Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dexniguldipine-HCl (DNIG)--a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MDR)--was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303 +/- 27 pmol/mg protein; DNIG (3.3 mumol/l): 1,067 +/- 174 pmol/mg protein; F4-6P, solvent: 948 +/- 110 pmol/mg protein; n = 8-9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC50), 0.73 vs 5.4 mumol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (b) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.
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PMID:Reversal of multidrug resistance in Friend leukemia cells by dexniguldipine-HCl. 846 20

To determine whether markers of mucus secretion can be quantified in airway lining fluid from asthmatic and from healthy subjects, we measured levels of a mucin-like glycoprotein (MLG) and lactoferrin in sputum induced by inhalation of hypertonic (3%) saline in 18 asthmatic and in 10 healthy subjects. Because DNA, like mucin, contributes to the viscosity of airway secretions, we also measured DNA levels in the induced sputum samples. To control for the presence of saliva in sputum, we also analyzed saliva samples from all subjects. The entire sputum sample and the saliva sample were reduced using dithiotreitol, and biochemical analysis was performed on supernatants obtained after centrifugation. We found that induced sputum from asthmatic subjects had higher levels of MLG [2,574.4 +/- 907.8 (mean +/- SEM) versus 562.2 +/- 90.5 micrograms/ml, p < 0.007] and DNA (7.1 +/- 1.6 versus 3.6 +/- 0.6 micrograms/ml, p < 0.05), but the difference in lactoferrin levels failed to reach statistical significance. However, in the subgroup of asthmatic subjects who gave a history of sputum production (n = 9), lactoferrin levels were higher than in the healthy control subjects (118.9 +/- 46.3 versus 35.2 +/- 6.5 micrograms/ml, p < 0.05). The very low levels of MLG, DNA, and lactoferrin measured in saliva were not significantly different in asthmatic subjects from those in healthy subjects. We conclude that measurement of markers of mucus secretion in induced sputum is feasible in asthmatic and healthy subjects, and it reveals abnormally high markers of mucus secretion in subjects with stable asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Markers of mucus secretion and DNA levels in induced sputum from asthmatic and from healthy subjects. 848 21

Incomplete transfer of maternal antibodies specific to respiratory syncytial virus (RSV) has been suggested as an explanation for the increased risk of RSV infections in preterm infants. Antibodies directed against the two major RSV envelope glycoproteins, F and G, are protective in vitro and in vivo. Our study was conducted to measure IgG, IgG1, IgG2, and IgG3 antibody titers against the RSV F and G glycoproteins in cord sera from infants born at different gestational ages. Titers of neutralizing antibody were measured in a subset of the subjects. The mean (+/- SEM) log2 titers of IgG antibodies directed against the RSV F and G glycoproteins were significantly lower in infants born at < or = 28 weeks of gestation (11.2 and 10.8 for F and G glycoproteins, respectively) than in term infants (12.6 and 12.8 for F and G, respectively) (p < 0.05). Preterm infants born at > or = 29 weeks had titers of antibodies against the F glycoprotein comparable to those of term infants. The highest titers of RSV-specific antibodies were in the IgG1 and IgG2 subclasses. Mean (+/- SEM) neutralizing antibody titers were lower in infants born at < or = 28 weeks (7.7 +/- 0.4) than in term infants (10.2 +/- 0.3) (p < 0.001). We conclude that (1) RSV-specific antibody titers were lower than in term infants only in the most premature infants (< or = 28 weeks) and (2) preterm infants born at > or = 29 or > or = 33 weeks of gestation had RSV-specific titers against F and G glycoproteins, respectively, that were comparable to those of term infants. Preterm infants born at < or = 28 weeks could represent a target population for passive immunoprophylaxis.
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PMID:Respiratory syncytial virus-specific immunoglobulins in preterm infants. 849 62

Leukocytes attach to and roll on inflamed endothelium and on leukocyte monolayers that form on the endothelial cells. Leukocyte-leukocyte interactions occurring under hydrodynamic shear stress are mediated by binding of L-selectin to unknown sialomucin-like glycoproteins. We show that purified neutrophil PSGL-1, a sialomucin glycoprotein that serves as a ligand for both P- and E-selectin, can also support the attachment and rolling of free flowing neutrophils in vitro. Neutrophil rolling on PSGL-1 was abolished by the anti-L-selectin mAb DREG200 and by the anti-PSGL-1 mAb PL1, indicating that L-selectin can interact directly with PSGL-1. Neutrophil rolling on neutrophil monolayers was also blocked by PL1 (60 +/- 9% SEM inhibition); however, DREG200 blocked more efficiently (93 +/- 7% SEM inhibition), suggesting that other L-selectin ligands may exist on the neutrophil surface. These studies demonstrate that PSGL-1 on the neutrophil surface is a major functional ligand for L-selectin. The avidity of this L-selectin-dependent adhesion event was sufficient to allow individual neutrophils rolling on P-selectin to capture free flowing neutrophils, which progressed to form linear strings and discrete foci of rolling neutrophils. Neutrophil accumulation on P-selectin accelerated with time as a result of neutrophil-assisted capture of free flowing neutrophils. When neutrophil-neutrophil interactions were blocked by DREG200, neutrophils accumulated on P-selectin in a random pattern and at a uniform rate. Thus, leukocyte-assisted capture of flowing leukocytes may play an important role in amplifying the rate of initial leukocyte recruitment at sites of inflammation.
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PMID:Neutrophil-neutrophil interactions under hydrodynamic shear stress involve L-selectin and PSGL-1. A mechanism that amplifies initial leukocyte accumulation of P-selectin in vitro. 878 68

We have previously shown that surface levels of the adhesive glycoprotein, L-selectin, are diminished on cord blood neutrophils (polymorphonuclear leukocytes, PMN) and associated with impaired adherence to endothelium under flow conditions. To test the hypothesis that diminished surface levels reflect a total cellular deficiency, we measured L-selectin in PMN lysates and plasma from cord and adult blood. L-selectin content was decreased in cord blood PMN lysates compared with those of adults by both Western blot analyses and ELISA (cord blood, 1195 +/- 160 pg/mL; adult, 1870 +/- 260 pg/mL; X +/- SEM; p < 0.05). Soluble L-selectin levels were also decreased in cord blood plasma (324 +/- 24 ng/mL versus 537 +/- 28 ng/mLiter in adult plasma, p < 0.01). To evaluate L-selectin function, we next compared the dose dependent effect of several chemoattractants on shedding of L-selectin from cord blood and adult PMN. Adult PMN showed greater overall shedding of L-selectin as compared with cord blood PMN after stimulation with fMet-Leu-Phe (p < 0.03) and granulocyte-macrophage colony-stimulating factor (p < 0.02). In contrast, shedding of L-selectin was similar between groups after IL-8 tested stimulation. We conclude that cord blood PMN have a decreased cellular content of L-selectin in addition to an impaired ability to shed surface L-selectin in response to specific inflammatory mediators.
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PMID:Diminished soluble and total cellular L-selectin in cord blood is associated with its impaired shedding from activated neutrophils. 884 34

To examine the hypothesis that surface P-selectin-positive (degranulated) platelets are rapidly cleared from the circulation, we developed novel methods for tracking of platelets and measurement of platelet function in vivo. Washed platelets prepared from nonhuman primates (baboons) were labeled with PKH2 (a lipophilic fluorescent dye), thrombin-activated, washed, and reinfused into the same baboons. Three-color whole blood flow cytometry was used to simultaneously (i) identify platelets with a mAb directed against glycoprotein (GP)IIb-IIIa (integrin alpha 11b beta 3), (ii) distinguish infused platelets by their PKH2 fluorescence, and (iii) analyze platelet function with mAbs. Two hours after infusion of autologous thrombin-activated platelets (P-selectin-positive, PKH2-labeled), 95 +/- 1% (mean +/- SEM, n = 5) of the circulating PKH2-labeled platelets had become P-selectin-negative. Compared with platelets not activated with thrombin preinfusion, the recovery of these circulating PKH2-labeled, P-selectin-negative platelets was similar 24 h after infusion and only slightly less 48 h after infusion. The loss of platelet surface P-selectin was fully accounted for by a 67.1 +/- 16.7 ng/ml increase in the plasma concentration of soluble P-selectin. The circulating PKH2-labeled, P-selectin-negative platelets were still able to function in vivo, as determined by their (i) participation in platelet aggregates emerging from a bleeding time wound, (ii) binding to Dacron in an arteriovenous shunt, (iii) binding of mAb PAC1 (directed against the fibrinogen binding site on GPIIb-IIIa), and (iv) generation of procoagulant platelet-derived microparticles. In summary, (i) circulating degranulated platelets rapidly lose surface P-selectin to the plasma pool, but continue to circulate and function; and (ii) we have developed novel three-color whole blood flow cytometric methods for tracking of platelets and measurement of platelet function in vivo.
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PMID:In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. 887 31

This study was designed to investigate the relationships among anticonvulsant therapy, plasma alpha 1-acid glycoprotein (AAG) levels, and resistance to vecuronium blockade. Thirty-one patients scheduled for routine neurosurgery were included in the study. The patients were treated (TG; n = 20) with phenytoin (n = 15) and/or carbamazepine (n = 4) and/or phenobarbital (n = 3) for > or = 6 days or were left untreated (UG; n = 11, control group). TG patients were further assigned to one of two subgroups according to the plasma anticonvulsant level measured the day before surgery and found to be within (TGW, n = 10) or below (TGB, n = 10) the therapeutic range. Finally, the 31 patients were divided into two more groups according to their plasma AAG levels: higher than (HAAG, n = 17) or within (NAAG, n = 14) the normal range (25-94 mg dl-1). Anesthesia was induced and maintained with propofol and sufentanil. Muscle relaxation was obtained with vecuronium 0.1 mg kg-1. A train-of-four (TOF) stimulation mode at 2 Hz was applied to the ulnar nerve every 15 s, and neuromuscular transmission was assessed using a TOF-Guard accelograph monitor. Plasma AAG concentrations (means +/- SEM) were 103.7 +/- 7.6 mg dl-1 in TG, 80.7 +/- 6.7 mg dl-1 in UG, 95.9 +/- 13.2 mg dl-1 in TGW, 111.6 +/- 7.6 mg dl-1 in TGB. 114.9 +/- 7.4 mg dl-1 in HAAG, and 71.4 +/- 3.8 mg dl-1 in NAAG groups. The differences in plasma AAG concentrations between UG and TG and between HAAG and NAAG groups were statistically significant. No significant relationship was found between plasma AAG levels and phenytoin concentrations (r = -0.26). The time (mean +/- SEM) to recovery of T1 to 25% of control was significantly shorter in TG (28.2 +/- 1.4 min) than in UG (42.2 +/- 3.1 min) but did not differ significantly according to the plasma anticonvulsant level (27.3 +/- 2.0 min in TGW; 29.1 +/- 1.9 min in TGB) and the plasma AAG level 31.7 +/- 1.9 min in HAAG; 35.3 +/- 3.3 min in NAAG). The time for the TOF ratio to recover to 25% yielded similar profiles and statistical significance levels: TG, 32.9 +/- 2.2 min; UG, 51.2 +/- 4.0 min; TGW, 35.0 +/- 3.9 min; TGB, 30.7 +/- 1.8 min; HAAG, 38.1 +/- 3.1 min; NAAG, 42.0 +/- 4.1 min. We conclude that anticonvulsant therapy induces an increase in plasma AAG independently of the plasma anticonvulsant level. However, duration and recovery of vecuronium blockade do not differ according to plasma AAG levels. Consequently, elevated AAG does not contribute to the resistance to vecuronium blockade induced by anticonvulsants.
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PMID:Elevated plasma alpha 1-acid glycoprotein levels: lack of connection to resistance to vecuronium blockade induced by anticonvulsant therapy. 901 32

This study reports plasma bupivacaine concentrations in 13 neonates who received lumbar epidural anesthesia during major abdominal surgery. A bolus of 1.8 mg/kg of bupivacaine (2.5 mg/mL) was administered after induction of anesthesia, followed by a continuous infusion of 0.2 mg.kg-1.h-1 (1.25 mg/mL). Plasma concentrations of total and free bupivacaine and alpha 1-acid-glycoprotein (AAG) were determined. Results are presented as mean (+/-SEM). At 48 h, five of nine patients still had increasing total plasma concentrations, and the total bupivacaine concentrations ranged between 0.7 and 3.1 micrograms/mL. The plasma levels of AAG increased significantly between 1 and 24 h (4.3 +/- 2.3 nM and 7.7 +/- 2.3 nM, respectively) (P = 0.018). The free concentrations of bupivacaine were relatively unchanged at 1 and 24 h (84 +/- 20 ng/mL and 58 +/- 15 ng/mL, respectively). No adverse events occurred during the study period. In conclusion, the dose administered in this study appears to be safe. However, a substantial number of patients still had increasing concentrations of total plasma bupivacaine at 48 h. Furthermore, the interindividual variation was considerable. These observations cause concern about the safety of epidural infusions longer than 48 h in the age group studied.
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PMID:Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. 905 90

The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale < or = 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even-numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin-1 beta, interleukin-6 (IL-6), tumor necrosis factor alpha, alpha 1-acid-glycoprotein, C-reactive protein, and albumin. Time-invariant and time-variant Michaelis-Menten models were fit to the phenytoin concentration-time data. Protein intake was closely monitored. The mean (+/- SEM) unbound fraction of phenytoin increased from 0.17 +/- 0.02 on day 1 to 0.24 +/- 0.04 on day 10 (P < 0.05). The time-variant model was superior in describing the concentration-time data of unbound phenytoin in eight of nine patients. Mean (+/- SEM) pharmacokinetic parameter estimates for unbound phenytoin were: Vmax delta = 605 +/- 92 mg/day, VmaxB = 149 +/- 26.3 mg/day, K(ind) = 0.013 +/- 0.004 hr-1. Interleukin-6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin-6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin-6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.
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PMID:Effect of acute phase response on phenytoin metabolism in neurotrauma patients. 905 39

Our objective was to investigate the initial levels of circulating proinflammatory cytokines, such as interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), of certain acute-phase proteins, such as C-reactive protein (CRP), fibrinogen (FBN) and albumin, and of the glycoprotein fibronectin at presentation and their daily variation during the clinical course of community-acquired pneumonia (CAP) in relation to clinical and laboratory indices of infection. Thirty otherwise healthy hospitalized patients aged 48 +/- 3 years (mean +/- SEM) and with bacteriologically confirmed CAP were studied prospectively. IL-1 beta and IL-6 were found to be 15-fold higher on admission (122 +/- 9 pg mL-1 and 60 +/- 4 pg mL-1 respectively), whereas TNF-alpha was three-fold higher (102 +/- 5 pg mL-1) than those of controls, all of them showing a decline towards normal. Initial CRP levels were increased 90-fold (416 +/- 1 mg L-1), whereas fibronectin levels were reduced (242 +/- 9 mg dL-1). The presence of parapneumonic effusion was associated with a higher TNF-alpha serum level (127 +/- 7 vs. 86 +/- 4 pg mL-1, P = 0.0002), a more rapid daily decline in TNF-alpha (-7.2 +/- 0.7 vs. -3.8 +/- 0.5 pg mL-1 day-1, P = 0.0005), a slower rate of decline in CRP (-42.8 +/- 3.0 vs. -54.6 +/- 3.0 mg L-1 day-1, P = 0.02) and a slower rate of increase in FBN (5.9 +/- 1.0 vs. 11.7 +/- 1.0 mg dL-1 day-1), P = 0.001]. Furthermore, daily progression of serum levels of cytokines and acute-phase proteins correlated strongly with pyrexia, erythrocyte sedimentation rate (ESR), neutrophil count, alveolar-arterial oxygen difference and radiographic resolution, clinically manifested by improvement in the patients' condition.
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PMID:Daily variation in circulating cytokines and acute-phase proteins correlates with clinical and laboratory indices in community-acquired pneumonia. 913 79


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