/adverse effects , Anesthesia, Spinal/mortality , Anesthetics, Local/administration & dosage , Anesthetics, Local/adverse effects , Cause of Death , Dibucaine/administration & dosage , Dibucaine/adverse effects , Dibucaine/blood , Dibucaine/metabolism , Forensic Medicine/methods , Gas Chromatography-Mass Spectrometry , Humans , Mepivacaine/administration & dosage , Mepivacaine/adverse effects , Mepivacaine/blood , Mepivacaine/metabolism , Middle Aged , Tetracaine/administration & dosage , Tetracaine/adverse effects
6.
J Pharmacol Toxicol Methods ; 46(3): 131-6, 2001.
Article in English | MEDLINE | ID: mdl-12183188

ABSTRACT

INTRODUCTION: The purpose of the present study was to develop a simple method for the simultaneous determination of mepivacaine, tetracaine, and p-butylaminobenzoic acid (BABA) in human plasma using high-performance liquid chromatography (HPLC) with a multiwavelength detector. METHODS: Human blood samples containing heparin, as an anticoagulant, and physostigmine (100 microg/ml), as an anticholinesterase, or human plasma containing physostigmine were spiked with various concentrations of mepivacaine, tetracaine and, in some cases, BABA. Blood samples were centrifuged and plasma was deproteinized with trifluoroacetic acid (TFA; 7%). After centrifugation, the pH was adjusted to 4.5 and an aliquot of 20, 50 or 100 microl was injected into the HPLC apparatus. The detection was done simultaneously at wavelengths of 214 and 300 nm. Analytical chromatography was done on a Waters microBondapak C(18) reverse-phase column (3.9 x 300 mm; particle size 10 microm) with a 30-min increasing linear gradient of 20-40% acetonitrile+0.05% TFA in H(2)O+0.05% TFA at a flow rate of 1 ml/min. The Waters HPLC system included two pumps, an automatic injector, a column oven, and a M490 multiwavelength detector. Quantification was done using integration of peak areas with peaks of authentic mepivacaine, tetracaine, and BABA standards. RESULTS: Calibration curves for standards of mepivacaine, tetracaine, and BABA were linear in the concentration ranges from 0.1 to 100 microg/ml, and the correlation coefficients exceeded.99 for all compounds. The lower limits of detection were 100 ng/ml for mepivacaine and 50 ng/ml for tetracaine and BABA. The yields for mepivacaine, tetracaine, and BABA were 91+/-2.1%, 82+/-3.3%, and 88+/-2.0% (mean+/-S.E.M., n=6), respectively. Degradation of tetracaine by human plasma at 37 degrees C was inhibited by physostigmine. DISCUSSION: The method is sensitive enough to allow blood concentration determinations of mepivacaine and tetracaine or its metabolite, BABA, following local anesthesia induced by these two drugs, especially when their toxic effect may be present. This method also may be useful in forensic medicine for determination of the cause of death after local anesthesia with mepivacaine and/or tetracaine.


Subject(s)
4-Aminobenzoic Acid/blood , Chromatography, High Pressure Liquid/methods , Mepivacaine/blood , Tetracaine/blood , para-Aminobenzoates , Humans
7.
Dig Dis Sci ; 43(1): 203-13, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9508526

ABSTRACT

It has been suggested that enteric-coated pancreatin microsphere (ECPM) preparations with sphere sizes larger than 1.7 mm pass through the stomach at a slower rate than a meal and therefore may be less efficacious in restoring pancreatic enzyme activity than preparations with smaller sphere sizes. The aim of this study was to investigate the gastric transit profile of a 2-mm ECPM preparation in relation to that of a solid meal and to simultaneously measure enzyme activities in eight patients with pancreatic exocrine insufficiency due to chronic pancreatitis. Gastric transit was assessed by double-isotope scintigraphy. A pancake was labeled with 99mTc. A 2-mm ECPM preparation was labeled with 171Er. Intraluminal pancreatic enzyme activities were assessed during a 6-hr period with the cholesteryl-[14C]octanoate breath test (for carboxyl ester lipase activity) and the N-benzoyl-L-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test (for chymotrypsin activity). The ECPM preparation passed through the stomach more rapidly (median 24 min) than the pancake (median 52 min, P < 0.05). During ECPM therapy, mean cumulative 14CO2 outputs rose significantly from 30% to 70% (P < 0.05), but remained below outcomes in healthy volunteers. Mean cumulative plasma PABA concentrations rose significantly from 46% to 87% (P < 0.05) and were not significantly different from outcomes in healthy volunteers. In chronic pancreatitis, a 2-mm ECPM preparation does not pass through the stomach more slowly than a solid meal, but in fact faster. Digestion of ester lipids and proteins showed an improvement to subnormal and normal levels, respectively.


Subject(s)
Gastric Mucosa/metabolism , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/pharmacokinetics , Pancreatin/administration & dosage , Pancreatin/pharmacokinetics , Pancreatitis/metabolism , 4-Aminobenzoic Acid/blood , Adult , Aged , Breath Tests , Cholesterol Esters/analysis , Chronic Disease , Female , Gastrointestinal Transit , Humans , Male , Microspheres , Middle Aged , Pancreatitis/enzymology , Tablets, Enteric-Coated , Technetium
8.
Clin Chem ; 42(10): 1659-65, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8855151

ABSTRACT

A novel, sensitive, and selective method has been developed for determination of p-aminobenzoic (PABA) and p-aminosalicylic (PAS) acids in the N-benzoyl-L-tyrosyl-PABA/ PAS test. PAS is measured as a ternary complex with terbium and EDTA (lambda(ex) = 324 nm, lambda(em) = 546 nm) in alkaline aqueous solution (pH approximately 12.6), whereas both compounds (PABA and PAS) are measured as ternary complexes with terbium and tri-n-octylphosphine oxide (lambda(ex) = 292 nm, lambda(em) = 546 nm) in weakly acidic aqueous solution (pH approximately 5.5). We inve stigated and implemented optimum conditions for formation of these complexes, yielding respective detection limits for PABA and PAS of 0.07 and 0.02 micromol/L and ranges of application of 0-10 and 0-40 micromol/L (final concentration). The method has been successfully applied to determinations of PABA and PAS in urine and, after alkaline hydrolysis, to determinations of PABA in serum that has been deproteinized with acetonitrile. Within-run imprecision of the PABA determination ranges from 0.8% to 4.2 % for urine samples and from 3.9% to 8.2% for serum samples; day-to-day imprecision varies from 3.2% to 10% for serum samples.


Subject(s)
4-Aminobenzoic Acid/analysis , Aminosalicylic Acid/analysis , Body Fluids/chemistry , Luminescent Measurements , Spectrometry, Fluorescence/methods , Terbium , 4-Aminobenzoic Acid/blood , 4-Aminobenzoic Acid/urine , Acetonitriles , Aminosalicylic Acid/blood , Aminosalicylic Acid/urine , Edetic Acid , Humans , Hydrogen-Ion Concentration , Hydrolysis , Sensitivity and Specificity , Spectrometry, Fluorescence/statistics & numerical data
9.
J Anal Toxicol ; 20(5): 318-22, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8872242

ABSTRACT

A sensitive method for simultaneous determination of ester-type local anesthetic drugs (procaine, tetracaine, and T-caine) has been developed using wide-bore capillary gas chromatography with nitrogen-phosphorus detection (GC-NPD). The extraction procedure, the experimental conditions for heptafluorobutyryl (HFB) derivative formation, and the percentage of the ester-type local anesthetic drugs from the human serum are described. The HFB derivatives of ester-type local anesthetic drugs showed sensitivity of approximately 2-3 fold higher than that without derivatization. The detection limits of HFB derivatives of the ester-type local anesthetic drugs were approximately 60-70 pg on column. Recoveries from the human serum were 85-94%. This method could be used to determine concentrations as low as 24-28 ng/mliters of the ester-type local anesthetic drugs.


Subject(s)
Anesthetics, Local/analysis , Procaine/analysis , Tetracaine/analysis , para-Aminobenzoates , 4-Aminobenzoic Acid/analysis , 4-Aminobenzoic Acid/blood , Anesthetics, Local/blood , Humans , Nitrogen/chemistry , Phosphorus/chemistry , Procaine/blood , Sensitivity and Specificity , Solvents/chemistry , Tetracaine/blood
10.
Eur J Clin Chem Clin Biochem ; 34(4): 311-4, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8704047

ABSTRACT

Using the substrate N-acetyl-L-tyrosyl-p-aminobenzoic acid, we determined chymotrypsin activity in the small intestine of calf, pig, and poultry. Orally administered N-acetyl-L-tyrosyl-p-aminobenzoic acid is enzymatically cleaved in vivo, and the released p-aminobenzoic acid is determined by HPLC. We found that the p-aminobenzoic acid concentration in plasma and urine was significantly influenced by the feeding of soya flour. After soybean flour feeding, the p-aminobenzoic acid concentration significantly increased in the plasma of calves and hens, in contrast to pigs, where the p-aminobenzoic acid concentration significantly decreased. This shows that the oral administration of N-acetyl-L-tyrosyl-p-aminobenzoic acid with subsequent determination of p-aminobenzoic acid is suitable for the estimation of exocrine pancreatic function and for determination of changes in intestinal proteolytic activity caused by antinutritive substances.


Subject(s)
4-Aminobenzoic Acid/analysis , Chymotrypsin/metabolism , Intestines/enzymology , Pancreas/enzymology , para-Aminobenzoates , 4-Aminobenzoic Acid/blood , 4-Aminobenzoic Acid/metabolism , 4-Aminobenzoic Acid/urine , Animal Feed , Animals , Cattle , Chickens , Chromatography, High Pressure Liquid , Feces/chemistry , Female , Male , Swine
11.
J Chromatogr B Biomed Appl ; 677(1): 69-75, 1996 Feb 23.
Article in English | MEDLINE | ID: mdl-8925104

ABSTRACT

A simple, accurate and sensitive high-performance liquid chromatographic method with fluorescence detection was used for measuring plasma concentrations of p-aminobenzoic acid (PABA) and its three metabolites: p-acetaminobenzoic acid (PAABA), p-aminohippuric acid (PAHA) and p-acetaminohippuric acid (PAAHA). A Cosmosil MS-C18 column (250 x 4.6 mm, 5 microns) was used under temperature control at 40 degrees C. The mobile phase was H2O-CH3CN-CH3COOH (100:3:1, pH 4.0) with a flow-rate of 1.5 ml/min. The excitation and emission wavelengths for fluorescence detection were set at 270 and 350 nm, respectively. Plasma samples (200 microliters) were acidified by the addition of 150 microliters of 1 m HClO4 solution containing salicylic acid (SA) as the internal standard. After centrifugation, 30 microliters of the supernatant were injected onto the column. Using this method, PABA and its three metabolites could be determined within 25 min. Within the investigated concentration ranges of PABA (0.1-50 micrograms/ml), PAABA (0.2-50 micrograms/ml), PAHA (0.1-50 micrograms/ml) and PAAHA (0.5-50 micrograms /ml), good linearity (r > 0.99) for the standard curves was obtained. The validation of this method showed coefficient of variance (C.V.) that was well below 15% for all compounds. After intravenous (i.v.) administration of PABA (20 mg/kg) to rabbits (n = 7), PABA followed a one-compartment open model elimination with a half-life of 10.90 +/- 1.03 min. The mean half lives for PAABA, PAHA and PAAHA were 24.61 +/- 6.42, 12.81 +/- 6.04 and 11.27 +/- 2.77 min, respectively.


Subject(s)
4-Aminobenzoic Acid/blood , 4-Aminobenzoic Acid/administration & dosage , 4-Aminobenzoic Acid/pharmacokinetics , Animals , Biotransformation , Calibration , Chromatography, High Pressure Liquid , Half-Life , Indicators and Reagents , Injections, Intravenous , Male , Quality Control , Rabbits , Reference Standards , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet
12.
Clin Biochem ; 28(5): 531-40, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8582053

ABSTRACT

OBJECTIVE: To evaluate glycine conjugation of para-aminobenzoic acid (PABA) to the hippurated metabolites, para-aminohippuric acid (PAHA), and para-acetamidohippuric acid (PAAHA) as a quantitative liver function test in patients with liver disease. DESIGN AND METHODS: Serum concentrations of PABA and metabolites were measured by high pressure liquid chromatography in 24 controls and 50 patients with hepatobiliary disease. RESULTS: Hippurate formation was significantly decreased in all patient groups with chronic liver disease versus controls. The hippurate ratio (% hippurated metabolites formed) correlated with severity of disease, serum albumin, and factor VII concentrations. PAHA concentration was a better prognostic indicator than factor VII concentrations in patients with acute liver disease; concentrations of zero correctly predicted a poor outcome in patients with fulminant liver failure. CONCLUSIONS: Glycine conjugation of PABA may be useful as a quantitative liver function test in patients with hepatobiliary disease and as a prognostic index in patients with fulminant liver failure.


Subject(s)
4-Aminobenzoic Acid/metabolism , Glycine/metabolism , Liver Diseases/diagnosis , Liver Function Tests/methods , 4-Aminobenzoic Acid/blood , Acute Disease , Adolescent , Aminohippuric Acids , Child , Child, Preschool , Chronic Disease , Factor VII/metabolism , Female , Hippurates/blood , Hippurates/metabolism , Humans , Infant , Liver Diseases/metabolism , Male , Predictive Value of Tests , Prognosis , Serum Albumin/metabolism , p-Aminohippuric Acid/blood , p-Aminohippuric Acid/metabolism , para-Aminobenzoates
13.
Clin Chem ; 41(4): 599-604, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7720253

ABSTRACT

Two noninvasive tests for assessing pancreatic exocrine function, the cholesteryl-[14C]octanoate breath test and the HPLCN-benzoyl-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test, were simultaneously performed in nine patients with pancreatic exocrine insufficiency due to chronic pancreatitis and in nine healthy volunteers. 14CO2 output in breath and plasma PABA concentration rose slowly in patients but increased rapidly in healthy subjects. The measurement time giving the best discrimination between both groups was 120 min for the cholesteryl-[14C]octanoate breath test and 90 min for the plasma PABA test. At these points, both single-sample tests had essentially identical diagnostic sensitivity. The diagnostic sensitivities of the two single-sample tests were equal to that of the cumulative 6-h urinary PABA recovery and the cumulative 6-h urinary PABA/PAS ratio. We conclude that, for both the cholesteryl-[14C]octanoate breath test and the plasma PABA test, a single test sample is sufficient for rapid detection of impaired exocrine pancreatic function.


Subject(s)
4-Aminobenzoic Acid/blood , Breath Tests , Cholesterol Esters/analysis , Pancreas/physiopathology , Pancreatitis/diagnosis , 4-Aminobenzoic Acid/urine , Adult , Aged , Aminosalicylic Acid/urine , Carbon Radioisotopes , Chronic Disease , False Positive Reactions , Female , Humans , Kinetics , Male , Middle Aged , Pancreatitis/physiopathology , Reference Values
15.
Tierarztl Prax ; 21(2): 159-62, 1993 Apr.
Article in German | MEDLINE | ID: mdl-8488504

ABSTRACT

The BT-PABA/Xylose test was used in 10 healthy cats and 49 cats with chronic diarrhea. In seven cats the test was performed three times in order to investigate individual variability. There was a statistically significant difference between the control group and the patients in the mean peak concentration of xylose, but no difference between groups of different diseases. The mean peaks of PABA were not significantly different between the control group and the patient group. Due to high individual variation in healthy cats the BT-PABA/Xylose test cannot be considered to be a useful test in feline diagnosis.


Subject(s)
Cat Diseases/diagnosis , Diarrhea/veterinary , Pancreatic Function Tests/veterinary , Xylose , para-Aminobenzoates , 4-Aminobenzoic Acid/blood , Animals , Cats , Chronic Disease , Diarrhea/diagnosis , Xylose/analysis
16.
J Pediatr ; 121(3): 413-6, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1517919

ABSTRACT

We assessed the diagnostic capability of the bentiromide test using a high-pressure liquid-chromatography method to analyze p-aminobenzoic acid and its metabolites in plasma as an indirect measure of exocrine pancreatic function. Mean total amine concentration in pancreatic-insufficient subjects was significantly lower than in control subjects. There were 3 of 15 false-negative results and no false-positive results. We conclude that this chromatographic method is an effective means of analyzing p-aminobenzoic acid and its metabolites after ingestion of bentiromide.


Subject(s)
4-Aminobenzoic Acid/blood , Chromatography, High Pressure Liquid/methods , Exocrine Pancreatic Insufficiency/diagnosis , para-Aminobenzoates , 4-Aminobenzoic Acid/metabolism , Child , Child, Preschool , Cystic Fibrosis/blood , Cystic Fibrosis/complications , Exocrine Pancreatic Insufficiency/blood , Exocrine Pancreatic Insufficiency/etiology , False Negative Reactions , Female , Humans , Infant , Male
17.
Mol Biochem Parasitol ; 52(2): 185-94, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1620158

ABSTRACT

De novo folate biosynthesis is required for the growth of malarial parasites and is inhibited by several important antimalarial agents. We show here that exogenous p-aminobenzoic acid (pABA) can be utilized by malaria parasites to synthesize folates. The transport of pABA into parasite infected red cells was therefore characterized. Normal red cells transport pABA in a saturable and energy-dependent manner, with a dissociation constant of 83 nM. pABA transport in parasite-infected red cells may use the same mechanism, as demonstrated by similarities in time course, concentration-response, and dissociation constant (111 nM). The transport capacity of red cells is temperature-, energy- and pH-dependent. It is inhibited by the proton ionophore, carbonylcyanide m-chlorophenylhydrazone (CCCP), but not by the sodium ionophores nigericin and monensin. p-Aminosalicylic acid (PAS) inhibits pABA transport competitively, with a inhibition constant of 378 nM. Phloritin, flufanamic acid, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DITS), which are inhibitors of the anion transporter (band 3), and oxalic acid, a substrate of this transporter, partially inhibit pABA transport into both normal and infected red cells. Interestingly, in both normal and infected red cells, the inhibitory effects of PAS and the anion transport inhibitors are additive, suggesting the involvement of 2 independent mechanisms.


Subject(s)
4-Aminobenzoic Acid/metabolism , Erythrocytes/parasitology , Folic Acid/biosynthesis , Plasmodium falciparum/metabolism , 4-Aminobenzoic Acid/blood , Adenosine Triphosphate/blood , Aminosalicylic Acid/pharmacology , Animals , Biological Transport, Active , Erythrocytes/drug effects , Erythrocytes/metabolism , Humans , Hydrogen-Ion Concentration , Iodoacetamide/pharmacology , Ionophores/pharmacology , Kinetics , Temperature
18.
Res Vet Sci ; 52(1): 97-104, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1553443

ABSTRACT

The effects of pancreatic duct anastomosis to stomach (stomach group) or duodenum (duodenal group) on pancreatic function were examined in dogs following two thirds pancreatectomy. Normal fasting blood glucose concentrations were maintained in both groups despite significant reductions in glucose tolerance in the stomach group, and reductions in fasting insulin and insulin peak response in both groups. Pancreatic exocrine function was significantly decreased in both groups, though plasma p-aminobenzoic acid (PABA) concentrations were generally higher in the duodenal group. A correlation was found between plasma trypsin-like immunoreactivity (TLI) and pancreatic weight. These results indicate that anastomosis of the pancreas to bowel can be undertaken with minimal postoperative complications and that the site of the anastomosis influences pancreatic function. They suggest that preservation of more than one third of the pancreas is required for optimal function. The complementary information provided by the PABA and TLI tests suggests their dual application will be clinically useful for the detection and characterisation of naturally occurring pancreatic diseases.


Subject(s)
Dogs/surgery , Duodenum/surgery , Pancreatectomy/veterinary , Pancreatic Ducts/surgery , Stomach/surgery , 4-Aminobenzoic Acid/blood , Anastomosis, Surgical/veterinary , Animals , Blood Glucose/analysis , Dogs/physiology , Female , Insulin/blood , Islets of Langerhans/physiology , Male , Pancreas/physiology , Trypsin/blood
19.
J Pharmacol Exp Ther ; 259(3): 1241-6, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1762071

ABSTRACT

The expression of arylamine N-acetyltransferase (NAT) in leukocytes was investigated using p-aminobenzoic acid (PABA) and sulfamethazine (SMZ), substrates which are preferentially acetylated by the monomorphic NAT1 and polymorphic NAT2 enzymes, respectively. Activity towards both substrates was detected in mononuclear leukocytes (MNL; preparation containing approximately 80% lymphocytes), monocytes and neutrophils. PABA and SMZ acetylation rates were highly correlated in each of the isolated cell types. The NAT in leukocytes displayed a much higher affinity and turnover rate for the acetylation of PABA than for SMZ. These kinetic characteristics suggest that the acetylating activity in human leukocytes is predominantly attributable to the monomorphic enzyme NAT1. Neutrophils showed evidence of biphasic kinetics for SMZ which would indicate the coexpression of NAT1 and low levels of the polymorphic enzyme, NAT2. NAT activity in MNL was not influenced by the acetylator phenotype of the individual. There was, however, a significant correlation between NAT activity in MNL and the in vivo acetylation (urinary metabolite ratio) of p-aminosalicylic acid, which is monomorphically acetylated in humans. The expression of NAT1 in leukocytes and the virtuall absence of NAT2 may have important toxicological implications. The in vitro/in vivo correlation suggests that leukocytes may be a useful marker of systemic NAT1 activity.


Subject(s)
Arylamine N-Acetyltransferase/blood , Leukocytes, Mononuclear/enzymology , 4-Aminobenzoic Acid/blood , Acetyl Coenzyme A/blood , Acetylation , Adult , Aged , Caffeine/urine , Female , Humans , Kinetics , Liver/enzymology , Male , Middle Aged , Monocytes/enzymology , Neutrophils/enzymology , Phenotype , Sulfamethazine/blood
20.
J Pharm Sci ; 80(12): 1153-6, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1815074

ABSTRACT

In a previous study, we developed a multiple-unit type of oral floating dosage system, which is a new type of floating pill composed of both an effervescent layer and a swellable membrane layer coated on sustained-release pills. The system was shown to have excellent floating ability and sustained-release characteristics in vitro, irrespective of the pH and viscosity of the medium. In the present study, the floating ability and the sustained-release characteristics of the system in the gastrointestinal tract have been evaluated in vivo. In beagle dogs and humans in the fed state, most of the new type of pills containing barium sulfate were floating in the stomach at 10 min, and they kept floating for at least 3 h after administration (observed by periodic X-ray photographs), while some control pills without the effervescent layers were already transited into the small intestine by 3 h. Moreover, in order to evaluate the sustained-release characteristics of the drug from the new type of floating pills, p-aminobenzoic acid (PABA), with a limited absorption site, and isosorbide dinitrate (ISDN), with wide absorption sites in the gastrointestinal tract, were employed as model drugs. Floating pills of the new type, with the same sustained-release rate as that of non-floating pills (control pills) were prepared. In beagle dogs in the fed state, the new type of floating pills containing PABA showed higher plasma PABA levels at 5 and 6 h after dosing and 1.61 times greater AUC than the control pills.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
4-Aminobenzoic Acid/administration & dosage , Isosorbide Dinitrate/administration & dosage , Models, Biological , 4-Aminobenzoic Acid/blood , Administration, Oral , Animals , Delayed-Action Preparations , Dogs , Gastric Emptying , Humans , Isosorbide Dinitrate/blood , Radiography , Stomach/diagnostic imaging
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