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Biomedical subjects

David Goldman

Publications and source records attributed to David Goldman.

100 records · Page 6Linked to original sources
PubMed2002

Mechanism for further enhancement in drug dissolution from solid-dispersion granules upon storage.

The present study was performed to investigate the further increase in drug dissolution on storage of ternary solid-dispersion granules containing poorly water-soluble drugs. Ternary solid-dispersion granules of the drug, a dispersion carrier, and a surface adsorbent were prepared using hot-melt granulation. Two proton-donating drugs, BAY 12-9566, naproxen, and a nonproton-donating drug, progesterone, were studied. Gelucire 50/13 and polyethylene glycol 8000 were evaluated as solid-dispersion carriers with low melting point. Neusilin US2 (magnesium aluminosilicate), a proton acceptor, was used as the surface adsorbent. The proposed mechanism for further increase in drug dissolution (BAY 12-9566 and naproxen) on storage at 40 degrees C/75% RH (relative humidity) is based on hydrogen bonding between the proton-donating drugs and the surface adsorbent, Neusilin US2 (proton acceptor). We propose that there is enough mobility in the solid-dispersion granules at elevated temperatures of storage to allow an increase in the ratio of the hydrogen bonded drug to the crystalline drug. These changes are mediated through the saturated solid solution state, and manifest themselves as increased drug dissolution upon storage. Fourier transform infrared spectroscopy studies are indicative of an increase in the amount of drugs (BAY 12-9566 and naproxen) hydrogen bonded to Neusilin on storage. A corresponding decrease in the crystallinity of these drugs was measured using x-ray powder diffractometry. Granules containing progesterone (a nonproton-donating drug) do not show an increase in the amount of drug hydrogen-bonded to Neusilin upon storage. In contrast to the proton-donating drugs, decreased drug dissolution was found on storage of progesterone-containing granules.

Antineoplastic Agents↗
PubMed2002

Determination of melting temperature for variant detection using dHPLC: a comparison between an empirical approach and DNA melting prediction software.

Detection of DNA sequence variants by the use of denaturing high-performance liquid chromatography (dHPLC) is a relatively new method (Underhill et al., 1997) and has distinct advantages over other methods such as single-strand conformation polymorphism (SSCP), direct sequencing, and DNA chip hybridization. The dHPLC-based single-nucleotide polymorphism (SNP) screening relies on different DNA thermodynamic properties between perfectly matched base pairs in homoduplex molecules and single base-pair mismatches in heteroduplex DNAs. Separation of the two forms of duplex DNAs by dHPLC is based on ionic forces between the negatively charged DNA and the hydrophobic stationary phase, which consists of C(18) chains on PSDVB (polystyrene-divinylbenzene) beads coated with a positively charged ion-pairing agent (TEAA, triethylammonium acetate). Removal of the DNA from the TEAA-coated beads is dependent upon a mobile organic phase, in the form of a linear acetonitrile gradient. The major factor that influences the success of dHPLC to detect sequence variation is the thermal stability of the duplex DNA, which is determined by the melting temperature (TM(50)), where 50% of the DNA strand is single stranded and 50% is double stranded. The TM(50) predicts the best probability of detecting a single base-pair change based on the altered thermodynamics it imparts to the DNA duplex. Generally, there are two ways to determine this melting temperature, either empirically or with the aid of predictive DNA melting analysis software. Such programs include the DNAMelt program located on the Stanford University DNA Sequencing and Technology Center website, MeltCalc (Schutz and von Ahsen 1999), and WAVEMAKER, the proprietary melting analysis software provided with the Transgenomic WAVE dHPLC system. The goal of the current study was to determine whether currently available predictive DNA melting programs could be used to increase efficiency and throughput of SNP detection. A wide range of amplicons, differing in both size and GC composition, were selected for analysis to simulate the broad spectrum of PCR products that may be encountered during a large-scale dHPLC screening project.

Chromatography, High Pressure Liquid↗
PubMed2002

A proline-threonine substitution in codon 351 of ADH1C is common in Native Americans.

BACKGROUND: The alcohol dehydrogenase (ADH) genes have been repeatedly associated with protection against alcoholism. Until now, only four protein coding variants have been identified (ADH1C Arg271Gln, Ile349Val, ADH1B Arg47His, and Arg369Cys), and only two of these (ADH1CIle349Val and ADH1B Arg47His) have been routinely tested in association studies with alcoholism. METHODS: The new ADH1C*351Thr allele was identified by direct sequencing of DNA samples that gave different typing results for the ADH1C Ile349Val polymorphism with different typing protocols. RESULTS: A new coding variant has been identified at codon 351 of ADH1C. This allele is found in most Native American populations that we have studied with allele frequencies of the new ADH1C*351Thr allele as high as 26%. Only two instances of this allele have been seen in a large survey of African and Eurasian populations. CONCLUSIONS: The changes in charge, size, and rotational mobility caused by this amino acid substitution should be significant. Because this new variant codes for a new enzyme form in Native Americans, the kinetics of this enzyme should be studied and considered in studies of the role of in the protection against alcoholism in Native Americans.

Alcohol Dehydrogenase↗
PubMed2002

Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder.

OBJECTIVE: Genetic epidemiologic and clinical data suggest that comorbid panic disorder may define a subtype of bipolar disorder. Comorbid panic disorder might thereby influence the strength of association between bipolar disorder and genes that have been implicated in bipolar disorder on the basis of their function in monoamine neurotransmission and previously reported linkage results. Polymorphic markers at catechol O-methyltransferase (COMT), serotonin transporter (5-HTT), and tryptophan hydroxylase (TPH) genes were analyzed in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. METHOD: Unrelated subjects of Italian descent meeting DSM-III-R criteria for lifetime bipolar disorder (N=111), with (N=49) or without (N=62) comorbid lifetime panic disorder, were compared to 127 healthy subjects. DNA was extracted from blood leukocytes. The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined. Genotype and allele frequency comparisons between affected (bipolar disorder, bipolar disorder without panic disorder, or bipolar disorder with panic disorder) and unaffected individuals were carried out with chi-square tests or Fisher's exact tests. RESULTS: Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes. The differences in the frequencies of the TPH IVS7+218A alleles and genotypes approached statistical significance. CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders.

Adult↗
PubMed2002

A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition.

OBJECTIVE: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. METHOD: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. RESULTS: Subjects with only the low-activity met allele made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. CONCLUSIONS: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.

Adult↗
PubMed2002

The relationship between two intermediate phenotypes for alcoholism: low voltage alpha EEG and low P300 ERP amplitude.

OBJECTIVE: There is considerable evidence that the amplitude of the heritable P300 event-related potential (ERP) is reduced in alcoholics and their alcohol-naive children. Low voltage alpha (LVA), a heritable resting electroencephalogram (EEG) trait present in 7-14% of the population, has been shown to be associated with alcoholism and anxiety disorders. A few studies have demonstrated a modest correlation between pre-stimulus alpha power and P300 amplitude. We aimed to test this finding in community volunteers, hypothesizing that LVA would be associated with low P300 amplitude. METHOD: Digitized resting EEG was recorded at the central parietal site (Pz) from 85 male and 113 female community volunteers (120 unrelated). ERPs were elicited at Pz by auditory and visual oddball paradigms. All participants were interviewed with the Schedule for Affective Disorders, Lifetime Version (SADS-L) and assigned blind-rated psychiatric diagnoses according to the American Psychiatric Association DSM-III-R criteria. RESULTS: LVA participants (including alcoholics and nonalcoholics) had significantly lower auditory and visual P300 amplitudes. Absolute alpha power was modestly correlated with auditory and visual P300 amplitude and was associated with 9.4% and 4.6% of the variance, respectively. CONCLUSIONS: The association between LVA and low P300 amplitude, two distinct electrophysiological traits, suggests that, at least in individuals with the LVA trait, some aspects of resting, unstimulated brain activity and activated brain function in the form of attentional response may be fundamentally related.

Adolescent↗