SEARCH · PubMed Health

Results for “variable methylation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,243 records · Page 69Linked to original sources

PubMed2004

Identification and occurrence of tryptamine- and tryptophan-derived tetrahydro-beta-carbolines in commercial sausages.

The identification and occurrence of tetrahydro-beta-carbolines were studied in different kinds of commercial sausages including cooked, fresh, dry-fermented, and ripened sausages, such as salamis and Spanish chorizo, salchichon, fuet, and morcilla, both smoked and unsmoked. Four compounds were identified in several sausages by high-performance liquid chromatography-mass spectrometry (HPLC-MS): 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1), 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid diastereoisomers (2a,b), 1,2,3,4-tetrahydro-beta-carboline (3), and 1-methyl-1,2,3,4-tetrahydro-beta-carboline (4). The latter two (3 and 4) are now reported for the first time in meat products. The presence and occurrence of tetrahydro-beta-carbolines were highly variable depending on each particular sample of sausage, and it did not follow a single specific pattern. The concentration range taken as a sum of the four carbolines varied from undetectable levels to 33 microg/g, with the highest content found in ripened, dry-fermented, and smoked sausages (salami, chorizo, and morcilla) and the lowest in cooked sausages (Frankfurt). Formation of tetrahydro-beta-carbolines might occur during elaboration and the ripening process from a chemical condensation between tryptophan or tryptamine and aldehydes (formaldehyde and acetaldehyde). Smoked samples had higher concentrations of formaldehyde-derived 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1) and 1,2,3,4-tetrahydro-beta-carboline (tryptoline) (3) than those unsmoked. Also, 1 and 3 were more concentrated in the outer part of the sausage, likely to be in contact with smoke. It is concluded that some dry-fermented and/or smoked sausages may be significant dietary sources of tetrahydro-beta-carbolines.

Aldehydes↗

PubMed2006

MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease.

Germline MLH1 and MSH2 mutations are scarce in young colorectal cancer patients with negative family history of the disease. To evaluate the contribution of germline MSH6 mutations to early-onset colorectal cancer, we have analysed peripheral blood of 38 patients diagnosed with this disease before 45 years of age and who presented no family history of hereditary nonpolyposis colorectal cancer-related cancers. Blood samples from 108 healthy volunteers were analysed for those genetic alterations suspected to affect the function of MSH6. Of the seven (18.4%) MSH6 alterations found, we have identified three novel germline mutations, one 8 bp deletion leading to a truncated protein and two missense mutations resulting in the substitution of amino acids belonging to different polarity groups. High-frequency microsatellite instability was found in the patient with the MSH6 deletion, but not in the other 27 carcinomas analysed. No MLH1 promoter methylation was detected in tumour tissue. Our findings suggest that germline MSH6 mutations contribute to a subset of early-onset colorectal cancer. Further studies are warranted to understand the genetic and environmental factors responsible for the variable penetration of MSH6 germline mutations, as well as to identify other causes of early-onset colorectal cancer.

Adolescent↗

PubMed2003

Strain-specific brain metallothionein II (MT-II) gene expression, its ethanol responsiveness, and association with ethanol preference in mice.

BACKGROUND: Metallothioneins (MTs) are ubiquitously expressed intracellular proteins that bind heavy metals such as zinc, copper, and cadmium. Although their specific function has yet to be discovered, they are known to regulate the metabolism of these metals as well as respond to cellular stress agents, particularly oxidants. METHODS: Brain RNA from experimental (8 g/kg 25% ethanol injection) and control (saline injection) mice from four strains (A/J, BALB/cJ, C57BL/6J, DBA/2J) that are known to differ with respect to ethanol preference was used in differential displays. This report includes molecular results on one gene (MT-II) identified. RESULTS: Our results on differential displays suggest that a proportion of genes are differentially expressed across pair-wise strain comparisons. We identified MT-II as a strain-specific and ethanol-responsive gene. The level of MT-II messenger RNA (mRNA) in control mice of A/J, BALB/cJ, C57BL/6J, and DBA/2J strains was variable (0.50, 0.51, 0.90, and 0.14 times G3PDH expression, respectively). The degree of up-regulation in experimental mice was also somewhat variable among strains, ranging from 2.5 to 3.2 times expression over the matched controls. Experiments indicate that the promoter and genomic organization of the MT-II gene is identical in sequence for all four strains, and methylation studies revealed that the MT-II promoter region is unmethylated in the brains of these mice. Interestingly, MT-II expression in control mice demonstrated a positive correlation with the ethanol preference phenotype. CONCLUSION: An increase in MT-II mRNA levels after injection of ethanol is attributed to the antioxidant properties of MT-II. The differential mRNA levels of this gene among four strains are not accounted for by the genomic organization, DNA sequence, or methylation status of this gene. Furthermore, the observed correlation between MT-II mRNA levels and ethanol preference raises an interesting hypothesis about the possible role of MT-II in ethanol effects and preference in mice.

Alcohol Drinking↗

PubMed2000

Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents.

Recently, selective and systemically active antagonists for the metabotropic glutamate 5 receptor (mGlu(5)) were discovered, and the most potent derivative was found to be MPEP (2-methyl-6-(phenylethynyl)pyridine). Given the high expression of mGlu(5) receptors in limbic forebrain regions, it was decided to evaluate the anxiolytic potential of MPEP. After an acute oral administration, MPEP attenuated the anxiety-dependent variable in a variety of well established anxiety test paradigms. In rats, MPEP (10, 30, and 100 mg/kg) increased punished responses in the Geller-Seifter test, but none of these effects reached statistical significance. MPEP significantly increased the ratio (open/total arm entries; 0.1, 1, and 10 mg/kg), the number of open arm entries (0.1, 1, and 10 mg/kg), as well as time spent on open arm (0.1 and 1 mg/kg) in the elevated plus maze test. Furthermore, MPEP (0.3 and 1 mg/kg) significantly increased the time spent in social contact in the social exploration test. In mice, MPEP attenuated stress-induced hyperthermia (15 and 30 mg/kg) and decreased the number of buried marbles in the marble burying test (7.5 and 30 mg/kg). Finally, MPEP (0.01, 0.1, 1, 10, and 100 mg/kg) was tested on spontaneous locomotor activity in mice, and only a dose of 100 mg/kg significantly reduced vertical activity; no effect was seen on horizontal activity. MPEP (7.5, 15, and 30 mg/kg) was ineffective on d-amphetamine-induced (2.5 mg/kg) locomotor activity in mice and prepulse inhibition in rats (1, 3, or 10 mg/kg). Thus, these findings indicate that MPEP exhibits anxiolytic-like effects and low risks for sedation and psychotomimetic side-effects in rodents.

Animals↗

PubMed1975

Comprehensive evaluation of fatty acids in foods. I. Dairy products.

A thorough search of the post-1960 world's literature has produced a voluminous amount of information of the fatty acid content of milk fat. The composition and quantity of fat in cow's milk are affected by many variables, including breed, nutrition, stage of lactation, and season. Seasonal fluctuation in fatty acid content was considered in compiling data. Data were evaluated with reference to adequacy of esterification procedure and gas chromatographic analysis. Techniques for converting methyl ester data to a form suitable for food table use are illustrated. The detailed fatty acid profile of milk fat derived through the current study is presented. Reliable and up-to-date tables of fatty acids in dairy and selected non-milk fat products are provided for the use of dieticians, nutritionists, and workers in food technology and related fields.

Animals↗

PubMedDate not supplied

[Impregnation and liberation of nicotine with hydrogen copolymer discs].

Reticulated copolymers with products N-vinyl-2 pyrrolidone (NVP), hydroxy-2 ethyl (HEMA) and methyl methacrylate (MMA) were realized in disc form. Nicotine was used as active principle. On these discs the following study was carried out: permeation, percentage of liquid absorbed, texture, as well as nicotine release kinetics. A 2-variable (NVP and HEMA/MMA), 5-level experimental plan has enabled the outlining of the significant differences on the action of these parameters. The release kinetics show particularly that these discs behave as forms of prolonged released and that the released quantities are sufficient to envisage the use of these reticulated copolymers within the framework of a transdermal system.

Administration, Cutaneous↗

PubMed2002

The prediction of defibrillation outcome using a new combination of mean frequency and amplitude in porcine models of cardiac arrest.

UNLABELLED: We estimated the predictive power with respect to defibrillation outcome of ventricular fibrillation (VF) mean frequency (FREQ), mean peak-to-trough amplitude (AMPL), and their combination. We examined VF electrocardiogram signals of 64 pigs from 4 different cardiac arrest models with different durations of untreated VF, different durations of cardiopulmonary resuscitation, and use of different drugs (epinephrine, vasopressin, N-nitro-L-arginine methyl ester, or saline placebo). The frequency domain was restricted to the range from 4.33 to 30 Hz. In the 10-s epoch between 20 and 10 s before the first defibrillation shock, FREQ and AMPL were estimated. We introduced the survival index (SI; 0.68 Hz(-1). FREQ + 12.69 mV(-1). AMPL) by use of multiple logistic regression. Kruskal-Wallis nonparametric one-way analysis was used to analyze the different porcine models for significant difference. The variables FREQ, AMPL, and SI were compared with defibrillation outcome by means of univariate logistic regression and receiver operating characteristic curves. SI increased predictive power compared with AMPL or FREQ alone, resulting in 89% sensitivity and 86% specificity. The probabilities of predicting defibrillation outcome for FREQ, AMPL, and SI were 0.85, 0.89 and 0.90, respectively. FREQ, AMPL, and SI values were not sensitive in regard to the four different cardiac arrest models but were significantly different for vasopressin and epinephrine animals. IMPLICATIONS: We present a retrospective data analysis to evaluate the predictive power of different ventricular fibrillation electrocardiogram variables in pigs with respect to defibrillation outcome. We showed that our combination of variables leads to an improved forecast, which may help to reduce harmful unsuccessful defibrillation attempts.

Algorithms↗

PubMed1987

DNA repair synthesis in fibroblast strains from patients with actinic keratosis, squamous cell carcinoma, basal cell carcinoma, or malignant melanoma after treatment with ultraviolet light, N-acetoxy-2-acetyl-aminofluorene, methyl methanesulfonate, and N-methyl-N-nitrosourea.

Fibroblast strains derived from skin biopsies of patients with actinic keratosis (6), malignant melanoma (18), squamous cell carcinoma (11), and basal cell carcinoma (12) were investigated for DNA repair synthesis, with 16 fibroblast strains for normal donors as controls. Cells were exposed to UV light, the "UV-like" carcinogen (Ac)2ONFln, and the methylating carcinogens MeSO2OMe and MeNOUr. Dose-response experiments, which included 10 dose levels, were performed, the data analyzed by linear regression, and the slope of the regression line (term: G0) used as a measure of DNA repair synthesis. The mean experimental variability of G0 of individual fibroblast strains was 9.5%-15.4%, depending upon exposure. For comparison of all cell strains belonging to the same skin malignancy group with those of the control group, G0 values of the individual strains were combined to yield group-specific weighted mean G0 values. In addition, the capacity to incise UV-damaged DNA was measured in 24 cell strains from patients with skin tumors using the alkaline elution technique. For quantitating DNA-incising capacity, the initial velocities of the elution curves were plotted versus the UV dose, and the slope of the resulting regression line was used to obtain the characteristic value E0. The mean experimental variability of E0 of individual strains was +/- 22%. These E0 values were combined to yield weighted mean values of groups. The fibroblast strains in the groups of patients with actinic keratosis and malignant melanoma were found to have normal mean G0 values when DNA repair synthesis was challenged with UV light or one of the three carcinogens. However, the squamous cell carcinoma group exhibited significantly lower mean G0 values after treatment with UV light (82% that of normal donors), (Ac)2ONFln (70%), MeSO2OMe (70%), and MeNOUr (69%). The basal cell carcinoma group showed significantly diminished repair synthesis upon treatment with UV light (81% that of normal donors) and MeSO2OMe (67%). In contrast to these findings, in no skin malignancy group was post UV DNA-incising capacity (E0) significantly diminished, although it should be noted that group sizes were only half as large as for G0 determinations. These data may be interpreted as indicating that DNA excision repair is impaired in fibroblast strains from patients with squamous cell carcinoma and-to a lesser extent-basal cell carcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetoxyacetylaminofluorene↗

PubMed2026

DNA methylation biomarkers for early detection of ovarian cancer.

Ovarian cancer (OC) remains difficult to detect at an early stage, and current screening approaches using CA125 and transvaginal ultrasonography have not demonstrated sufficient benefit for population screening. DNA methylation is a promising biomarker class because epigenetic alterations may arise early in tumourigenesis, can be detected in circulating cell-free DNA (cfDNA), and may provide tissue-of-origin information. This review critically evaluates recent evidence on DNA methylation biomarkers for early OC detection. PubMed/MEDLINE, Web of Science, and Scopus were searched for studies published between January 2020 and September 2025, supplemented by selected earlier studies of biological or methodological relevance. Evidence was synthesised across single-gene biomarkers, multi-locus panels, genome-wide signatures, assay platforms, and machine-learning classifiers, with emphasis on early-stage performance, histological representation, comparator populations, analytical methodology, and validation design. Single-gene markers such as BRCA1, RASSF1A, OPCML, HOXA9, and HIC1 show variable performance, while multi-gene and classifier-based approaches generally provide stronger discrimination. However, many studies remain limited by retrospective case-control designs, small FIGO stage I-II subsets, predominance of serous disease, and insufficient prospective validation. Integration with CA125 may improve sensitivity but can reduce specificity, which is critical in low-prevalence screening. Clinical translation will therefore require minimal and reproducible methylation signatures, standardised low-input cfDNA workflows, rigorous external validation, and prospective longitudinal evaluation in intended-use populations.

Humans↗

PubMed2005

NMDA antagonists and neuropathic pain--multiple drug targets and multiple uses.

NMDA (N-methyl-D-aspartate) receptors are one class of ionotropic receptor for the ubiquitous excitatory neurotransmitter L-glutamate. The receptor is made up of four protein subunits combined from a larger library of proteins, which gives this receptor a great deal of variability. This explains the large number of modulatory sites, a variety of sites at which antagonists can interact, and therefore a number of potential drug targets. Sensitivity of the NMDA ion channel to ambient levels of Mg++ gives it a voltage dependence that suits a function of responding to intense synaptic activation; the ability of the channel to admit Ca++ tends to trigger long-term processes. The receptor is thereby involved in long-term physiological processes such as learning and memory as well as in pathological processes such as neuropathic pain. Separating these functions therapeutically with NMDA antagonists has been a major difficulty, and has not yet been achieved with currently-available agents. This review summarises the preclinical rationale, based on animal models, and the clinical evidence on the use of NMDA antagonists in pain states. It also summarises the details of the receptor so as to explain the rationale for targeting either specific sites on the receptor, or exploiting anatomical differences in subtype expression, so as to provide the beneficial effects of NMDA receptor block with an improved side effect profile. In particular, agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.

Animals↗

PubMed2003

Processing factors and variability of pyrimethanil, fenhexamid and tolylfluanid in strawberries.

An HPLC-MS/MS method for the analysis of three pesticides in strawberries was developed and validated. Recoveries were measured at three spiking levels and ranged from 85 to 99% (mean recoveries). The effects of processing of strawberries ranging from rinsing to jam production were investigated for the three fungicides tolylfluanid, fenhexamid and pyrimethanil, which were applied under field conditions. Kresoxim-methyl was also applied in the field, but was not found in any of the samples investigated. The effect of parameters such as preharvest interval, dose, harvest time and observed pesticide concentration after harvest (initial concentration, mg kg(-1)), were examined with respect to possible reduction of the pesticides. The results from rinsing showed that all three pesticides were reduced on average by 37% for tolylfluanid, by 34% for fenhexamid and by 19% for pyrimethanil. For tolylfluanid and fenhexamid, the initial concentration significantly affected the reduction. For fenhexamid, dose could also have a minor influence on reduction. For pyrimethanil, none of the parameters significantly influenced the reduction. For jam production, cooking significantly reduced tolylfluanid by an average of 91%. For fenhexamid and pyrimethanil, a smaller reduction was seen, 25% and 33%, respectively. The reduction of tolylfluanid and pyrimethanil was affected by the preharvest interval, while fenhexamid was affected by the initial concentration. The unit-to-unit variability of fungicide contents was also investigated and the variability factors for the three fungicides were from 1.9 to 2.8.

Amides↗

PubMed2003

Variability in human metabolism of arsenic.

Estimating the nature and extent of human cancer risks due to arsenic (As) in drinking water is currently of great concern, since millions of persons worldwide are exposed to arsenic, primarily through natural enrichment of drinking water drawn from deep wells. Humans metabolize and eliminate As through oxidative methylation and subsequent urinary excretion. While there is debate as to the role of methylation in activation/detoxification, variations in arsenic metabolism may affect individual risks of toxicity and carcinogenesis. Using data from three populations, from Mexico, China, and Chile, we have analyzed the distribution in urine of total arsenic and arsenic species (inorganic arsenic (InAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA). Data were analyzed in terms of the concentration of each species and by evaluating MMA:DMA and (MMA+DMA):InAs ratios. In all persons most urinary As was present as DMA. Male:female differences were discernible in both high- and low-exposure groups from all three populations, but the gender differences varied by populations. The data also indicated bimodal distributions in the ratios of DMA to InAs and to MMA. While the gene or genes responsible for arsenic methylation are still unknown, the results of our studies among the ethnic groups in this study are consistent with the presence of functional genetic polymorphisms in arsenic methylation leading to measurable differences in toxicity. This analysis highlights the need for continuing research on the health effects of As in humans using molecular epidemiologic methods.

Arsenic↗

PubMed1994

Metabolic response of preterm infants to variable degrees of respiratory illness.

In older children and adults, physiologic instability associated with severe illness causes increased cellular oxygen consumption (VO2), increased serum lactate and cortisol levels, and more negative nitrogen balance. To determine the metabolic response of preterm infants to severity of respiratory illness, we analyzed VO2, nitrogen balance, urinary 3-methyl-histidine and norepinephrine concentrations, and serum levels of lactate and cortisol as a function of ventilatory index (VI). Twelve 2-day-old premature infants who were appropriate in size for gestational age (mean +/- SEM birth weight: 1460 +/- 251 gm) and who required mechanical ventilation for respiratory distress syndrome had VO2 and carbon dioxide production measured by indirect calorimetry and blood and urine samples obtained concurrently. All infants received amino acids, 1.0 gm/kg per day, and a mean energy intake of 27 +/- 3 kcal/kg per day, provided as a parenteral dextrose solution. The resting energy expenditure exceeded energy intake in all infants. The VO2 value ranged from 5.5 to 9.2 ml/kg per minute and was directly correlated with VI (r = 0.79; p = 0.002). Nitrogen balance ranged from -160 to 53 mg/kg per day (mean: -33 +/- 21 mg/kg per day) but was not dependent on VI (r = 0.04) or VO2 (r = 0.01). The serum lactate level correlated directly with VI (r = 0.82; p = 0.002) and VO2 (r = 0.60; p = 0.05), but cortisol and urinary norepinephrine levels did not. We conclude that preterm infants with respiratory distress syndrome have increased VO2 rates and serum lactate concentrations directly related to the degree of respiratory illness. They are generally in a state of mildly negative nitrogen balance, the degree of which is not related to severity of illness. Although these infants may require increased energy delivery during illness, they do not appear to require excessive amounts of amino acids.

Energy Metabolism↗

PubMed2000

Analysis of DNA fragments by microchip electrophoresis fabricated on poly(methyl methacrylate) substrates using a wire-imprinting method.

Microfluidic devices were fabricated on poly(methyl methacrylate) (PMMA) substrate using two small-diameter (79 microm) wires to create a cross impression in plastics softened by low-temperature heating. The resulting channels had a rounded shape and 75 microm in depth. The variability of the channel dimensions was found to be less than 6% from different locations of the same channel and less than 10% between chips. Moreover, the fabricated PMMA chip appeared to sustain an electric field strength up to 300 V/cm without significant Joule heating. The function of resulting devices for electrophoretic injection and separation of a DNA size marker, HaeIII digest of (phiX174, was also characterized. Results indicated that all of the 11 DNA fragments of the size marker could be identified in less than 3 min with relative standard deviations less than 0.4% and 8% for migration time and peak area, respectively. Moreover, with the use of near infrared (IR) dye, fluorescence signals of the higher molecular weight fragments (> 603 bp in length) could be detected at total DNA concentrations as low as 0.1 microg/mL (S/N = 4.2). In conclusion, the performance of wire-imprinted devices on PMMA substrate were comparable to those fabricated by other professional means.

Animals↗

PubMed1990

Chlorophyll a fluorescence measurements of isolated spinach thylakoids obtained by using single-laser-based flow cytometry.

Flow cytometry data of spinach thylakoid membrane preparations indicate the presence of a homogeneous thylakoid population. Fluorescence data from a flow cytometer and comparison with data from two other fluorometers show that chlorophyll a fluorescence detected with a flow cytometer has the character of maximum fluorescence (Fmax), not of the constant component (Fo). This conclusion is important since Fo measures fluorescence that is affected mostly by changes in excitation energy transfer and Fmax-Fo (the variable fluorescence) by changes in photochemistry. This was demonstrated by: 1) The light intensity as well as diffusion rate dependence of the quenching effect of various quinones (p-benzoquinone, phenyl-benzoquinone, and 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone, DBMIB) on fluorescence yield; quenching for the same concentration of these quinones was lower at the higher than at the lower light intensities. 2) Temperature dependence of the fluorescence yield; increasing the temperature from 20 to 70 degrees C did not show an increase in fluorescence yield using a flow cytometer in contrast to measurements with weak excitation light, but similar to those obtained for Fmax. 3) Addition of an inhibitor diuron up to 100 microM did not change the fluorescence intensity. A comparison of quenching of fluorescence by various quinones obtained by flow cytometry with those by other fluorometers suggests that the high intensity used in the cytometry produces unique results: the rate of reduction of quinones in much larger than the rate of equilibration with the bulk quinones.

Chlorophyll↗

PubMed1985

Stability-indicating liquid chromatographic determination of etoposide and benzyl alcohol in injectable formulations.

Simple and specific assays for etoposide, related impurities, and benzyl alcohol, as well as its degradation product, benzaldehyde, in injectable formulations were developed using high-performance liquid chromatography (HPLC). Etoposide, benzyl alcohol, benzaldehyde, and four etoposide impurities were determined with a mobile phase containing 26% acetonitrile in pH 4.0 acetate buffer with methyl p-aminobenzoate as the internal standard. Two etoposide precursors were additionally determined using 60% acetonitrile in the mobile phase with biphenyl as the internal standard. The assays were run sequentially. The etoposide assay had a total variability of less than 1% (RSD) and a recovery from placebo of 99.4%. Mean recovery of impurity standards spiked at the 2% level relative to the etoposide level was 98%. Recoveries for benzyl alcohol and benzaldehyde were 100.5% and 102.2%, respectively. Absorbance ratios generated from samples and compared with undegraded standards demonstrated specificity for etoposide. Similar response regression equations with correlation coefficients greater than 0.99 were obtained for etoposide and four impurities over the 2-8 micrograms/mL concentration range, indicating that an etoposide standard could be used to quantitate low impurity levels down to 0.2% relative to the etoposide injectable concentration. Benzaldehyde could be reliably detected at concentrations down to 0.5 micrograms/mL, equivalent to 0.16% of the benzyl alcohol level.

Benzaldehydes↗

PubMed1976

Pharmacokinetics and pharmacodynamics of methyl proscillaridin in healthy man.

The aim of this study was to obtain data about the pharmacological properties of a new glycoside derivative in man. Plasma concentrations and ECG parameters were measured after oral and intravenous administration of a single dose of 1.2 mg methyl proscillaridin in 16 healthy volunteers, using a strictly randomized, two-period change-over design. Glycoside concentrations were measured using a modified 86Rb-erythrocyte-assay. QT-duration, corrected for frequency (QTc), was the principal variable measured in the ECG. By either route, there was a maximum plasma level after 1 hour, which had decreased to a minimum at 3 hours, followed by a second peak at 4 to 10 hours (orally greater than iv). From 10 to 72 hours the concentrations decreased with a median t 1/2 of 23.3 hours (iv) and 33.0 hours (orally). Comparison of the ratio of plasma concentrations following oral and iv administration resulted in a bioavailability of 69% using the 48 hour plasma levels, and 59% using the areas under the concentration-time curves. The mean QTc was maximally shortened to 28 msec at 1 hour after iv and to 19 msec at 10 hours after the oral dose. A distinct similarity between time-concentration and time-QTc curves was seen after the initial distribution phase, both after oral and intravenous administration. The new derivative shows a rapid elimination. Its bioavailability is reasonably high.

Administration, Oral↗

PubMed2001

Evaluation of native GABA(A) receptors containing an alpha 5 subunit.

The type A receptor for gamma-aminobutyric acid (GABA), or GABA(A) receptor, is a pentamer of highly variable quaternary structure. It includes two alpha subunits, drawn from a pool of six genes, which largely determine benzodiazepine pharmacology of the receptor. In brain sections, both [(3)H]RY-80 (ethyl-8-acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate) and [(3)H]L-655,708 (ethyl (S)-11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate), which are selective for the benzodiazepine site of alpha 5 subunit-containing receptors, showed high-affinity, specific binding, but to fewer regions than did the nonselective benzodiazepine, [(3)H]flunitrazepam. The pattern mirrored alpha 5 mRNA distribution, and was similar to that previously reported for [(3)H]L-655,708 binding. Displacement of [(3)H]RY-80 bound to hippocampal homogenates, and of [(3)H]flunitrazepam bound to cerebellar and hippocampal homogenates showed comparable displacement by flumazenil (K(i)'s 5--7 nM). However, the K(i)'s for diazepam and for clobazam to displace [(3)H]RY-80 binding in hippocampus were about fourfold higher than for [(3)H]flunitrazepam, and the K(i) for clonazepam was sixfold larger, suggesting that these benzodiazepine receptor agonists bind with relatively lower affinity at hippocampal alpha 5-containing receptors.

Alkynes↗