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PubMed1981

Pharmacokinetics of theophylline in neonates.

Theophylline is a safe, effective drug for the treatment of apnea of prematurity. The pharmacokinetics of theophylline have been studied extensively in preterm neonates. There is some inter-infant variability, but generally, compared to children and adults, prolonged half-life values and low clearance rates have been found: the apparent volume of distribution is larger and protein binding of the drug is decreased. A unique pattern of metabolism involving methylation to caffeine has been identified. Theophylline maintenance dose requirements are much lower in neonates than in children. When therapy is begun, a useful guide is to give a loading dose of 5 mg/kg anhydrous theophylline followed by maintenance doses of 2 mg/kg every 12 hr. In many infants, this will suffice to prevent apnea without producing signs of toxicity. After commencement of therapy, doses must be individualized for each infant on the basis of serum theophylline concentration monitoring and monitoring for apnea. Evidence of theophylline toxicity in neonates may be subtle, and only scanty data are available regarding possible long-term effects of chronic theophylline treatment of neonates.

Apnea↗

PubMed1993

Conformation of dehydropeptides. Synthesis and solution structure of model peptides containing (E) and (Z) dehydroaminobutyric acid residues.

Six model dipeptide methylamides containing dehydroaminobutyric acid (delta Abu) of the type Boc-X-delta z Abu-NHCH3 and Box-X-delta E Abu-NHCH3, X = Ala, Val, Phe (Boc = tert-butoxycarbonyl), have been synthesized and their solution conformations explored using 300 MHz 1H NMR and IR spectroscopy. Studies based on delineation of intramolecularly hydrogen bonded NH groups in CDCl3 and (CD3)2SO revealed that none of the NH groups is appreciably solvent shielded. Difference NOE (Nuclear Overhauser Effect) studies have also failed to detect the presence of any discernible turn structure in these peptides. These studies indicate that the conformational preferences of peptides containing, alpha, beta-dehydroaminobutyric acid are different from those of delta ZPhe and delta ZLeu. It appears that steric interactions due to the beta-substituent in the dehydroamino acid moiety play an important role. Unlike delta ZPhe and delta ZLeu, which have relatively large beta-substituents, phenyl and isopropyl, respectively, and stabilize a beta-turn, the beta-methyl group of delta ZAbu or delta EAbu is readily accommodated in extended conformation. Clearly, the size of beta-substituent in dehydroamino acid crucially influences the conformational preferences. Thus, it may be possible to use different dehydroamino acids to introduce variable but definite constraints in synthetic peptides.

Dipeptides↗

PubMed1999

Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes.

The oxidative metabolism of irbesartan, a new nonpeptide angiotensin II receptor antagonist, was investigated on 12 human fully characterized hepatic microsomes and purified cytochrome P-450 (CYP) isoforms. After incubation of microsomes with irbesartan and NADPH, four main hydroxy metabolites were formed, as confirmed by liquid chromatography-mass spectrometry analysis. Irbesartan oxidation follows Michaelis-Menten kinetics, consistent with the involvement of a single CYP isoform in these hydroxylation processes. Only a low interindividual variability (2-fold difference) was observed in drug oxidation, even in preparations lacking CYP2D6. Km and Vmax for irbesartan oxidation were 54 +/- 6.5 microM and 0.62 +/- 0.18 nmol/min/mg, respectively. Irbesartan oxidation correlated (r2 = 0. 769) with tolbutamide (CYP2C9 substrate) 4-methyl-hydroxylation. Oxidation of irbesartan was markedly inhibited by sulfaphenazole (CYP2C9 inhibitor), but not by any of several other CYP inhibitors. In the same manner, both tolbutamide and warfarin (CYP2C9 substrates), were competitive-type inhibitors of irbesartan oxidation with Ki values of 500 and 30 microM, respectively. Moreover, irbesartan was a competitive-type inhibitor of tolbutamide 4-methylhydroxylation (Ki = 317 microM). Nifedipine also potentially decreased irbesartan oxidation, whereas neither ketoconazole and triacetyloleandomycin (CYP3A inhibitors), nor diltiazem and verapamil, (CYP3A4 substrates), exhibited an inhibitory effect. Additional studies demonstrated that nifedipine was an inhibitor of irbesartan (Ki = 20 microM) and tolbutamide oxidation processes, whereas irbesartan had no effect at all on nifedipine dehydrogenation. Enzyme kinetics suggest that nifedipine is a noncompetitive-type inhibitor of CYP2C9-mediated catalytic activities. Finally, only microsomes containing recombinant human liver CYP2C9 were capable of oxidizing irbesartan. These results provide evidence that CYP2C9 plays a major role in irbesartan oxidation.

Adult↗

PubMed2000

Hepatic disposition of neurotoxins and pesticides.

The hepatic disposition of pesticides and neurotoxins may influence susceptibility to Parkinson's disease. Therefore we examined the behaviour of paraquat, dichlorodiphenyltrichloroethane (DDT), malathion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in perfused rat liver using the multiple indicator-dilution technique. The values for the recovery of paraquat, DDT, malathion and MPTP were 1.05+/-0.12, 0.32+/-0.01, 0.11+/-0.02 and 0.02+/-0.01, respectively. The volumes of distribution were 0.28+/-0.13, 0.69+/-0.12, 3.30+/-0.58 and 5.10+/-6.00 ml/g, respectively. The permeability-surface area products suggest that transport of DDT and MPTP across cell membranes is by simple diffusion. However, there may be a specific influx mechanism for malathion and a specific efflux mechanism for paraquat. There is considerable variability in the hepatic disposition of putative neurotoxins such as MPTP and pesticides. Factors that influence the hepatic disposition of neurotoxins may alter susceptibility to neurotoxic diseases however the effects will be diverse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

Improving the sensitivity and dynamic range of reagentless fluorescent immunosensors by knowledge-based design.

The variable fragment (Fv) of an antibody can be transformed into a reagentless fluorescent biosensor by mutating a residue into a cysteine in the neighborhood of the paratope (antigen-binding site) and then coupling an environment-sensitive fluorophore, e.g., N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole (IANBD ester), to the mutant cysteine. For some residues, named operational, the formation of the conjugate does not affect the affinity of the Fv fragment for the antigen, and the binding of the antigen generates a measurable variation in the fluorescence intensity of the conjugate. We tested if this signal variation could be increased by coupling several molecules of fluorophores to the same molecule of Fv. Seven operational residues have been previously identified in the single-chain Fv (scFv) of monoclonal antibody D1.3 (mAbD1.3), directed against lysozyme. Ten double mutants of scFvD1.3, involving these residues, were constructed and coupled to the IANBD ester. The fluorescence of the double conjugates revealed a transfer of resonance energy between the two identical fluorescent groups. This homotranfer could be more important in the free state of the conjugate than in its antigen-bound state and increase its sensitivity for the detection of the antigen by up to 2.9-fold. A poorly sensitive conjugate could be improved by coupling a second molecule of fluorophore to residues located far from the paratope. Mutations altering the affinity of scFvD1.3 for lysozyme were introduced into one of its fluorescent conjugates. Using a mixture of three mutant derivatives of this unique conjugate, we could titrate lysozyme with precision in a concentration range encompassing 3 orders of magnitude.

Binding Sites↗

PubMed1981

Four positional isomers of sialyloligosaccharides isolated from the urine of a patient with sialidosis.

Four positional isomers of sialyloligosaccharides were isolated from the urine of an adult patient with sialidosis with partial deficiency of beta-galactosidase. From structural studies including compositional sugar analysis, exoglycosidase digestion, chemical ionization mass spectrometry, proton nuclear magnetic resonance spectrometry, and methylation analysis, their structures were deduced to be as follows: 1. AcNeu alpha 2 leads to 3 Gal beta 1 leads to 4GlcNac beta 1 leads to 2Man alpha 1 leads to 3Man beta 1 leads to 4GlcNac 2. AcNeu alpha 2 leads to 3Gal beta 1 leads to 4GlcNac beta 1 leads to 2Man alpha 1 leads to 6Man beta 1 leads to 4GlcNac 3. AcNeu alpha 2 leads to 6Gal beta 1 leads to 4GlcNac beta 1 leads to 2Man alpha 1 leads to 3Man beta 1 leads to 4GlcNac 4. AcNeu alpha 2 leads to 6Gal beta 1 leads to 4GlcNac beta 1 leads to 2Man alpha 1 leads to 6Man beta 1 leads to 4GlcNac Sialyloligosaccharides 1 and 3 have previously been found in the liver and urine of patients with mucolipidosis I, II, and variable forms, but sialyloligosaccharides 2 and 4 have not previously be found in human urine.

Carbohydrate Conformation↗

PubMed2005

Cell cycle analysis of Taxus suspension cultures at the single cell level as an indicator of culture heterogeneity.

Single cell growth and division was measured via flow cytometry in order to characterize the metabolic variability of Taxus cuspidata suspension cultures, which produce the valuable secondary metabolite Taxol. Good agreement was observed between the cell cycle distribution and biomass accumulation over the batch culture period. Specific growth rates of 0.13 days(-1) by fresh weight and 0.15 days(-1) by dry weight were measured. Elicitation with methyl jasmonate (MJ) significantly decreased both cell cycle progression and biomass accumulation, as the specific growth rate decreased to 0.027 days(-1) by fresh and dry weight. Despite the decrease in biomass accumulation for MJ elicited cultures, sucrose utilization was not significantly different from control cultures. MJ elicitation also increased the accumulation of paclitaxel and other taxanes. The accumulation of upstream taxanes (baccatin III and 10-deactylbaccatin III) increased during exponential growth, reached a maximum around day 12, and then declined throughout the stationary phase. The paclitaxel concentration increased during both exponential growth and stationary phase, reaching a maximum around days 20-25. Throughout the culture period, greater than 70% of the cells were in G(0)/G(1) phase of the cell cycle. Studies using bromodeoxyuridine (BrdU) incorporation showed that approximately 65% of the Taxus cells are noncycling, even during exponential growth. Although the role of these cells is currently unknown, the presence of a large, noncycling subpopulation can have a significant impact on the utilization of plant cell culture technology for the large-scale production of paclitaxel. These results demonstrate that there is a high degree of metabolic heterogeneity in Taxus cuspidata suspension cultures. Understanding this heterogeneity is important for the optimization of plant cell cultures, particularly the reduction of production variability.

Bromodeoxyuridine↗

PubMed2005

Long-term potentiation of exogenous glutamate responses at single dendritic spines.

Long-term increases in the strength of excitatory transmission at Schaffer collateral-CA1 cell synapses of the hippocampus require the insertion of new alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) into the synapse, but the kinetics of this process are not well established. Using microphotolysis of caged glutamate to activate receptors at single dendritic spines in hippocampal CA1 cells, we report the long-lasting potentiation of AMPAR-mediated currents with only a single pairing of photoreleased glutamate and brief postsynaptic depolarization. This potentiation was N-methyl-d-aspartate receptor (NMDAR)-dependent and was reversed with low-frequency photostimulation in an NMDAR-dependent manner, suggesting that it is mediated by the same mechanism(s) as conventional synaptic long-term potentiation. Potentiation of photolytic responses developed rapidly in a stepwise manner after a brief and variable delay (<60 s) at spines, but could not be induced at extrasynaptic sites on the dendritic shaft. Potentiation was accompanied by a concomitant decrease in postsynaptic, polyamine-dependent paired-pulse facilitation of the photolytic currents, indicating that a change in the subunit composition of the AMPARs underlying the response contributed to the potentiation. These changes are consistent with an increase in the proportion of GluR2-containing AMPARs in the spine head. These results demonstrate that activation of postsynaptic glutamate receptors by glutamate is not only necessary, but sufficient, for the induction of NMDAR-dependent long-term potentiation and reveal additional aspects of its expression.

Animals↗

PubMed1992

Rearrangement and expression of immunoglobulin genes in transgenic mice.

Transgenic mice are discussed which carry a rearrangement test transgene. The methylation status of the transgene varies, depending on the background mouse strain. When the transgene is bred into the C57BL/6 strain, it is completely methylated and not rearranged in lymphoid organs. After several generations of crossing into DBA/2 or SJL the transgene becomes unmethylated and rearranges at high frequency. A strain specific modifier of DNA methylation (Ssm-1) was mapped close to the Friend virus susceptibility locus (Fv-1) on mouse chromosome 4. Rearranged transgenes from spleen, bone marrow and thymus of adult mice or fetal liver were cloned and sequenced. A great variety of joints was found, with about 1/3 being in the correct reading frame. Small deletions into the V- and J-coding ends as well as N region additions contributed to the variability. The fetal joints showed no N regions. Since no functional immunoglobulin (Ig) gene can be created from this artificial test gene, the data indicate that the rearrangement mechanism of the fetus differs from that of the adult.

Animals↗

PubMed2002

Facilitation at single synapses probed with optical quantal analysis.

Many synapses can change their strength rapidly in a use-dependent manner, but the mechanisms of such short-term plasticity remain unknown. To understand these mechanisms, measurements of neurotransmitter release at single synapses are required. We probed transmitter release by imaging transient increases in [Ca(2+)] mediated by synaptic N-methyl-D-aspartate receptors (NMDARs) in individual dendritic spines of CA1 pyramidal neurons in rat brain slices, enabling quantal analysis at single synapses. We found that changes in release probability, produced by paired-pulse facilitation (PPF) or by manipulation of presynaptic adenosine receptors, were associated with changes in glutamate concentration in the synaptic cleft, indicating that single synapses can release a variable amount of glutamate per action potential. The relationship between release probability and response size is consistent with a binomial model of vesicle release with several (>5) independent release sites per active zone, suggesting that multivesicular release contributes to facilitation at these synapses.

2-Chloroadenosine↗

PubMed2003

Methyl parathion toxicity in vegetated and nonvegetated wetland mesocosms.

Methyl parathion (MeP) was introduced into constructed wetlands for the purpose of assessing the influence of emergent vegetation on transport and toxicity of the pesticide. Two vegetated (90% cover, mainly Juncus effusus) and two nonvegetated wetland cells (each with a water body of 50 x 5.5 x 0.2 m) were each dosed with 6.5 m3 of water containing active ingredient of MeP at 6.6 mg/L associated with suspended soil at 400 mg/L to simulate a storm runoff event. Acute toxicity was assessed by sampling benthic macroinvertebrates at 5, 10, 20, and 40 m from the inlet before and 96 h after contamination and by in situ exposure of Chironomus tentans (Diptera) up to 24 h after contamination. Methyl parathion was detected throughout the nonvegetated wetland cells (70 microg/L at 20 m, 8 microg/L at 40 m), whereas the pesticide was not transported through the vegetated wetland cells (20 microg/L at 20 m, < 0.1 microg/L at 40 m). A three-way analysis of variance using contamination (repeated measure variable), location, and vegetation indicated significant negative effects of contamination on various insect taxa, such as mayfly nymphs and caddisfly larvae. Seven out of the total of 15 species revealed a significant contamination x vegetation effect, with individuals in the vegetated wetlands being less affected. Four species showed a significant contamination x location effect, confirming a higher toxicity in the inlet area of the wetlands. A significant three-way interaction of contamination x vegetation x location was detected in Chironomus sp., which was most strongly affected at the inlet area of the nonvegetated wetland cells. The in situ bioassay employing C. tentans confirmed the positive effect of wetland vegetation on MeP toxicity. These results demonstrate the importance of vegetation for pesticide mitigation in constructed wetlands.

Analysis of Variance↗

PubMed1999

Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A.

BACKGROUND: Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability, and an in vivo probe to measure such differences would serve several purposes. The erythromycin breath test (ERBT) is an established approach that has proven useful in this regard, but it has several limitations. More recently, the hydroxylation of midazolam has been suggested as an alternative in vivo probe approach, because it is possible to estimate CYP3A activity in the intestinal epithelium as well as in the liver. The purpose of this study was to investigate the relationship, if any, between the ERBT and midazolam's CYP3A-mediated metabolism. METHODS: Twenty healthy, medication-free young (24 to 46 years) European Americans (10 women) each received on separate days, in random order, either 3 microCi [14C-N-methyl]-erythromycin intravenously, 1 mg midazolam intravenously, or 2 mg midazolam orally. An ERBT value was determined 60 minutes after administration, and clearances were estimated after midazolam administration. In addition, an endogenous 0- to 4-hour urinary 6beta-hydroxycortisol/cortisol ratio was measured. RESULTS: All three measured drug trait values varied approximately threefold to fivefold, whereas the endogenous phenotype measure exhibited far greater variability (>100-fold). No statistically significant (P < .05) correlations existed between any of the trait values, including the ERBT value, obtained after intravenous administration of the radiolabeled probe and the systemic clearance of midazolam, expressed in terms of either total or unbound drug, or on an absolute or a body weight-corrected basis (r = 0.03 to r = 0.24; P = .08 to P = .90). Substratification according to sex generally did not improve such relationships. CONCLUSION: Although both erythromycin N-demethylation and the metabolism of midazolam by hydroxylation are mediated by CYP3A, the phenotypic trait measures associated with these two in vivo probe drugs do not provide the same information about the catalytic activity of the enzyme. An indirect measure such as the ERBT may reflect CYP3A activity and be useful for some purposes, but the estimation of the oral and intravenous clearance of midazolam has additional advantages, and they may be more applicable and have broader usefulness as quantitative estimates of CYP3A activity.

Adult↗

PubMed1977

S-adenosylmethionine: protein-arginine methyltransferase. Purification and mechanism of the enzyme.

Protein methylase I (S-adenosylmethionine: protein-arginine methyltransferase, EC 2.1.1.23) has been purified from calf brain approximately 120-fold with a 14% yield. The final preparation is completely free of any other protein-specific methyltransferases and endogenous substrate protein. The enzyme has an optimum pH of 7.2 and pI value of 5.1. The Km values for S-adenosyl-L-methionine, histone H4, and an ancephalitogenic basic protein are 7.6 X 10(-6), 2.5 X 10(-5), and 7.1 X 10(-5) M, respectively, and the Ki value for S-adenosyl-L-homocysteine is 2.62 X 10(-6) M. The enzyme is highly specific for the arginine residues of protein, and the end products after hydrolysis of the methylated protein are NG,NG-di(asymmetric), NG,N'G-di(symmetric), and NG-monomethylarginine. The ratio of [14C]methyl incorporation into these derivatives by enzyme preparation at varying stages of purification remains unchanged at 40:5:55, strongly indicating that a single enzyme is involved in the synthesis of the three arginine derivatives. The kinetic mechanism of the protein methylase I reaction was studied with the purified enzyme. Initial velocity patterns converging at a point on the extended axis of abscissas were obtained with either histone H4 or S-adenosyl-L-methionine as the varied substrate. Product inhibition by S-adenosyl-L-homocysteine with S-adenosyl-L-methionine as the varied substrate was competitive regardless of whether or not the enzyme was saturated with histone H4. On the other hand, when histone H4 is the variable substrate, noncompetitive inhibition was obtained with S-adenosyl-L-homocysteine under conditions where the enzyme is not saturated with the other substrate, S-adenosyl-L-methionine. These results suggest that the mechanism of the protein methylase I reaction is a Sequential Ordered Bi Bi mechanism with S-adenosyl-L-methionine as the first substrate, histone H4 as the second substrate, methylated histone H4 as the first product, and S-adenosyl-L-homocysteine as the second product released.

Animals↗

PubMed1996

Cardiovascular and respiratory actions of U50,488H in the unanaesthetized ovine foetus.

In an effort to evaluate the feasibility of kappa-opioid receptor agonists for use in pregnancy, we have investigated the actions of U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide) on cardiovascular and respiratory control in the unanaesthetized ovine foetus. Intravenous administration of U50,488H (1.0 mg/kg) to the foetus resulted in an immediate increase in foetal blood pressure (P < 0.0001) and heart rate (P < 0.0001) which lasted 15 min, followed by a prolonged loss of heart rate variability for up to 3 h. There was also a significant suppression of foetal breathing movements for 2-3 h (P < 0.008). Pretreatment with naloxone (12 mg/h) completely blocked the hypertensive and tachycardiac response to U50,488H, but was unable to prevent the loss of variation in heart rate or respiratory depression. These data suggest that U50,488H can exert direct cardiovascular and respiratory actions in the ovine foetus via both opioid and non-opioid mechanisms. The naloxone-insensitive suppression of foetal breathing would severely limit the use of U50,488H as an obstetrical analgesic.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2003

Positive allosteric modulator of the human 5-HT2C receptor.

The human 5-hydroxytryptamine-2C (5-HT2C) receptor has been the target of potential anxiolytics and antiobesity drugs, and its positive allosteric modulator was discovered to be l-threo-alpha-d-galacto-octopyranoside, methyl-7-chloro-6,7,8-trideoxy-6-[[(4-undecyl-2-piperidinyl)carbonyl]amino]-1-thiomonohydrochloride (2S-cis) (PNU-69176E). The drug at low micromolar concentrations (<25 microM) markedly enhanced [3H]5-HT binding (more than 300%) by increasing its affinity for low-affinity sites but with no appreciable effect on antagonist ([3H]mesulergine) binding. Functionally, PNU-69176E alone rendered receptors constitutively active, producing the pheno-types of 5-HT-activated receptors, as measured with mesulergine-sensitive guanosine 5'-O-(3-[35S]thio)triphosphate binding, transient inositol 1,4,5-triphosphate release, and [3H]inositol phosphate accumulation. These actions of PNU-69176E were observed with the human 5-HT2C receptor expressed in several mammalian cell lines (human embryonic kidney 293, NIH3T3, and SH-EP) at variable receptor densities (6 to 45 pmol/mg of protein), but not with analogous 5-HT and dopamine receptors (human 5-HT2A, 5-HT2B, 5-HT6, 5-HT7, and dopamine D2-long and D3 receptors). Structurally, PNU-69176E consists of a long alkyl chain and a polar moiety, including the alpha-d-galactopyranoside. Its analogs with shorter alkyl chains (methyl to n-hexyl instead of n-undecyl group) failed to enhance [3H]5-HT binding, and also long alkyl amides are without allosteric modulation. We propose that PNU-69176E may represent a new class of membrane receptor modulators, which probably need a long alkyl chain as a membrane anchor and target a selective polar head group to receptor modulatory sites near the membrane surface.

Allosteric Regulation↗

PubMed1995

Excitatory amino acids in health and disease.

PURPOSE: To review the role of excitatory neurotransmitters in normal mammalian brain function, the concept of excitotoxic neuronal death as an important final common path in a variety of diseases, and modification of excitatory synaptic transmission as an important new pharmacological principle. These principles are discussed, with special emphasis on diseases of importance to older adults. DATA SOURCES: A MEDLINE search from 1966 to May 1995 was undertaken, as well as a manual search of current issues of clinical and basic neuroscience journals, for articles that addressed glutamate N-methyl-D-aspartate and/or excitotoxicity. STUDY SELECTION: A total of 5398 original and 68 review articles were identified that addressed animal and human experimentation relevant to excitotoxic neuronal death. There were 364 articles with potential significance for clinical application identified; 132 of the most recent references are provided. DATA EXTRACTION: All articles were classified into three categories: general receptor, biology pathogenesis of disease, and pharmacotherapy. RESULTS: Glutamic and aspartic acids are the physiological mediators of most excitatory synaptic transmission. This is critical to several normal nervous system functions, including memory and long-term modification of synaptic transmission and nociception. Activation of the inotropic NMDA and non-NMDA receptors increases transmembrane calcium and sodium fluxes, and the metabotropic glutamate receptor activation results in generation of inositol triphosphate and inhibition of adenylate cyclase. Numerous modulatory sites exist, especially on the NMDA receptor. Nitric oxide, arachidonic acid, superoxide, and intracellular calcium overload are the ultimate mediators of neuronal death. Glutamate re-uptake transporters belong to a unique family of amino acid transport systems, the malfunction of which is intricately involved in disease pathogenesis. Ischemic stroke, hypoglycemia, Parkinson's disease, alcohol intoxication and withdrawal, Alzheimer's disease, epilepsy, and chronic pain syndromes are only some of the important clinical neurological disorders with a major pathogenic role for the excitatory amino acids. CONCLUSIONS: Pharmacological manipulation of the excitatory amino acid receptors is likely to be of benefit in important and common diseases of the nervous system. Only a few of the currently available drugs that modify excitatory neurotransmission, such as remacemide, lamotrigine, and tizanidine, have an acceptable therapeutic index. The identification of numerous receptor subtypes, topographic variabilities of distribution, and multiple modulatory sites will provide a true challenge to the neuropharmacologist.

Aged↗

PubMed1997

Altered consciousness states and endogenous psychoses: a common molecular pathway?

Interest in the role of indolamines in the pathogenesis of psychoses has been renewed in recent years by the development of atypical antipsychotic drugs such as clozapine, olanzapine, and risperidone, which act on serotonin receptors. Discovery of the hallucinogenic compounds called methylated indolealkyalamines (MIAs) (e.g. N,N-dimethylserotonin, or bufotenin, and N,N-dimethyltryptamine, or DMT) led proponents of the transmethylation hypothesis of schizophrenia to theorize that through some inborn error of metabolism, serotonin or tryptamine might undergo the addition of extra methyl radicals, thereby forming MIAs with hallucinogenic properties. Various studies have attempted to detect the excretion of MIAs, especially DMT, in the body fluids of psychotic patients and normal controls. Some of these studies have demonstrated elevated MIA concentrations in psychotic patients, including those with schizophrenia, compared with normal persons, and others have not. A number of variables may account for these contradictory findings. The mechanism whereby the beverage ayahuasca, which is used in certain cure and divination rituals in the Amazon Basin, exerts its hallucinogenic effects may serve as a model to explain the mechanism underlying hallucinogenic symptoms in schizophrenia and may lend support to the transmethylation hypothesis. Certain studies suggest that specific perceptual disturbances manifested by schizophrenic patients could contribute to progressive deterioration and negative symptomatology. All these findings point to the need for further study of the neurophysiology of MIAs and their pathogenetic role in endogenous psychoses.

Consciousness↗

PubMed2005

Skewed X inactivation of the normal allele in fully mutated female carriers determines the levels of FMRP in blood and the fragile X phenotype.

BACKGROUND: The variable phenotype in female carriers of a full mutation is explained in part by non-random X-chromosome inactivation. The molecular diagnosis of fragile X syndrome is based on the resolution of the number of CGG triplet repeats and the methylation status of a critical CpG in the fragile X mental retardation gene (FMR1) promoter. Neighboring CpGs in the FMR1 promoter are supposed to be equally methylated or unmethylated. METHOD: Southern blot analysis was performed with double digestion, either with EcoRI/EagI or with HindIII/SacII. The EagI restriction site was studied by sequencing. The fragile X encoded protein (FMRP) was detected in white blood cells by Western blot. The fragile X phenotype was evaluated by specific clinical examinations. RESULTS: Within one family we found three female carriers of a full mutation and a different degree of methylation of the normal allele that correlated with the levels of FMRP in blood and the fragile X phenotype. Complete methylation at the EagI CpG target (but partially methylated SacII CpG site) was associated with extremely skewed X inactivation (confirmed by analysis of the methylation status at the PGK locus), undetectable FMRP in blood, and a male-like phenotype. CONCLUSIONS: In fully mutated female carriers the methylation status at the EagI restriction site correlates with the levels of FMRP in blood and the fragile X phenotype. Neighboring CpG sequences in the FMR1 promoter can be differentially methylated, which should be taken into consideration for molecular diagnosis.

Alleles↗