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At least 649 records · Page 36Linked to original sources
PubMed1987

Preliminary report on 8-amino-9-(2-thienylmethyl)guanine (PD 119,229), a novel and potent purine nucleoside phosphorylase inhibitor.

PD 119,229 [8-amino-9-(2-thienylmethyl)guanine] is a novel and potent inhibitor of human erythrocyte purine nucleoside phosphorylase (PNP) with a Ki of 0.067 microM. In a cell line assay using human MOLT-4 (T cell) and MGL-8 (B cell) lymphoblasts, PD 119,229 alone had no effect on the growth of either cell line at the highest concentration tested (100 microM). However, in the presence of a nontoxic concentration of 2'-deoxyguanosine (10 microM), the IC50 values of PD 119,229 for MOLT-4 and MGI-8 40-fold either cell line at the highest concentration tested (100 microM). However, in the presence of a nontoxic concentration of 2'-deoxyguanosine (10 microM), the IC50 values of PD 119,229 for MOLT-4 and MGI-8 were 0.9 and greater than 100 microM, respectively. The inhibition of growth of MOLT-4 was accompanied by a 40-fold increase in dGTP and a two-fold reduction in GTP, while no alteration in nucleotide profile was noted in MGL-8. Both the inhibition of growth of MOLT-4 and the accumulation of dGTP were substantially prevented by coaddition of 2'-deoxycytidine.

Cell Division↗
PubMed1993

PD 141955 and CI-972: 9-deazaguanine analog purine nucleoside phosphorylase inhibitors. I. Suppression of the human mixed lymphocyte reaction (MLR).

Inhibitors of purine nucleoside phosphorylase (PNP) are of interest as potential T-cell-selective immunosuppressive agents and for other uses. PD 141955 (9-deaza-9-(3-thienylmethyl)guanine; 2-amino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin -4-one) is 12- to 100-fold more potent than CI-972 (8-amino-9-deaza-9-(3-thienylmethyl)guanine; 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrim idin-4- one) in PNP enzyme inhibition assays. In the human MLR, PD 141955 has IC50s of 2.8 and 12.8 microM in the presence and absence, respectively, of 15 microM GdR (means from 10 assays), while the IC50s of CI-972 tested in parallel are > 30 microM. Concentration-dependent accumulation of dGTP occurs in PD 141955-treated MLRs under conditions in which CI-972 lacks detectable activity. Thus, consistent with its greater PNP inhibitory activity in a cell free system, PD 141955 is significantly more potent than CI-972 in its ability to suppress the MLR.

Cells, Cultured↗
PubMedDate not supplied

PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist.

Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimer's disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 142676, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676 decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases, and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.

Animals↗
PubMed1998

Plasma GH responses to GHRH, arginine, L-dopa, pyridostigmine, sequential administrations of GHRH and combined administration of PD and GHRH in Turner's syndrome.

To investigate GH secretory capacities in patients with Turner's syndrome, GHRH, arginine, L-dopa and pyridostigmine (PD) were administered singly and GHRH was administered sequentially for 3 days. In addition, plasma GH and TSH responses to GHRH and TRH after pretreatment with PD were analyzed to investigate whether the hypothalamic cholinergic somatostatinergic system functioned normally. The maximal GH responses to GHRH, L-dopa and PD were significantly smaller in Turner's syndrome (no.=14) than in normal short children (NSC, no.=14). However, there was no difference in plasma GH responses to arginine between the two groups. In ten patients with Turner's syndrome, the plasma GH response to GHRH did not improve even after the sequential 3-day administrations. Although plasma GH and TSH responses to GHRH and TRH were significantly enhanced by the pretreatment of PD in NSC (no.=12), these responses were not enhanced in Turner's syndrome. Plasma GH response to GHRH in Turner's syndrome with normal body fat was still significantly lower than in NSC. It is therefore concluded that somatotroph sensitivity to GHRH is decreased in Turner's syndrome and that this may be due to the primary defects of the somatotrophs rather than to the increased body fat. In addition, the network of cholinergic-somatostatinergic systems seemed to be impaired in these patients, while the activity of hypothalamic somatostatin neurons was thought to be maintained.

Adolescent↗
PubMed2000

Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414 against human tumor xenografts.

PURPOSE: The involvement of the EGF receptor (EGFr) family of receptors in cancers suggests that a selective inhibitor of the tyrosine kinase activity of the EGFr family could have a therapeutic effect. PD 0169414, an anilinoquinazoline, is a potent irreversible inhibitor of the EGFr family tyrosine kinase activity with IC(50) values of 0.42 nM against the isolated EGF receptor, and 4.7 nM and 22 nM against EGF- and heregulin-mediated receptor phosphorylation in A431 and MDA-MB-453 cells, respectively. METHODS AND RESULTS: Oral administration of 260 mg/kg per day PD 0169414 for 15 days to animals bearing advanced-stage A431 epidermoid carcinoma produced a 28.2-day delay in tumor growth and resulted in three complete and three partial tumor regressions in six animals. Toxicity at this dose level was limited to <6% loss of initial body weight. Doses of 160 and 100 mg/kg per day produced tumor growth delays of 29.5 and 20.9 days and two and one complete regressions in six animals, respectively. Subcutaneous, intraperitoneal, and oral routes of administration have also shown in vivo antitumor activity of PD 0169414 in a panel of human tumor xenografts. Responsive tumor lines include A431 (human epidermoid carcinoma), H125 (NSCL carcinoma), MCF-7 and UISO-BCA1 (human breast carcinoma), and SK-OV-03 (human ovarian carcinoma). The therapeutic effect ranged from delayed tumor growth (6.4 days delayed tumor growth for 14 days of treatment) to tumor regressions (32.2 days delayed tumor growth and five partial regressions in six animals) in these model systems. CONCLUSION: PD 0169414 is a specific, irreversible inhibitor of EGFr family tyrosine kinases with significant in vivo activity against a variety of relevant human tumor xenografts.

3T3 Cells↗
PubMed2005

DFT studies on isomerization reactions in the copolymerization of ethylene and methyl acrylate catalyzed by Ni-diimine and Pd-diimine complexes.

Gradient corrected density functional theory (DFT) has been used to investigate the isomerization reactions in the process of the ethylene/methyl acrylate copolymerization catalyzed by Pd-dimine and Ni-dimine complexes, modeled by a generic system NwedgeN-M-(CH3)+; NwedgeN=-N(H)-C(H)-C(H)-N(H)-. The influence of the polar group and of the metal on the isomerization mechanism was studied. The results show that for the Pd-catalyst the isomerization follows the standard mechanism observed in homopolymerization processes, with the beta-hydrogen-transfer to the metal and formation of a pi-olefin-hydride complex. Electron withdrawing character of the polar group results in an increase of the hydride energy and the isomerization barrier. For the Ni-catalyst the overall isomerization picture is modified by the formation of a sigma-olefin-hydride complex, in which the olefin is coordinated to the metal by the oxygen atom of the polar group. Such a sigma-olefin-hydride is lower in energy for the Ni catalyst than the pi-olefin-hydride complex by 9.6 kcal mol(-1) . The latter is preferred by 2.6 kcal mol(-1) for the Pd-based system. The calculated isomerization barriers are 20.9 and 24.0 kcal mol(-1) (with respect to the initial 4-member chelate) for the Pd-catalyst and Ni-catalyst, respectively. This can result in a larger fraction of ester group directly connected to the copolymer backbone observed experimentally for the Ni-catalyst. [Figure: see text]. Structure of the four-membered and five-membered chelates formed after 2,1-insertion of methyl acrylate into the metal-alkyl bond of the catalyst.

Acrylates↗
PubMed2006

Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model.

The plasma concentration-time profile of a drug is essential to explain the relationship between the administered dose and the kinetics of drug action. However, in some cases such as in pre-clinical pharmacology or phase-III clinical studies where it is not always possible to collect all the required PK information, this relationship can be difficult to establish. In these circumstances several authors have proposed simple models that can analyse and simulate the kinetics of the drug action in the absence of PK data. The present work further develops and evaluates the performance of such an approach. A virtual compartment representing the biophase in which the concentration is in equilibrium with the observed effect is used to extract the (pharmaco)kinetic component from the pharmacodynamic data alone. Parameters of this model are the elimination rate constant from the virtual compartment (KDE), which describes the equilibrium between the rate of dose administration and the observed effect, and the second parameter, named EDK(50) which is the apparent in vivo potency of the drug at steady state, analogous to the product of EC(50), the pharmacodynamic potency, and clearance, the PK "potency" at steady state. Using population simulation and subsequent (blinded) analysis to evaluate this approach, it is demonstrated that the proposed model usually performs well and can be used for predictive simulations in drug development. However, there are several important limitations to this approach. For example, the investigated doses should extend from those producing responses well below the EC(50) to those producing ones close to the maximum response, optimally reach steady state response and followed until the response returns to baseline. It is shown that large inter-individual variability on PK-PD parameters will produce biases as well as large imprecision on parameter estimates. It is also clear that extrapolations to dosage routes or schedules other than those used to estimate the parameters should be undertaken with great caution (e.g., in case of non-linearity or complex drug distribution). Consequently, it is advised to apply this approach only when the underlying structural PD and PK are well understood. In any case, K-PD model should definitively not be substituted for the gold standard PK-PD model when correct full model can and should be identified.

Adenosine↗
PubMed1979

Coordination of Gly-Tyr . Pd(II) complex to ATP and ADP nucleotides.

The coordination of the glycyl-L-tyrosinate . Pd(II) complex to adenosine 5' -diphosphate (ADP) and adenosine 5' -triphosphate (ATP) has been studied using 13C, 1H NMR and electronic spectral methods. Two dominant species have been found in solution, a monomeric ternary complex with Gly-Tyr . Pd(II) bound to the N-1 purine nitrogen and a dimer in which two dipeptide . Pd(II) complex molecules are coordinated to the nucleotide by N-1 and N-7 nitrogens. Monomeric ternary complexes having metal coordination to N-7 were not detected. The influence of the aromatic ring of tyrosine upon the chemical shifts for the bonded nucleotide molecule suggest that the plane of the purine ring and of the Gly-Tyr . Pd(II) complex are almost perpendicular to each other.

Adenosine Diphosphate↗
PubMed1995

Characterization of binding of [3H]PD 128907, a selective dopamine D3 receptor agonist ligand, to CHO-K1 cells.

PD 128907 [4a R, 10 b R-(+)-trans-3, 4, 4a, 10 b - tetrahydro - 4- n -propyl2 H,5H-[1]benzop-yrano[4,3-b]1,4-oxazin-9-ol.], a selective dopamine (DA) D3 receptor agonist ligand exhibits about a 1000-fold selectivity for human D3 receptors (Ki, 1 nM) versus human D2 receptors (Ki, 1183 nM) and a 10000-fold selectivity versus human D4 receptors (Ki, 7000 nM) using [3H]spiperone as the radioligand in CHO-K1-cells. Studies with [3H]PD 128907, showed saturable, high affinity binding to human D3 receptors expressed in CHO-K1 cells (CHO-K1-D3) with an equilibrium dissociation constant (Kd) of 0.99 nM and a binding density (Bmax) of 475 fmol/mg protein. Under the same conditions, there was no significant specific binding in CHO-K1-cells expressing human D2 receptors (CHO-K1-D2). The rank order of potency for inhibition of [3H]PD 128907 binding with reference DA agents was consistent with reported values for D3 receptors. These results indicate that [3H]PD 128907 is a new, highly selective D3 receptor ligand with high specific activity, high specific binding and low non-specific binding and therefore should be useful for further characterizing the DA D3 receptors.

Animals↗
PubMed1995

Chemosensitization of CCNU in KHT murine tumor cells in vivo and in vitro by the agent RB 6145 and its isomer PD 144872.

The cytotoxicity and chemosensitizing potential of the nitrohetercyclic agent RB 6145 and its R enantiomer PD 144872 were determined in rodent tumor cells grown in tissue culture or as solid tumors. Using a clonogenic cell survival assay the degree of selective cytotoxicity of these bioreductive drugs was first determined in KHT/iv cells. Cells treated under hypoxic conditions were observed to be approximately 50-80-fold more susceptible to the action of RB 6145 or PD 144872 than were cells exposed under air. To assess the in vitro chemosensitizing potential of RB 6145 and PD 144872, doses of these agents which led to survival values between 0.5 and 1.0 under hypoxic conditions were administered, and were then combined concomitantly with variable doses of the nitrosourea CCNU. Exposure to the nitrosourea was for 1 h. The results showed that inclusion of either sensitizer enhanced the cell killing of the chemotherapeutic agent 2.4-2.6-fold. Subsequent experiments evaluated the therapeutic benefit of combining these bioreductive agents with CCNU in KHT sarcoma-bearing C3H/HeJ mice. When given at times ranging from 90 min before to 60 min after CCNU exposure, these bioreductive drugs increased the tumoricidal activity of the chemotherapeutic agent. Complete dose response curves combining RB 6145 and PD 144872 and a range of CCNU doses also were evaluated. The sensitizers (0.75 mmol/kg) were administered 30 min prior to the chemotherapeutic agent and survival of clonogenic tumor cells 22-24 h after treatment was used to assay tumor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Interaction of (dien)Pd(II) with cytidine and cytidine 5'-monophosphate. Influence of the phosphate group on the kinetics and mechanism.

The kinetics and the equilibrium of (dien)PdCl+ interaction with cytidine (C) and cytidine 5'-monophosphate (CMP) were studied by spectrophotometry and by stopped-flow methods. In both cases, the mechanism implies a (dien)Pd(H2O)2+ intermediate with a significant contribution of the solvent path at low chloride concentrations. With CMP, the rate is affected due to the addition of a mechanistic path via an intermediate formed between (dien)Pd(II) and the phosphate group of CMP. The kinetic and thermodynamic parameters have been determined and reflect the favorable electrostatic interactions due to the presence of the phosphate group of CMP. Furthermore, these parameters are in agreement with a transient (dien)Pd(II)-phosphate complex of CMP leading to the formation of the thermodynamically favored (dien)Pd(II)-N3 complex as final product.

Journal Article↗
PubMed1992

Enhancement of alkylating agent activity in vitro by PD 128763, a potent poly(ADP-ribose) synthetase inhibitor.

The ability of DNA repair inhibitors to potentiate alkylating agent cytotoxicity was explored with PD 128763, a dihydroisoquinolinone known to effectively inhibit poly(ADP-ribose) synthetase. The cytotoxic activity of streptozotocin in L1210 leukemia cells was maximally potentiated (7-fold decrease in IC50) under conditions of 24 hr exposure to PD 128763 following treatment with the alkylating agent for 1 hr. Similar treatment conditions resulted in a much greater effect (36-fold enhancement in activity) for the 2-nitroimidazole RSU 1069. In contrast, 3-aminobenzamide was only weakly effective at enhancing activity of either streptozotocin or RSU 1069 (2-3 fold potentiation). However, PD 128763 was ineffective at potentiating the cytotoxicity of the bifunctional alkylating agents carmustine (BCNU) and lomustine (CCNU). Our results are consistent with a role for (poly-ADP) ribosylation in the repair of monofunctional alkylating agent damage. This study supports further exploration of the combination of PD 128763 and RSU 1069 as a potentially useful chemotherapeutic regimen.

Alkylating Agents↗
PubMed1995

The relative biological effectiveness of I-125 and Pd-103.

PURPOSE: To determine the relative biological effectiveness (RBE) of I-125 and Pd-103 relative to Co-60. METHODS AND MATERIALS: A cell line REC:ras, derived from rat embryo cells, was used. Cells in exponential or plateau phase were irradiated at dose rates of about 0.07 Gy/h and 0.14 Gy/h. To circumvent the interface effect, cells were grown and irradiated on membranes made of cellulose acetate, which has an effective Z of 7.5. I-125 and Pd-103 seeds were placed in a custom designed template that yielded a homogeneous dose distribution in the plane of the cell culture. The dose rates of irradiation were measured by calibrated thermoluminescence dosimetry (TLD) chips. RESULTS AND CONCLUSIONS: Our measurements yielded an RBE of about 1.4 for I-125 at dose rates of about 0.07 Gy/h, and an RBE of about 1.9 for Pd-103 at dose rates of about 0.07 Gy/h and 0.14 Gy/h. The RBE of I-125 is similar to those measured by other investigators, the RBE for Pd-103 is being reported for the first time.

Animals↗
PubMed1995

Tentative criteria for determining the in vitro susceptibilities of Haemophilus influenzae, including quality control parameters, to two fluoroquinolones (grepafloxacin and PD 131628).

Grepafloxacin (OPC 17116) and PD 131628 were evaluated against 150 Haemophilus influenzae isolates to propose susceptibility testing criteria for both broth dilution and disk diffusion procedures using haemophilus test medium. Grepafloxacin-susceptible isolates are defined as those for which minimum inhibitory concentrations (MICs) are < or = 0.06 micrograms/ml and zones of inhibition are > or = 27 mm. PD 131628-susceptible strains of H. influenzae included those that exhibited MICs < or = 0.03 micrograms/ml, and the zones were > or = 32 mm. All MICs were well below concentrations that can be achieved in the blood and tissues of patients treated with either study drug. Criteria for defining a resistant category cannot be determined until strains with elevated MICs are available for study. The proposed quality control guidelines for H. influenzae ATCC 49247 and the disk test are 32-39 mm in diameter for grepafloxacin and 34-42 mm for PD 131628. The preliminary broth microdilution MIC control limits for this strain are 0.002-0.016 micrograms/ml for grepafloxacin and 0.002-0.008 micrograms/ml for PD 131628.

Anti-Infective Agents↗
PubMed2004

Initial mercury evaporation from experimental Ag-Sn-Cu amalgams containing Pd.

This study examined the Hg evaporation during setting from experimental Ag-Sn-Cu alloy powders with and without Pd. Four series of alloy powders were fabricated to examine the effect on the Hg evaporation of the alloy compositions (all percentages in this report are weight percents): Pd (0-1.5), Cu (9.0-14.0), Ag (57.0-63.7), and Sn (24.9-29.5). These variations in composition produced alloy powders with gamma-Ag3Sn to beta-AgSn ratios varying from 0.0 to 23.9. The total amounts of Hg released from 10 min after trituration were measured from cylindrical specimens (4 x 8mm; n = 4 ) at 37 degrees C using a Hg vapor analyzer. The results were compared to those from commercial alloys (one high-Cu and one low-Cu alloy). All amalgams made from alloys containing 1.5% Pd exhibited lower Hg vapor release than any other amalgams, with the exception of the low-Cu amalgam. The results clearly showed that the alloy formulation affected the mercury evaporation behavior during setting of the resultant amalgams. A small addition of Pd to the alloy can produce amalgams with 50-60% less Hg vapor release during setting than a leading commercial high-Cu amalgam, Tytin.

Copper↗
PubMed2004

Catalytic reduction of N2O over Ag-Pd/Al2O3 bimetallic catalysts.

A study of the catalytic conversion of N2O to N2 over a bimetallic Ag-Pd catalyst is described in this article. Several Ag-Pd catalytic systems were prepared supported on Al2O3 with different ratios and their catalytic activity for the direct decomposition of N2O and their reduction with CO was measured. Based on the experimental results, it was observed that Ag-Pd bimetallic catalyst (5-0.5%) was the most active for both nitrous oxide reduction and direct decomposition. This high activity seems to be connected with a synergistic effect between Ag and Pd.

Air Pollutants↗
PubMed2004

Sleep episodes and daytime somnolence as result of individual susceptibility to different dopaminergic drugs in a PD patient: a polysomnographic study.

The association between excessive daytime somnolence (EDS) and idiopathic Parkinson's disease (PD) is often reported but still debated. The possible role of antiparkinsonian therapy or primarily of PD on excessive diurnal sleepiness is controversial. We describe the case of a 61-year-old patient affected by PD who experienced sleep episodes (SE) occurring during pramipexole plus L-Dopa therapy. Polysomnographic sleep studies and subjective evaluations of daytime sleepiness (Epworth Sleepiness Scale) were carried out under administration of pramipexole plus L-Dopa, L-Dopa monotherapy and cabergoline plus L-Dopa. The polysomnography revealed two sleep events during pramipexole plus L-Dopa. Moreover, the polysomnographic data showed an increase of both diurnal and nocturnal sleep under pramipexole plus L-Dopa compared with cabergoline plus L-Dopa and L-Dopa as monotherapy. In addition, while Epworth Sleepiness Scale (ESS) Score showed a mild sleepiness under pramipexole (ESS score=11), ESS scores were normal under both L-Dopa and cabergoline plus L-Dopa. Sleep episodes also disappeared under both L-Dopa and cabergoline plus L-Dopa (2- and 12-month follow-up). We hypothesize that an individual susceptibility to specific antiparkinsonian drug may play a significant role in the genesis of sleepiness in our PD patient.

Disorders of Excessive Somnolence↗
PubMed2006

Putamen FDOPA uptake and its relationship tot cognitive functioning in PD.

Impaired executive functioning is frequently found in PD patients. As a result, impairments in the executive components of other cognitive functions such as memory, visuo-spatial functions and fluency are also present. From a neuroanatomical point of view, different loops are mediating cognitive, emotional and motor functions. The putamen is part of the motor loop, while the caudate nucleus is part of the motor loop but also of the cognitive loop. In PD, multiple neurotransmitter systems are involved in cognitive functioning, including the dopaminergic system. Cognitive functioning in PD is related to striatal FDOPA uptake. This is particularly true for the caudate nucleus, but also for the putamen. We found a relationship between putaminal FDOPA uptake and measures for executive functioning, memory and fluency in a group of 28 non-demented advanced PD patients. This is a surprising finding since the putamen is part of the motor loop, but not the cognitive loop. One possible explanation is that the putamen is involved in motor actions after cognitive switching and is therefore related to neuropsychological test scores, as these require motor responses.

Fluorine Radioisotopes↗