Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to characterize the dynamics of progestin metabolism peripherally and across the uterus during normal baboon pregnancy and to determine whether the decline in placental progesterone (P4) production which results from administration of the antiestrogen ethamoxytriphetol (MER-25) to baboons reflects a decrease in conversion of pregnenolone (P5) to P4 and thus delta 5-3 beta-hydroxysteroid dehydrogenase activity. To examine this possibility, the conversion of [3H]P5 to [3H]P4 was determined by the constant infusion method on day 100 (midgestation) and day 175 (near term) of gestation in baboons that received MER-25 (25 mg/day X kg BW, po) on days 95-100 or 140-175 (term = 184 days). Baboons were sedated with ketamine HCl, then received a constant iv infusion of [3H]P5 (1.0 mu Ci/0.388 ml X min) and [14C]P4 (0.2 mu Ci/0.388 ml X min for 110 min. Radiolabeled progestins were purified from blood samples withdrawn from saphenous, uterine, and umbilical vessels, and the MCR of P4 and P5, uterine extraction of P5, and transfer constants (rho) for the peripheral, transuterofetoplacental, and transuteroplacental conversion of P5 to P4 were determined. The formation of P4 from P5 by incubates of placental cells obtained on day 175 from untreated and MER-25-treated baboons was also assessed. During normal baboon pregnancy the mean (+/- SE) % P5 extracted (i.e. metabolized) by the uterus was 31.0 +/- 3.3 at midgestation and 45.7 +/- 5.6 late in gestation. Peripheral and transuterofetoplacental rho values of P5 to P4 in untreated baboons were 6.9 +/- 1.8% and 37.3 +/- 7.9%, respectively, at midgestation and 6.1 +/- 0.6% and 46.8 +/- 10.1%, respectively, near term. The transuteroplacental rho of P5 to P4 was only slightly lower than the transuterofetoplacental values, indicating minimal conversion of P5 to P4 by the fetus. The peripheral contribution of P5 production to the total production rate of P4 at term in baboons was 1%. The contribution of uteroplacental conversion of P5 to P4 to the total conversion of P5 to P4 at midgestation was estimated to be 22%. MER-25 caused a 53% decline (P less than 0.01) in serum P4 concentrations from a mean (+/- SE) of 12.5 +/- 2.4 ng/ml during the pretreatment period to 5.4 +/- 0.3 ng/ml between days 140 and 175 of gestation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transuterofetoplacental conversion of pregnenolone to progesterone in antiestrogen-treated baboons. 365 27

Two major classes of immunoreactive cholecystokinin peptides (iCCK) have been identified in rat and pig brains: (i) large basic peptides (big iCCK) resembling the 33-amino acid porcine cholecystokinin (pCCK33) in size and charge; (ii) small acidic peptides (small iCCK) resembling the COOH-terminal fragments of CCK. Boiling 0.1 M HCl maximally extracts big iCCK; boiling 0.1 M NaOH maximally extracts small iCCK. The differences in hormonal forms removed by these extractants are not likely to be due to enzymatic conversion during the extraction procedures. Fractionation on Sephadex G-50 and starch gel electrophoresis combined with radioimmunoassay using three antisera of different specificities--(i) directed towards the NH2 terminus of pCCK33, (ii) produced by immunization with COOH-terminal fragment CCK8, (iii) produced by immunization with COOH-terminal fragment CCK4--are consistent with the hypothesis that a major fraction of big iCCK may represent intact cholecystokinin with a COOH-terminal extension, as has recently been suggested for gastrin, a molecule having a COOH-terminal pentapeptide identical with that of cholecystokinin.
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PMID:Extraction and immunochemical characterization of cholecystokinin-like peptides from pig and rat brain. 616 93

A major egg glycoprotein (MEG) was purified from a crude soluble extract of Schistosoma mansoni ova (Egyptian strain) by successive steps of lectin affinity and ion-exchange chromatography. Radioiodinated MEG exhibited a single precipitation band upon immunodiffusion against antiserum from chronically infected mice, and ran as a single band on PAGE (Rf 0.38) and SDS-PAGE (Rf 0.36). Its estimated m.w. was 70,000. The degree of stage and species specificity of MEG and the effect of various treatments on its serologic reactivity were determined by radioimmunoassay (RIA). A low degree of cross-reactivity between MEG and similarly prepared soluble antigens from adult worms and cercariae was demonstrated by RIA inhibition tests, whereas a high degree of cross-reactivity was found between MEG and a crude soluble S. haematobium egg antigen. In similar RIA inhibition tests, the Puerto Rican S. mansoni had a lower degree of cross-reactivity with S. haematobium than the Egyptian strain. MEG was four times more abundant in SEA from a Puerto Rican strain of S. mansoni than in SEA from the Egyptian strain. The serologic reactivity of MEG was stable to heat at 100 degrees C for 60 min, to 0.1 N NaOH or HCl, and to 10% TCA. Treatment of MEG with pronase caused a limited fragmentation of the molecule and some loss of its serologic reactivity. Periodate oxidation resulted in a substantial loss of molecular mass and of serologic reactivity, leaving a low residual activity that is only partially cross-reactive with the bulk of MEG. These results suggest the importance of both carbohydrate and peptide moieties of MEG for its serologic reactivity.
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PMID:Characterization of a purified glycoprotein from Schistosoma mansoni eggs: specificity, stability, and the involvement of carbohydrate and peptide moieties in its serologic activity. 617 18

Two major classes of immunoreactive cholecystokinin peptides (iCCK) have been identified in rat and pig brains: (1) large basic peptides (Big iCCK) resembling pCCK33 in size and charge; (2) small acidic peptides (Small iCCK) resembling the COOH-terminal fragments of CCK. Boiling 0.1 N HCl maximally extracts Big iCCK; boiling 0.1 N NaOH maximally extracts Small iCCK. The differences in hormonal forms removed by these extractions are not likely to be due to enzymatic conversion during the extraction procedures. Fractionation on Sephadex G50 and starch gel electrophoresis combined with radioimmunoassay using 3 antisera of different specificities: (1) directed towards the NH2-terminus of pCCK33; (2) produced by immunization with CCK8; (3) produced by immunization with CCK4; are consistent with the hypothesis that a major fraction of Big iCCK may represent intact CCK with a COOH-terminus extension as has recently been suggested for gastrin, a molecule having a COOH-terminal pentapeptide identical with that of CCK.
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PMID:Nature of immunoreactive CCK in rat and pig brain. 617 97

Administration of the antiestrogen ethamoxytriphetol (MER-25) during baboon gestation results in a marked decline in placental progesterone production. Since this effect in primates may be modulated via an estrogen receptor, the present study investigated the possible existence of an estrogen receptor in human placenta. Villous tissue of human, term placentas was homogenized in 0.01M Tris-HCl, ethylenediaminetetraacetic acid, dithiothreitol, glycerol buffer. Cytosol was incubated with 10(-8)M [3H] 17 beta-estradiol (E2) in the presence or absence of 10(-6)M diethylstilbestrol (DES). A single peak of [3H]E2 binding occurred in the 5.2 S region after glycerol density gradient centrifugation, which was competed for by DES, E2, and enclomiphene. Scatchard analysis demonstrated E2 binding, which was saturable, of high affinity (Kd = 1.90 X 10(11)M) and of low capacity (N = 0.13 X 10(-14) moles/mg cytosolic protein). Competition for [3H]E2 binding was DES greater than E2 greater than estrone greater than MER-25 greater than enclomiphene, whereas androgens, progestins, and corticosteroids were ineffective. The results fulfill the criteria for a specific estrogen receptor. The influence of antiestrogen and, possibly, estrogen upon placental function in baboons may be modulated by an estrogen receptor.
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PMID:A specific cytosolic estrogen receptor in human term placenta. 714 4

We evaluated efficacy and safety of naltrexone for antagonizing carfentanil immobilization in 12 captive Rocky Mountain elk (Cervus elaphus nelsoni) using a randomized incomplete block experiment. In three replicate trials, elk were hand-injected with 10 micrograms carfentanil citrate/kg body weight intramuscularly. Fifteen min after each elk became recumbent, we administered naltrexone HCl (25% of dose intravenously, 75% subcutaneously) dosed at 0 (control), 25, 50, or 100 mg/mg carfentanil; after an additional 15 min of immobilization, controls received 500 mg naltrexone HCl/mg carfentanil. Elk were immobilized in 34 of 36 attempts; the mean (+/-SE) induction time was 3.1 +/- 0.2 min. Regardless of dose, all elk stood < 9 min after receiving naltrexone; controls remained immobilized until they received antagonist. Mean recovery times did not differ with increasing naltrexone dose (P = 0.31) or among individuals (P = 0.16). None of the elk receiving 100 or 500 mg naltrexone/mg carfentanil renarcotized, but three of eight and seven of nine elk receiving 50 and 25 mg naltrexone/mg carfentanil, respectively, showed signs of mild renarcotization 8 to 24 hr later (P = 0.0002). We observed no adverse clinical effects in elk receiving < or = 500 mg naltrexone/mg carfentanil. Based on these data, we recommend 100 mg/mg carfentanil as a minimum effective dose for rapidly antagonizing immobilization and preventing renarcotization.
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PMID:Efficacy and safety of naltrexone hydrochloride for antagonizing carfentanil citrate immobilization in captive Rocky Mountain elk (Cervus elaphus nelsoni). 872 60

A near-infrared spectroscopic method to quantify drugs or excipients within polymeric matrixes is proposed. Cylindrical implants were fabricated by a melt-mold technique containing various ratios of poly(epsilon-caprolactone) (PCL) and poly(ethylene glycol) (PEG) and various loadings of lomefloxacin HCl with a constant ratio (70:30 w/w) of PCL/PEG. Near-infrared (NIR) spectra were obtained on intact sections of larger implants using a Foss NIRSystems Model 5000 monochrometer equipped with a Rapid Content Analyzer. Spectral data were treated with second derivative transformation followed by linear regression and PLS to obtain correlation with lomefloxacin or PEG content. Lomefloxacin content was separately determined by UV analysis (287 nm) using a validated extraction procedure. The NIR method was tested by comparing predicted loadings of test implants with either theoretical values based on weight (PEG) or with UV analysis results (lomefloxacin). Second derivative spectral values at particular wavelength ratios (PEG, 2064 nm/1698 nm; lomefloxacin, 2172 nm/2226 nm and 1824 nm/1862 nm) yielded linear results for PEG or lomefloxacin content. PEG content determined by NIR spectroscopy was in excellent agreement with theoretical content. Lomefloxacin content determined by NIR spectroscopy was also in excellent agreement with UV analysis. NIR analysis is interpreted through the use of corresponding mid-infrared spectral data.
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PMID:Diffuse reflectance near-infrared spectroscopy as a nondestructive analytical technique for polymer implants. 1058 33

An original dosage form for oral delivery based on the encapsulation of both, lipophilic and hydrophilic drugs, in poly(epsilon-caprolactone) (PCL) microparticles prepared either by the oil-in-water (o/w) or the water-in-oil-in-water (w/o/w) solvent evaporation method was developed. Microparticles were characterized in terms of morphology, size, encapsulation efficiency and drug release. The physical state of the drugs and the polymer was determined by scanning electron microscopy (SEM), X-ray powder diffractometry, and differential scanning calorimetry (DSC). Nifedipine (calcium antagonist) and propranolol HCl (beta-blocker), used for the treatment of hypertension, were chosen as lipophilic and hydrophilic drugs. The microparticles were spherical with diameters in the range of 191-351 microm by the o/w-method, and in the range of 302-477 microm by the w/o/w-method. The encapsulation efficiency (EE) was 91% for nifedipine and 37% for propranolol HCl with the o/w-method, and 83% for nifedipine and 57% for propranolol HCl with the w/o/w-method. DSC and X-ray diffraction studies showed that PCL maintained its semi-crystalline structure, while the drugs were either dispersed or dissolved in the polymer. In vitro release studies revealed a controlled release of nifedipine and propranolol HCl from microparticles prepared by the o/w-method; a burst release of propranolol HCl was observed from microparticles prepared by the w/o/w-method. In conclusion, microparticles containing both a hydrophilic and a lipophilic drug were successfully prepared.
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PMID:The preparation and evaluation of poly(epsilon-caprolactone) microparticles containing both a lipophilic and a hydrophilic drug. 1069

With the aim of developing inhibitors of EGFR tyrosine kinase, the 7-methoxymethyl-[1,4]dioxano[2,3-g]quinazolines (3a-b) and 7-mono- or di-alkylaminomethyl-[1,4]dioxano[2,3-g]quinazolines (4a-i) were prepared and evaluated for the inhibition of EGFR tyrosine kinase and the growth inhibition of human tumor cell lines. Among them, compounds 4d and 4h showed potencies against both EGFR tyrosine and the A431 cell line similar to that of PD153035 with greater aqueous solubilities of their HCl salts.
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PMID:7-Substituted-[1,4]dioxano[2,3-g]quinazolines as inhibitors of epidermal growth factor receptor kinase. 1250 97

Erlotinib HCl (Tarceva; Genentech, Inc, South San Francisco, CA) is an orally available, highly selective, reversible inhibitor of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase. Inhibition of tyrosine kinase activity prevents HER1/EGFR phosphorylation, the associated downstream signaling events, and may block tumorigenesis mediated by inappropriate HER1/EGFR signaling. In vitro and in vivo studies show that erlotinib has activity against human colorectal, head and neck, non-small cell lung, and pancreatic tumor cells. Recent preclinical studies suggest that erlotinib may also have activity against tumors that are dependent on HER2 activation for growth and/or survival. Preclinical studies have addressed the feasibility of using erlotinib in combination with various chemotherapeutic agents, radiotherapy, and targeted agents. Combining agents that have different mechanisms of action has the potential to improve efficacy and inhibit the development of resistance. For example, in preclinical studies, combining erlotinib with cisplatin, doxorubicin, gemcitabine, or low-dose paclitaxel has an additive effect on antitumor activity with no increase in toxicity. Preclinical data provide a strong rationale for investigating erlotinib in the clinical setting. However, additional studies are required to gain further insights into the processes that regulate or influence the antitumor activity of erlotinib.
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PMID:Preclinical studies with Erlotinib (Tarceva). 1284 Jul 97


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