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Biomedical subjects

G L Larsen

Publications and source records attributed to G L Larsen.

At least 73 records · Page 4Linked to original sources
PubMed1992

Altered prednisolone pharmacokinetics in patients with cystic fibrosis.

Prednisolone pharmacokinetics were evaluated in eight patients with cystic fibrosis (CF) (aged 1.8 to 20 years) by assessing absorption of orally administered prednisone (in its active form, prednisolone) and elimination of prednisolone after intravenous administration. After an overnight fast, subjects received intravenously administered doses of prednisolone or orally administered doses of prednisone, 40 mg/1.73 m2 body surface area, before a standardized breakfast. Serial blood samples were collected for 12 hours and analyzed for prednisolone concentration. Prednisolone pharmacokinetics were compared in eight age-matched patients with asthma who required steroids after intravenous administration of prednisolone. The prednisolone pharmacokinetic parameters derived demonstrated an increased total clearance (by 60%), an increased volume of distribution (by 46%), a lower peak concentration (by 35%), and no difference in elimination half-life in patients with CF compared with those with asthma. Bioavailability averaged 88.4% +/- 20.1% of the administered dose. Prednisolone clearance was markedly increased in those with CF. There was a proportional increase in nonrenal clearance, with no difference in renal clearance in those with asthma or CF. The plasma protein binding of prednisolone was only slightly decreased in patients with CF and did not account for the observed pharmacokinetic alteration. The marked increase in prednisolone clearance may necessitate the use of more frequent or higher doses of this steroid in the treatment of patients with CF, leading to a potentially less favorable benefit/risk ratio.

Administration, Oral↗
PubMed1992

Asthma pathogenesis and the implications for therapy in children.

Gaining greater insight into the pathogenesis of asthma has redefined the approach to treatment of children with asthma. Clearly, the Expert Panel of the National Heart, Lung, and Blood Institute National Education Program has played a major role in taking the message to a wide audience of health care providers. Although only early trends are evident at this point in time, within several years therapeutic trends underway currently will be more commonplace, and we may observe how asthma continues to impact society and our health care system. The approach to therapy will continue to evolve and most likely be controversial for years to come.

Asthma↗
PubMed1992

Airway response to electrical field stimulation in sensitized inbred mice. Passive transfer of increased responsiveness with peribronchial lymph nodes.

We have examined the effects of repeated exposure to antigen on airway responses to cholinergic stimulation in two inbred strains of mice that are similar in underlying cholinergic airway responsiveness, yet differ in their ability to produce IgE. Both BALB/c and SJL/J mice were repeatedly exposed to ovalbumin by inhalation for a 10-d period. While the BALB/c mice developed IgE antibody to this allergen, the SJL/J strain failed to mount an appreciable IgE response. In vitro assessments of the response of tracheal smooth muscle from saline exposed mice (controls) of both strains demonstrated responses to both methacholine and electrical field stimulation that were not significantly different between the strains. Following exposure to ovalbumin, the BALB/c strain developed a significant increase in their response to electrical field stimulation, while their response to methacholine was unaltered. In contrast, the in vitro responsiveness to these stimuli did not increase in SJL/J mice following similar exposure to inhaled nebulized ovalbumin. The passive transfer of cells from the peribronchial lymph nodes of ovalbumin-sensitized BALB/c mice into syngeneic nonimmune mice also led to increases in responsiveness of tracheal smooth muscle to electrical field stimulation. In contrast, transfer of cells from nonsensitized mice did not alter responsiveness. These results suggest that murine species capable of developing an IgE response to allergen also develop alterations in the neural control of their airways. Further, this alteration appears to be lymphocyte dependent, in that cells found within peribronchial lymph nodes following allergen exposure are capable of transferring this increase in responsiveness to nonimmune mice.

Animals↗
PubMed1992

Comparative metabolism of the cysteine and homocysteine conjugates of propachlor by in situ perfused kidneys of rats.

1. 14C-Cysteinyl- and homocysteinylpropachlor were metabolized to their respective mercapturic acids by rat kidneys in situ. First-pass elimination of 14C in urine was 47.5% for the cysteine conjugate and 36% for the homocysteine conjugate. 2. About half of the perfused 14C-labelled material isolated from urine from kidneys perfused with homocysteinylpropachlor was unchanged homocysteinylpropachlor and about half was the corresponding mercapturic acid. However, only the corresponding mercapturic acid and the S-oxide of this mercapturic acid (31.4% and 1.7% of the dose) were found in urine from kidneys perfused with cysteinylpropachlor, indicating that rat kidneys more efficiently acetylated the natural substrate, the cysteine conjugate.

Acetanilides↗
PubMed1991

The effect of intravascular complement activation and brief episodes of hypoxia on protein in bronchoalveolar lavage fluid in C5 sufficient and deficient mice.

Our earlier investigations indicated that systemic complement activation with iv cobra venom factor (CVF) or infused zymosan-activated rabbit plasma or rabbit C5a does not significantly increase bronchoalveolar lavage albumin in rabbits (Am Rev Respir Dis 1982; 125:335-340); but that complement activation due to CVF combined with a brief episode of hypoxia increases lavage albumin and is associated with the presence of neutrophils for its expression (J Clin Invest 1985; 75:902-910). In order to determine if intravenous CVF and hypoxia cause similar alterations in mice, and to investigate the time course of the response as well as the importance of C5 fragments to the process, we challenged the B10.D2/nSn strain of C5 sufficient mice (C5+) and the congenic B10.D2/oSn strain of C5 deficient mice (C5-) with intravenous CVF, 15 min of 12% oxygen, or CVF followed by hypoxia. Neither C5+ nor C5- mice had significant increases in lavage protein after either CVF or hypoxia. However, the combined insults significantly increased lavage protein in C5+ but not C5- mice; polyacrylamide gel electrophoresis showed increased amounts of proteins of low and high molecular weights in lavage fluid from the C5+ strain. While the time course of abnormalities in mice was different from that in rabbits, both meclofenamate pretreatment and neutrophil depletion attenuated the increases in lavage protein after the combined insults in both animal species. Infusion of prostaglandin E2 (PGE2) with CVF in the C5+ mice also led to significant increases in lavage protein. We conclude that in mice, intravenous complement activation, as an isolated event, does not cause a significant increase in lavage protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A methylsulfonyl metabolite of a polychlorinated biphenyl can serve as a ligand for liver fatty acid binding protein in rat intestinal mucosa.

When a 100,000 x g supernatant from rat intestinal mucosa was incubated with 4,4'-bis([3H]methylsulfonyl)-2,2',5,5'-tetrachlorobiphenyl, [(CT3SO2)2TCB] a (CT3SO2)2TCB-protein complex was formed. The (CT3SO2)2TCB-protein complex was isolated and purified using gel filtration and ion-exchange chromatography. The protein portion of this complex was characterized to be liver fatty acid binding protein (L-FABP) by SDS-polyacrylamide gel electrophoresis and immunoblot analysis. No cross reactivity was observed in the immunoblot analysis between the purified protein and anti-heart or anti-intestinal fatty acid binding protein. (CT3SO2)2TCB was extractable from L-FABP and therefore not covalently bound to L-FABP.

Animals↗
PubMed1991

Bronchoalveolar lavage fluid mediator levels 5 minutes after allergen challenge in atopic subjects with asthma: relationship to the development of late asthmatic responses.

Inflammatory mediators have been implicated in the pathogenesis of human asthma and have been demonstrated to increase in bronchoalveolar lavage fluid during the time of the immediate asthmatic response (IAR) after allergen instillation in the lungs. However, the relationship of these mediators, measured early to the late asthmatic response (LAR), airway reactivity, and clinical asthma, is unknown. In the present study, we evaluated mediator levels in bronchoalveolar lavage fluid before and 5 minutes after allergen challenge from three subject groups: atopic subjects without asthma (N = 7), atopic subjects with asthma and without LAR [-) LAR) (N = 6), and atopic subjects with asthma and with LAR [+) LAR) (N = 6). Subjects with asthma were differentiated into subjects with and without LARs based on at least a 15% decrease in FEV1 between 3 to 8 hours postallergen inhalation. The mediators, prostaglandin D2 thromboxane B2 leukotriene C4 (LTC4), and histamine, were measured both before and after allergen instillation. Baseline prechallenge levels were similar, except in the case of LTC4. LTC4 was detectable at baseline significantly more frequently in the atopic subjects with asthma with and without LAR when these subjects were compared to the atopic subjects without asthma (nine of 12 detectable versus one of seven detectable). In all groups, significant increases in mediator levels were observed in the groups with asthma postallergen challenge, compared to the atopic subjects without asthma. Atopic subjects with asthma and without LAR had significantly higher levels of all four mediators after challenge than atopic subjects with asthma and with LAR and atopic subjects without asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Urinary leukotriene E4 in patients with asthma. Effect of airways reactivity and sodium cromoglycate.

A group of 17 patients with allergic asthma was challenged with aerosolized antigen, and the excretion of the peptidoleukotriene metabolite leukotriene (LT) E4 in the urine was determined as an index of leukotriene synthesis. The allergen challenge caused a drop in FEV1 of 25 to 59% within the first 2 h in all patients. This was associated with an increase in urine LTE4 excretion during the subsequent 12 h. The amount of urinary LTE4 excreted increased from a 12-h baseline level of 46 +/- 6.8 ng to a postallergen challenge level of 92 +/- 13 ng. In a similar experimental protocol methacholine challenge alone did not significantly increase urinary LTE4 excretion. In comparing all individuals as a group, there was no significant positive correlation between the magnitude of the drop in FEV1 during the immediate asthmatic response (IAR) and the increased amount of LTE4 excreted in the urine (p = 0.08). These parameters were still not significantly correlated when airways reactivity (log PC20) was also considered (p = 0.057). However, when each individual was compared to self in the presence and absence of cromoglycate, a significant correlation was found to exist between the drop in FEV1 during the IAR, the excretion of urinary LTE4, and the airways reactivity. No correlation was found between the increase in urine LTE4 excreted during the 12 h following allergen challenge and the severity of late (3 to 12 h) responses to allergen, but there was a significant prolonged (12 to 36 h) elevated urine LTE4 excretion in those patients with the most severe late asthmatic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Cholinergic mechanisms involved with histamine hyperreactivity in immune rabbit airways challenged with ragweed antigen.

The present study examines the effects of aerosolized ragweed antigen (RAg) on tracheal (TSM) and bronchial (BSM) smooth muscle contraction in rabbits actively immunized with RAg. Airway segments were isolated 48 h after aerosol challenge with either saline or RAg, and airway contractile responses to histamine were measured. Histamine remained a weak agonist in TSM segments after RAg challenge. In contrast, BSM responsivity to histamine was significantly increased after RAg challenge as evidenced by a parallel shift to the left (i.e., Fslope = 3.2; degrees of freedom (df) = 1,224; p = NS and Felev = 19.4; df = 1,225; p less than 0.001) of the mean dose-response relationship. In sham-immunized rabbits, the BSM contractile responses to histamine were similar after aerosol challenge with either RAg or normal saline. After the BSM segments were treated with 10(-6) M atropine, there was no significant difference in histamine reactivity between the RAg- and saline-challenged groups. The augmented BSM contractile response to histamine was only partially inhibited in the presence of either tetrodotoxin or hexamethonium. We conclude that 48 h after a single in vivo exposure to antigen in immune rabbits, the airway contractile responses to histamine in vitro are increased in BSM but not in TSM and that the mechanism of the augmented contractile responses in BSM likely involves the facilitated neural release of acetylcholine from both preganglionic and postganglionic sites.

Acetylcholine↗
PubMed1991

Methylprednisolone achieves greater concentrations in the lung than prednisolone. A pharmacokinetic analysis.

Previous studies in humans and rabbits demonstrated that methylprednisolone appears in the lung in greater concentration than prednisolone. To ascertain which pharmacokinetic properties of these drugs explain this difference, we gave methylprednisolone and prednisolone, 5 mg/kg intravenous bolus, to 23 adult rabbits. To measure the plasma concentration versus time curves for methylprednisolone and prednisolone, samples were obtained predose through 480 min postdose. To measure the bronchoalveolar lavage glucocorticoid concentration versus time curves, lavage was performed once per experiment at seven separate time points from 5 to 480 min post-dose (two to four experiments per time point). Bronchoalveolar lavage fluid (BALF) recovery ranged from 50 to 75% and was similar in both groups. Glucocorticoid concentration in plasma and BALF was determined by high performance liquid chromatography. To normalize for the dilutional effects of lavage, epithelial lining fluid (ELF) recovery was quantitated from BALF volume and BALF and plasma urea concentrations. Pharmacokinetic parameters of the two glucocorticoids were calculated both noncompartmentally and by a three-compartment model. The extrapolated plasma glucocorticoid concentrations at time zero of methylprednisolone and prednisolone are similar, but the volume of distribution and plasma half-life of methylprednisolone are significantly greater than those of prednisolone (p less than 0.05). Although the clearance of the two drugs are not significantly different, methylprednisolone appears to have a slower Cl than prednisolone. The mean residence time (the average time drug remained in body) was significantly longer for methylprednisolone than for prednisolone (p less than 0.05), and plasma glucocorticoid concentrations became significantly different in the two groups by 90 min (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge.

Sulfidopeptide leukotrienes have been implicated in the pathogenesis of asthma because of their ability to induce bronchospasm, airways hyperreactivity, and increased mucus production. In the present study, the leukotrienes (LT) C4, D4, and E4 were measured in bronchoalveolar lavage fluid (BALF) before and 5 min after endobronchial allergen challenge in four subject groups: nonatopic nonasthmatic, nonatopic asthmatic, atopic nonasthmatic, and atopic asthmatic. As determined by high performance liquid chromatography (HPLC), after allergen challenge, the predominant sulfidopeptide leukotriene found in BALF from atopic asthmatics was LTC4. Smaller amounts of LTD4 and LTE4 were detectable. The baseline level of leukotrienes in the atopic asthmatics was 64 +/- 18 pg/ml, with measurable levels being found in nine of 11 samples. Atopic nonasthmatics had measurable levels in only one of seven baseline samples, whereas five of six nonatopic subjects had undetectable levels. Allergen challenge in atopic asthmatics resulted in significant increases in LTC4 over prechallenge levels (64 +/- 18 to 616 +/- 193 pg/ml) (p less than 0.01) and over levels in the three control groups after challenge (p = 0.0297). The atopic nonasthmatic group also had detectable leukotriene levels after allergen challenge (88 +/- 32 pg/ml), whereas leukotrienes remained undetectable in five of the six nonatopic samples. For comparison, histamine and the prostanoids prostaglandin D2 (PGD2) and thromboxane B2 (TxB2) were also measured in BALF. The levels of all three of these mediators increased in BALF from atopic asthmatics after allergen challenge. After allergen challenge, the best correlation was found between the levels in BALF for the prostanoids PGD2 and TxB2 (r = 0.88).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

A methylsulphonyl metabolite of a polychlorinated biphenyl can serve as a ligand for alpha 2mu-globulin in rat and major-urinary-protein in mice.

1. Kidneys from rats given an intraperitoneal dose of 4,4'-bis[( 3H]methylsulphonyl)-2,2',5,5'- tetrachlorobiphenyl[(CT3SO2)2TCB)] contained (CT3SO2)2TCB associated with a protein which has been isolated and characterized by SDS-polyacrylamide gel electrophoresis (SDS-PAGE), immunoblot and immunodiffusion analysis to be alpha 2 mu-globulin (alpha 2 mu). 2. The same radioactive alpha 2 mu-globulin complex was isolated from urine of rats given an i.p. dose of (CT3SO2)2TCB. This complex represented 12.3% (0.27% dose) and 9.3% (0.06% dose) of the radioactivity excreted in 0-24 h and 24-48 h urine, respectively. 3. The radioactivity was extractable from alpha 2 mu and characterized by t.l.c. (co-chromatography in two solvent systems) to be (CT3SO2)2TCB. 4. A radioactive-protein complex was isolated from urine of mice given an i.p. dose of (CT3SO2)2 TCB. The radioactive-protein complex was characterized to be mouse major urinary protein (MUP) by SDS-PAGE, immunoblot and immunodiffusion analysis. This complex was not detected in mouse kidney. 5. Urinary excretion of radioactive-MUP complex represented 51.7% (2.3% dose) and 28% (1.3% dose) of the radioactivity excreted in 0-24 h and 24-48 h urine, respectively.

Alpha-Globulins↗
PubMed1990

Methylsulphone metabolites of m-dichlorobenzene as ligands for alpha 2u-globulin in rat kidney and urine.

1. Kidneys from rats given oral doses of either 3,5- or 2,4- dichlorophenyl[14C]methylsulphide contained the corresponding sulphones that were associated with a protein which has been isolated and characterized by SDS-polyacrylamide gel electrophoresis and immunoblot analysis to be alpha 2u-globulin. 2. The same methylsulphone-alpha 2u-globulin complex was isolated from the urine from rats doses with 3,5-dichlorophenyl[14C]methylsulphide (0.3-1.0% of dose, 8.5% of 14C in urine. 3. The stoichiometry of binding of the isolated methylsulphone-alpha 2u-globulin complex was shown to be 0.54-0.78 nmol/nmol protein. This binding was not covalent.

Alpha-Globulins↗
PubMed1990

Metabolism of the glutathione conjugate of propachlor by in situ perfused kidneys and livers of rats.

1. [1-14C]Propachlor-GSH was perfused at 0.34, 3.4 and 34 mumol/h through the portal vein or the right renal artery of anaesthetized rats with biliary and ureteral cannulas. Urine was the predominant route for elimination of the 14C regardless of the route of perfusion. 2. Mercapturic acid conjugates were found to be the end-products of metabolism of the 14C-propachlor-GSH by rat kidneys and liver, indicating that all enzymes necessary for the catabolism of GSH conjugates to mercapturates were present in each of these tissues. 3. Perfusion of 14C-propachlor-GSH at 34 mumol/h appeared to exceed the metabolic capacity of both liver and kidneys for this substrate. At this dose, parent compound was detected in the bile of portally perfused rats, and the amounts of 14C recovered in bile, kidneys and carcasses of renally perfused rats were greater than when smaller dosages were perfused.

Acetanilides↗
PubMed1990

Evidence for the absence of cysteine S-conjugate N-acetyltransferase activity in the metabolism of propachlor, naphthalene, and dichlobanil in calves.

1. The glutathione conjugate of 2-chloro-N-isopropyl[1-14C]acetanilide (14C-propachlor) was perfused through a calf kidney in situ; 23% of the dose was excreted in the perfused kidney urine as the cysteine conjugate, no mercapturic acid was detected. 2. A 5-day-old calf dosed orally with 14C-propachlor excreted 70% dose in the urine as the cysteine conjugate; no mercapturic acid was detected. Rumen microflora were established in the calf (5 weeks older) and the experiment was repeated with the same results. 3. When the same calf was dosed 1 week later with 14C-naphthalene, 99% dose was excreted in the urine, mostly as the dihydrodiol-glucuronide (34%) and the dihydrohydroxy-cysteine conjugate (47%); no mercapturate was detected. 4. A 9-day-old calf dosed orally with 2,6,-dichlorobenzo[14C]nitrile (14C-dichlobanil) excreted 67% dose in the urine as cysteine conjugates (34%), and products of cysteine conjugate beta-lyase cleavage of cysteine conjugates (30%); no mercapturates were detected. 5. Cysteine S-conjugate N-acetyltransferase activity in calf kidney and liver was about 10% of that in the corresponding rat tissues.

Acetanilides↗
PubMed1990

Postneonatal circumcision: population profile.

Because postneonatal circumcision includes the risk of general anesthesia and costs more than elective neonatal circumcision, a retrospective study was performed to describe the population currently undergoing postneonatal circumcision and to identify the factors influencing decisions that lead to this procedure. A chart review and follow-up telephone survey were done to gather information concerning patients admitted for postneonatal circumcision to two Salt Lake City hospitals during a 2-year period. From the 135 patients eligible for analysis, two distinct groups emerged: the "sick" group (n = 52)--those who had neonatal complications, and the "well" group (n = 83)--those with no neonatal complications. The median age at circumcision was 5.5 months for the boys in the sick group and 35 months for the boys in the well group (P less than .001, Student's t test). During the neonatal period, 32% of families in the well group received anticircumcision advice from their primary care physician. The decision in favor of circumcision was made by two thirds of the families of sick infants before their sons were 6 weeks of age. Other surgery was performed concurrent with the circumcision in 44% of patients in the sick group and 24% of patients in the well group (P less than .0001, chi 2). Balanitis, phimosis, or a physician's recommendation were listed as the primary reason for post-neonatal circumcision by 50% of patents in the well group. Phimosis was listed by the surgeon as an indication for postneonatal circumcision in 65% of all patients' charts, although only 13% of parents listed phimosis as an indication for their children's circumcision.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Metabolism of leukotriene E4 to 5-hydroxy-6-mercapto7,9-trans-11,14-cis-eicosatetraenoic acid by microfloral cysteine-conjugate beta-lyase and rat cecum contents.

Leukotriene E4 was incubated with cysteine-conjugate beta-lyase isolated from the intestinal bacterium Eubacterium limosum. The reaction was terminated by addition of iodoacetic acid or dimethyl sulfate, and the products formed were isolated by reverse-phase high-performance liquid chromatography. The structures of two adducts of a metabolite were determined by uv spectroscopy, by gas-liquid radiochromatography, and by comparisons with chemically synthesized reference compounds. They were 5-hydroxy-6-S-carboxymethylthio-7,9-trans-11,14-cis-eicosatetraeno ic acid (iodoacetic acid adduct) and 5-hydroxy-6-S-methylthio-7,9-trans-11,14-cis-eicosatetraenoic acid (dimethyl sulfate adduct) indicating that the structure of the underivatized metabolite was 5-hydroxy-6-mercapto-7,9,11,14-eicosatetraenoic acid (5,6-HMETE). The latter product is formed by beta-lyase-catalyzed cleavage of the cysteine C-S bond in leukotriene E4. Leukotriene E4 was also metabolized to 5,6-HMETE by rat cecal contents. A product formed was trapped as the iodoacetic acid derivative and identified as 5-hydroxy-6-S-carboxy-methylthio-7,9,11,14-eicosatetraenoic acid. It is concluded that intestinal leukotriene E4, originating from biliary excretion of systemic cysteinyl leukotrienes or produced in the intestine, is converted by microfloral cysteine-conjugate beta-lyase to 5,6-HMETE.

Animals↗