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Biomedical subjects

D Frederick

Publications and source records attributed to D Frederick.

At least 19 recordsLinked to original sources
PubMed2002

Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.

Adolescent↗
PubMed2001

Reduction of paclitaxel-induced peripheral neuropathy with glutamine.

PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.

Activities of Daily Living↗
PubMed2000

Cellular mechanisms regulating protein phosphatase-1. A key functional interaction between inhibitor-2 and the type 1 protein phosphatase catalytic subunit.

Inhibitor-1 (I-1) and inhibitor-2 (I-2) selectively inhibit type 1 protein serine/threonine phosphatases (PP1). To define the molecular basis for PP1 inhibition by I-1 and I-2 charged-to-alanine substitutions in the Saccharomyces cerevisiae, PP1 catalytic subunit (GLC7), were analyzed. Two PP1 mutants, E53A/E55A and K165A/E166A/K167A, showed reduced sensitivity to I-2 when compared with wild-type PP1. Both mutants were effectively inhibited by I-1. Two-hybrid analysis and coprecipitation or pull-down assays established that wild-type and mutant PP1 catalytic subunits bound I-2 in an identical manner and suggested a role for the mutated amino acids in enzyme inhibition. Inhibition of wild-type and mutant PP1 enzymes by full-length I-2(1-204), I-2(1-114), and I-2(36-204) indicated that the mutant enzymes were impaired in their interaction with the N-terminal 35 amino acids of I-2. Site-directed mutagenesis of amino acids near the N terminus of I-2 and competition for PP1 binding by a synthetic peptide encompassing an I-2 N-terminal sequence suggested that a PP1 domain composed of amino acids Glu-53, Glu-55, Asp-165, Glu-166, and Lys-167 interacts with the N terminus of I-2. This defined a novel regulatory interaction between I-2 and PP1 that determines I-2 potency and perhaps selectivity as a PP1 inhibitor.

Amino Acid Sequence↗
PubMed1996

New 5-HT1A receptor antagonist: [3H]p-MPPF.

A new 5-HT1A receptor antagonist ligand, [3H]p-MPPF, 4-(2'-methoxy-)-phenyl-1-[2'-(N-2"-pyridyl)-p-fluorobenzamido] ethyl-piperazine, was prepared and characterized. It demonstrated high affinity and selectivity toward 5-HT1A receptors (Kd = 0.34 +/- 0.12 nM and Bmax = 145 +/- 35 fmol/mg protein in rat hippocampal membrane homogenates). The binding is not sensitive to 100 microM Gpp(NH)p. Initial autoradiography studies of rat brain sections exhibit regional localization consistent with the known 5-HT1A receptor distribution. This potential 5-HT1A antagonist ligand may provide a powerful tool for 5-HT1A receptor pharmacology studies in the central nervous system.

Aminopyridines↗
PubMed1996

In vivo SPECT imaging of 5-HT1A receptors with [123I]p-MPPI in nonhuman primates.

The in vivo imaging of a novel iodinated phenylpiperazine derivative for 5-HT1A receptors, [123I]p-MPPI (4-(2'-methoxy-)phenyl-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido-] ethyl-piperazine), using single photon emission computed tomography (SPECT), was evaluated in nonhuman primates. After an i.v. injection, [123I]p-MPPI penetrated the blood-brain barrier quickly and localized in brain regions where 5-HT1A receptor density is high (hippocampus, frontal cortex, cingulate gyrus, entorhinal cortex). Maximum ratio of hippocampus to cerebellum was 3 to 1 at 50 min postinjection. The specific binding of the radioligand in the hippocampal region, an area rich in 5-HT1A receptor density, was blocked by a chasing dose of (+/-) 8-OH-DPAT (2 mg/kg, i.v.) or non-radioactive p-MPPI (1 mg/kg, i.v.), whereas the regional distribution of [123I]p-MPPI was unaffected by treatment with non 5-HT1A agents, such as ketanserin. Ex vivo and in vitro autoradiographic studies using monkey brain further confirmed that the specific binding of [123I]p-MPPI is associated with 5-HT1A receptor sites. However, the initial attempt at [123I]p-MPPI human imaging studies did not display specific localization of 5-HT1A receptors. This discrepancy observed for [123I]p-MPPI may be due to a dramatic difference in metabolic pathways between humans and monkeys.

Aminopyridines↗
PubMed1996

Novel TcVO(III) N2S2 complexes: interconversion by redox reaction.

To improve the versatility of ligands suitable for complexing a TcVO center core, a new bisaminoethanethiol (BAT) ligand, 7, was synthesized. A neutral and stable complex, [99mTc]7 (reduced), was initially formed. The reduced form of the Tc-99m complex can be converted to the oxidized form, and vice versa. Both Tc-99m complexes showed moderate uptakes in rat brain (0.17% and 0.1% dose/organ at 30 min for the reduced and oxidized forms, respectively). It may be possible to use the same reaction schemes to prepare various derivatives for further studies of these neutral and stable Tc-99m complexes.

Aniline Compounds↗
PubMed1995

IPT: a novel iodinated ligand for the CNS dopamine transporter.

An iodinated cocaine derivative, N-(3'-iodopropen-2'-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl) tropane (IPT), was evaluated as a probe for in vitro and in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters in Sprague-Dawley rat brain. Saturation analysis of [125I]IPT in rat striatal homogenates, in two different buffer solutions, Tris-HCl and phosphate, demonstrated a one-site binding with affinities (Kd) of 0.25 +/- 0.02 and 0.16 +/- 0.02 nM and densities (Bmax) of 939 +/- 161 and 1,982 +/- 137 fmol/mg protein, respectively. Competition by known DA transporter ligands showed a rank order of RTI-55 > IPT > GBR12909 > mazindol > (-)cocaine. Binding to 5-HT transporter sites was evaluated in rat cortical homogenates. Saturation experiment results showed a single site with a Kd value of 1.2 +/- 0.2 nM and a Bmax value of 100 +/- 20 fmol/mg protein. The rank order of potency of several monoamine uptake inhibitors (paroxetine > fluoxetine > mazindol > R-nisoxetine > GBR12909) suggests that [125I] IPT labels 5-HT transporters in rat cortical homogenates. Both ex vivo and in vitro autoradiographic studies revealed high densities of [125I]IPT binding sites in the caudate nucleus, putamen, olfactory tubercle and nucleus accumbens, areas known to be rich in dopaminergic innervation. Moderate accumulation of activity was also observed in the substantia nigra. The dorsal raphe, a region with a high density of 5-HT innervation, was labeled using in vitro autoradiography with [125I]IPT, but the labeling using ex vivo autoradiography was less prominent at 30 min postinjection and not noticeable at 60 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

New bisaminoethanethiol (BAT) ligands which form two interconvertible Tc-99m complexes.

Most commonly used radiopharmaceuticals in diagnostic nuclear medicine are labeled with Tc-99m. This is due to its superior physical characteristics (T1/2 = 6 h and gamma energy 140 KeV) and convenient availability from the 99Mo/99mTc generator. In an attempt to fine tune the properties of Tc-99m complexes, the synthesis and radiolabeling of two novel N2S2 ligands, N,-2-mercaptobenzyl-N'-(1-oxo-2-mercapto-2-methyl)propyl ethylene-diamine, 8, and N,-2-methylthiobenzyl-N'-(1-oxo-2-mercapto-2-methyl)propyl ethylenediamine, 11, with an ionizable SH or unionizable SMe group, respectively, for the formation of complexes with TcvO center cores, have been examined. Both ligands initially formed one apparently stable, lipophilic and neutral complex (HPLC, Rt = 7 min, reverse-phase column, acetonitrile: buffer, pH 7.0; 55/45; V/V; partition coefficient between 1-octanol and buffer of 410 and 335, respectively) with [99mTc]pertechnetate in the presence of stannous chloride. After treatment with a reducing agent, NaCNBH3, the initial [99mTc]8 and 11 complexes were reduced; the reduced complexes were less lipophilic (shorter retention time, Rt = 5 min, on the same reversed phase HPLC). However, only the oxidized form showed sufficient stability. The reduced forms of both [99mTc]8 and 11 were readily and completely converted back to the oxidized forms by a stream of air. Biodistribution studies in rats demonstrated that the [99mTc]8 (oxidized form) penetrated the blood-brain barrier (0.67% dose/organ at 2 min postinjection), but washed out from the brain quickly (0.29% dose/organ at 30 min postinjection).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

In vitro and in vivo characterization of R(+)-FIDA2: a dopamine D2-like imaging agent.

UNLABELLED: R(+)-FIDA2, (R)-(+)-2,3-dimethoxy-5-iodo-N-[(1-(4'-fluorobenzyl)-2-pyrrolid iny l)- methyl]benzamide, is a new dopamine D2-like receptor imaging agent that can be labeled with either 123I or 18F for SPECT or PET imaging. The purpose of this study was to characterize its in vitro and in vivo binding properties. METHODS: In vitro binding studies using [125I]R(+)-FIDA2 were performed in Sf9 cells expressing dopamine D2 or D3 receptors and in rat basal forebrain homogenates, which contain a high density of dopamine D2-like receptors. A series of in vivo SPECT imaging studies in nonhuman primates (cynomologous monkeys) were performed by intravenously injecting 7.1 +/- 1.0 mCi of [123I]R(+)-FIDA2. At least one control study and one displacement experiment, in which a cold compound was injected intravenously 90 min after tracer injection, was performed in each monkey. Data were acquired in 10-min frames for 180 min, and the activity in regions of interest (basal ganglia and cerebellum) were plotted versus time. RESULTS: Iodine-125-R(+)-FIDA2 displayed Kd values for D2 and D3 receptor subtypes expressed in Sf9 cells of 0.11 and 0.04 nM, respectively. As expected, SPECT images of monkey brain (transaxial sections, 2 mm) showed that the radioactivity was localized in the area of the basal ganglia and reached peak concentrations in 11.5 +/- 5.8 min postinjection. An injection of R(+)7-OH-PIPAT, a new ligand that is selective for dopamine D3 receptors and the high affinity state of dopamine D2 receptors, did not show significant displacement of [123I]R(+)-FIDA2 binding in the basal ganglia. CONCLUSION: These studies indicate that R(+)-FIDA2 may be a useful ligand for in vitro pharmacological characterization and in vivo imaging of CNS dopamine D2-like receptors.

Animals↗
PubMed1995

4-(2'-Methoxy-phenyl)-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido]-ethyl- piperazine ([125I]p-MPPI) as a new selective radioligand of serotonin-1A sites in rat brain: in vitro binding and autoradiographic studies.

Binding characteristics of a radioiodinated serotonin-1A (5-HT1A) receptor antagonist, 4-(2'-methoxy-phenyl)-1-[2'-(n-2"-pyridinyl)-p- iodobenzamido]-ethyl-piperazine ([125I]p-MPPI) were evaluated using in vitro homogenate binding and autoradiographic techniques in rat brains. [125I]p-MPPI displayed a Kd value of 0.32 +/- 0.04 nM (in the presence of MgCl2) and a Bmax value of 315 +/- 60 fmol/mg of protein in rat hippocampal homogenates. The number of 5-HT1A receptors labeled by [125I]p-MPPI was 40% higher than that labeled by trans-8-hydroxy-2-(N-n-propyl-N-3'-iodo-2'- propenyl)aminotetralin ([125I]R(+)8-OH-PIPAT) (225 +/- 47 fmol/mg of protein), a radioiodinated 5-HT1A agonist. The magnesium ion showed an inhibitory effect on [125I]p-MPPI binding but increased the specific binding of [125I]R(+)8-OH-PIPAT. A significant increase in Bmax values in the presence of guanyl nucleotides was observed for [125I]p-MPPI (control, 307 +/- 35 fmol/mg of protein; with GTP, 345 +/- 30 fmol/mg of protein; with guanylyl-imidodiphosphate, 362 +/- 35 fmol/mg of protein); however, both guanyl nucleotides significantly reduced the Bmax values measured by [125I]R(+)8-OH-PIPAT (control, 213 +/- 50 fmol/mg of protein; with GTP, 133 +/- 20 fmol/mg of protein; with guanylyl-imidodiphosphate, 108 +/- 20 fmol/mg of protein). The binding characteristics of [125I]p-MPPI for 5-HT1A receptors suggest that p-MPPI is an antagonist for 5-HT1A receptors. In vitro autoradiographic studies in rat brain sections with [125I]p-MPPI showed specific labeling of areas rich in 5-HT1A receptors and the regional distribution closely matched those labeled by [125I]R(+)8-OH-PIPAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyridines↗
PubMed1994

Binding of 125I-iodovinyltetrabenazine to CNS vesicular monoamine transport sites.

Binding characteristics of a novel radioiodinated tetrabenazine (TBZ) analog (iodovinyltetrabenazine; 125I-TBZ-Fraction I) were evaluated. In rat striatal homogenates, 125I-TBZ-I displayed a pharmacological profile consistent with specific binding to vesicular monoamine transport (VMAT) sites. In vitro autoradiographic studies using rat brain sections further demonstrated that 125I-TBZ-I labeled the regions rich in VMAT sites, and it may be a useful marker for these sites. This novel radioiodinated ligand, with high specific activity and high binding affinity, may provide a powerful tool for the in vitro assessment of neuronal loss in various neurodegenerative diseases.

Animals↗
PubMed1994

In vivo binding of [123I]4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)- p-iodobenzamido-]ethyl-piperazine, p-MPPI, to 5-HT1A receptors in rat brain.

The in vivo regional distribution and pharmacological profile of a novel iodinated phenylpiperazine derivative, [123I]p-MPPI (4-(2'-methoxy-)phenyl-1-[2'-(N-2"pyridinyl)-p-iodobenzamido-]ethy l- piperazine), in the rat brain were evaluated for use as a potential in vivo imaging agent for 5-HT1A receptors. The new ligand penetrated the blood-brain barrier quickly and efficiently, with 1.2% of the injected dose found in the whole brain at 2 min post i.v. injection. The rate of radioactivity washout was slowest from the hippocampal region, followed by the hypothalamus, cortex, striatum, and cerebellum. The maximum ratio of hippocampus/cerebellum was 3.3 at 30 min postinjection. The specific binding of the radioligand in the hippocampal region, an area rich in 5-HT1A receptor density, was blocked by pretreatment with a dose of (+/-) 8-OH-DPAT (2 mg/kg, i.v.) or WAY 100635 (1 mg/kg, i.v.), whereas the regional distribution of [123I]p-MPPI was unaffected by pretreatment with non-5-HT1A agents such as ketanserin or haloperidol. Ex vivo autoradiographic studies further confirmed that the specific binding of [125I]p-MPPI is associated with 5-HT1A receptor sites. These results indicate that [123I]p-MPPI may be a useful candidate for noninvasive single photon emission computed tomography (SPECT) imaging of 5-HT1A receptor sites in the living human brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Characterization of binding sites for [125I]R(+)trans-7-OH-PIPAT in rat brain.

Binding characteristics of a novel radioiodinated ligand, [125I]R(+)trans-7-hydroxy-2-(N-n-propyl-N-3'-iodo-2'-propenyl) aminotetralin ([125I]R(+)trans-7-OH-PIPAT), were evaluated using homogenate binding and autoradiographic techniques in rat brain. [125I]R(+)trans-7-OH-PIPAT bound to sites (dopamine receptors) in homogenates of rat basal forebrain (including caudate putamen, nucleus accumbens and olfactory tubercle) with a high affinity (Kd = 0.42 nM). A majority (70%) of the sites labeled by [125I]R(+)trans-7-OH-PIPAT in basal forebrain were GTP-sensitive. In rat hippocampal homogenates, specific and saturable binding of [125I]R(+)trans-7-OH-PIPAT to 5-HT1A receptors, with a Kd value of 1.4 nM and a Bmax value of 210 fmol/mg protein, was observed. Binding of [125I]R(+)trans-7-OH-PIPAT to sigma sites was also demonstrated in rat cerebellar homogenates. In the presence of GTP (to inhibit binding to D2 and 5-HT1A receptors) and DTG (to inhibit binding to sigma sites), dopamine D3 receptors could be selectively labeled with [125I]R(+)trans-7-OH-PIPAT. [125I]R(+)trans-7-OH-PIPAT offers several unique advantages, including high specific activity and high affinity binding, which make it an excellent probe for the investigation and characterization of the distribution of dopamine D3 receptors.

Animals↗
PubMed1991

Class II antigen-associated invariant chain mRNA in mouse small intestine.

MHC class II antigen-associated invariant (Ii) chain mRNA appears in mouse small intestine during postnatal development. Ii chain cDNA hybridizes to RNA from epithelial sheets dissociated from the lamina propria with EDTA. Of several mouse organs tested, only bone marrow and spleen contain higher levels of Ii chain mRNA than small bowel. Ii chain mRNA is not detected in stomach, colon, duodenum, testis, liver, submandibular gland, or L-cell RNA; brain contains a cross-reactive but uncharacterized sequence. cDNA amplification using primers specific for both Ii31 and Ii41 chain mRNAs showed that both forms occur in small intestine. These results support the conclusion that regulation of the class II Ii chain gene is associated with the ontogeny of intestinal immunity.

Animals↗
PubMed1989

Developmental regulation of cryptdin, a corticostatin/defensin precursor mRNA in mouse small intestinal crypt epithelium.

Cryptdin mRNA codes for the apparent precursor to a corticostatin/defensin-related peptide that accumulates to high levels in mouse intestinal crypt epithelium during postnatal development. The primary structure, intestinal cell distribution, and developmental appearance of cryptdin mRNA have been determined. Cryptdin mRNA is 450-480 nucleotides long. Translation of the partial cryptdin cDNA sequence reveals a 70-amino acid open reading frame that includes 32 carboxy-terminal residues that align with those in the consensus sequence, C.CR...C....ER..G.C....CCR, which is a common feature of leukocyte defensins and lung corticostatins (Selsted, M. E., D. M. Brown, R. J. DeLange, S. S. L. Harwig, and R. I. Lehrer. 1985. J. Biol. Chem. 260:4579-4584; Zhu, Q., J. Hu, S. Mulay, F. Esch, S. Shimasaki, and S. Solomon. 1988. Proc. Natl. Acad. Sci. USA. 85:592-596). In situ hybridization of cryptdin cDNA to paraformaldehyde-fixed, frozen sections of adult jejunum and ileum showed intense and specific labeling of epithelial cells in the base of all crypts. Analysis of sections from suckling mice showed that cryptdin mRNA is detectable in 10-20% of crypts in 10-d-old mice, in approximately 80% of crypts in 16-d-old mice, and in all crypts of mice 20 d and older. During the fourth week, the sequence accumulates in crypts to the maximal adult level. Cryptdin mRNA content in adult small intestine is independent both of T cell involvement and luminal bacteria. The role of cryptdin in small bowel physiology remains to be determined: cryptdin may inhibit bacterial translocation, modulate intestinal hormone synthesis, influence hormonal sensitivity of the intestinal epithelium, or exhibit a multiplicity of related activities.

Aging↗