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Biomedical subjects

A Link

Publications and source records attributed to A Link.

At least 19 recordsLinked to original sources
PubMed2002

[Therapy of verapamil poisoning with noradrenaline and the phosphodiesterase inhibitor enoximone].

HISTORY: A 40 year old patient was transferred to the intensive care unit five hours after the ingestion of 2.4 g of verapamil. ADMISSION FINDINGS: Clinical investigation and invasive monitoring showed signs of cardiogenic shock. THERAPY: Despite primary detoxification and administration of calcium and norepinephrine no adequate cardiovascular stabilization could be achieved. Only when the phosphodiesterase inhibitor enoximone was added, an increase in myocardial inotropy and a stable cardiovascular state was achieved which was also due to the vasoconstrictory effect of norepinephrine overcoming vasodilatation induced by enoximone. CONCLUSION: Detoxification, calcium supplementation and catecholamines are established therapeutic measures. An additional therapy with phosphodiesterase inhibitors is a promising step in conquering predominant heart failure and hypotension.

Adult↗
PubMed2002

MEG-analysis using the Hilbert transform.

Event-related fields (ERFs) measured by magnetoencephalography (MEG) upon visual stimulation are analysed by Hilbert transformation. The Hilbert transform of real-valued measured ERF is an analytic complex signal, represented by phase and amplitude. The temporal behaviour of the derivative of the phase, i.e. the instantaneous frequency, allows to distinguish time intervals containing meaningful signal from noise. On the basis of both phase and amplitude, energies and latencies of single event ERFs can be determined.

Evoked Potentials, Visual↗
PubMed2001

[Hypersensitivity syndrome during therapy with allopurinol in asymptomatic hyperuricemia with a fatal outcome].

HISTORY AND ADMISSION FINDINGS: A 86-year-old woman with chronic renal failure was treated with allopurinol for asymptomatic hyperuricemia. After one week she developed quickly progressive exanthema, bullous eruptions, epidermolysis, fever of 39.1; C and dyspnoea at rest. DIAGNOSIS, TREATMENT AND COURSE: The diagnosis of an allopurinol-induced hypersensitivity syndrome with toxic epidermal necrolysis was made from the history, the typical clinical picture and a skin biopsy. Initial therapy starts with steroids. Because of a lack of clinical improvement therapy was changed to immunoglobulins. In addition, systemic analgesia and cardiocirculatory supportive therapy were given. Because of increasing somnolence and severe pain intubation and controlled artificial ventilation were initiated. Despite intensive therapy progressive multi- organ failure developed and the patient died 3 weeks after start of symptoms. CONCLUSIONS: The life threatening hypersensitivity syndrome with fever, eosinophilia, hepatitis, renal failure and skin eruptions as severe as epidermal necrolysis is the most dangerous complication of therapy with allopurinol. The trigger seems to be oxipurinol, the main metabolite of allopurinol, which particularly accumulates in patients with renal failure and concomitant therapy with thiazides. There is no specific treatment of the disease. The use of allopurinol in patients with asymptomatic hyperuricaemia is not indicated in most cases. Dose adjustment according to the clearance of creatinine is mandatory.

Aged↗
PubMed2001

Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A(3) receptor with selectively enhanced affinity for amine-modified nucleosides.

Adenosine A(3) receptors are of interest in the treatment of cardiac ischemia, inflammation, and neurodegenerative diseases. In an effort to create a unique receptor mutant that would be activated by tailor-made synthetic ligands, we mutated the human A(3) receptor at the site of a critical His residue in TM7, previously proposed to be involved in ligand recognition through interaction with the ribose moiety. The H272E mutant receptor displayed reduced affinity for most of the uncharged A(3) receptor agonists and antagonists examined. For example, the nonselective agonist 1a was 19-fold less potent at the mutant receptor than at the wild-type receptor. The introduction of an amino group on the ribose moiety of adenosine resulted in either equipotency or enhanced binding affinity at the H272E mutant relative to wild-type A(3) receptors, depending on the position of the amino group. 3'-Amino-3'-deoxyadenosine proved to be 7-fold more potent at the H272E mutant receptor than at the wild-type receptor, while the corresponding 2'- and 5'-amino analogues did not display significantly enhanced affinities. An 3'-amino-N(6)-iodobenzyl analogue showed only a small enhancement at the mutant (K(i) = 320 nM) vs wild-type receptors. The 3'-amino group was intended for a direct electrostatic interaction with the negatively charged ribose-binding region of the mutant receptor, yet molecular modeling did not support this notion. This design approach is an example of engineering the structure of mutant receptors to recognize synthetic ligands for which they are selectively matched on the basis of molecular complementarity between the mutant receptor and the ligand. We have termed such engineered receptors "neoceptors", since the ligand recognition profile of such mutant receptors need not correspond to the profile of the parent, native receptor.

Adenosine↗
PubMed2001

Biotin labelling of amines by polymer-assisted solution-phase synthesis.

An efficient and simple polymer-assisted approach has been developed to biotinylate multifunctional compounds bearing an amino functionality. Biotin was immobilized on aminomethylated polystyrene via the Kenner safety catch linker, activated and subsequently transferred to the amino function of the target compounds chemoselectively, thus avoiding protecting group operations. This approach holds potential for the introduction of spacer-modified biotin derivatives.

Amines↗
PubMed2001

Aryl rings are part of the darpone pharmacophore.

In order to investigate structure-activity relationships in the antiproliferative darpone series, the derivatives 8a and 8b lacking the aryl substituents in either 2- or 4-position were synthesized and evaluated for cancer cell growth inhibition. Since both 8a and 8b were devoid of noteworthy antiproliferative activity, both aryl substituents can be considered as part of the darpone pharmacophore.

Antineoplastic Agents↗
PubMed2001

Variability of the QRS signal in high-resolution electrocardiograms and magnetocardiograms.

The variability of electric and magnetic signals from the heart during the depolarization phase is investigated. A signal processing method is developed, which provides estimates for the beat-to-beat variability of the QRS-complex. The method is based on the decomposition of the depolarization signal into bandpass signals by means of the Morlet wavelet transform. The beat variability of the depolarization signal is estimated by normalized variances of the envelope and instantaneous frequency of bandpass signals. Time intervals of the bandpass filtered depolarization signals having a high signal-to-noise ratio are selected applying an analysis based on phase statistics. The method was tested by computer simulation and experimental data taken from electrocardiographic and magnetocardiographic measurements of healthy persons and patients prone to malignant ventricular tachycardia (VT) or ventricular fibrillation (VF). Results suggest that the calculated variance parameters permit the characterization of beat variable depolarization signals and distinguish VT/VF patients from healthy persons.

Algorithms↗
PubMed2000

Quantitative MRS: comparison of time domain and time domain frequency domain methods using a novel test procedure.

For quantitative analysis of in vivo MR spectra, a state-of-the-art time domain method was compared with a recently reported time domain frequency domain method which uses wavelets for background characterization. The comparison was made on the basis of results for simulated test problems that were constructed by combining measured and simulated MRS data at different signal-to-noise ratios in order to simultaneously reflect real world difficulties, in particular the overlapping background problem, and to allow for quantitative judgment of a method's accuracy. Incorporating prior knowledge was also considered. The results obtained give insight into the accuracy of the methods when applied to measured MRS data. Due to the improved background characterization, the time domain frequency domain method outperformed the time domain method in some of the test cases. Both methods were also applied to serial brain MR spectra of a healthy volunteer on 10 occasions.

Brain↗
PubMed2000

Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia.

Although high-dose methotrexate has been extensively studied in children with newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated and have subclinical kidney dysfunction. We characterized the pharmacokinetics of adaptively controlled methotrexate given as a 24-h infusion during consolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 microM, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m2 per course. The mean steady-state plasma concentration (Cpss) of 68.0 microM was different (P = 0.025) than the predicted Cpss (mean = 87.4 microM; range 35.7-184 microM) had no adjustment in dose been made. The coefficient of variation in Cpss was reduced from 41% to 18% by individualizing doses. Predisposing factors that correlated with decreased methotrexate clearance were female sex (P = 0.03), age greater than 6 years (P = 0.01), and prior history of heavy amphotericin B treatment (>30 mg/kg) (P = 0.03), but no factor predicted low clearance as well as the measured initial methotrexate clearance during the infusion (P < 0.0001). There was no life-threatening toxicity with the regimen. We conclude that dosage individualization decreases interpatient variability and avoids potentially toxic methotrexate exposures in heavily pretreated ALL patients.

Adolescent↗
PubMed2000

Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.

Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP-competitive, inhibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3beta (GSK-3beta) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerative 'taupathies'. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.

Adenosine Triphosphate↗
PubMed2000

Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition.

A congeneric series of paullones were characterized using a 3-D QSAR with cyclin-dependent kinase 1 (CDK1) inhibition data. A homology model of CDK1-cyclin B was developed from the crystal structure of CDK2-cyclin A, which subsequently served as the basis for the structure-based design. Paullones were docked into the ATP binding site of the CDK1-cylin B models and were optimized with molecular mechanics. Hydropathic analyses of the paullone-CDK1 complexes were performed after the atom types were assigned based on each ligand's electronic properties calculated from quantum mechanics. Hydropathic descriptors formed a significant multiple regression equation that predicts paullone IC50 data. The results indicate that the combination of hydropathic descriptors with molecular mechanics geometries are sufficient to design overt steric and chemical complementarity of the ligands. However, the electronic properties derived from quantum mechanics helped direct synthetic chemistry efforts to produce ligands that promote better charge transfer and strengthen hydrogen bonding as facilitated by resonance stabilization. Compounds with low affinity for CDK1 were poor charge acceptors and made less than ideal hydrogen bonding arrangements with the receptor. These considerations led to the prediction that structures such as 9-cyanopaullone would be considerably more potent than the parent compound, a finding supported by enzyme inhibition data. Also, 9-nitropaullone emerged as a paullone which also had similar potency in enzyme inhibition as well as a favorable anti-proliferative activity profile in living cells.

Cyclin-Dependent Kinases↗
PubMed1999

Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity.

The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).

Animals↗
PubMed1999

Identification of proteins in complexes by solid-phase microextraction/multistep elution/capillary electrophoresis/tandem mass spectrometry.

A method to directly identify proteins in complex mixtures by solid-phase microextraction (micro-SPE)/multistep elution/capillary electrophoresis (CE)/tandem mass spectrometry (MS/MS) is described. A sheathless liquid-metal junction interface is used to interface CE and electrospray ionization MS/MS. A subfemtomole detection limit is achieved for protein identification through database searching using MS/MS data. The SPE serves as a semiseparation dimension using an organic-phase step-elution gradient in combination with the second separation dimension for increased resolving power of complex peptide mixtures. This approach improves the concentration detection limit for CE and allows more proteins in complex mixtures to be identified. A 75-protein complex from yeast ribosome is analyzed using this method and 80-90% of the proteins in the complex can be identified by searching the database using the MS/MS data from a complete analysis. This multidimensional CE/MS/MS methodology provides an alternative to multidimensional liquid chromatography/MS/MS for direct identification of small amounts of protein in mixtures.

Electrophoresis, Capillary↗
PubMed1999

Antitumor pyrido[3,2-d][1]benzazepines: synthesis and in vitro activity of thiophene analogs.

The bioisosteric replacement of benzene elements in the antitumor lead structures 2 and 3 led to the thienyl substituted 5H-pyrido[3,2-d][1]benzazepin-6(7H)-ones 8a and 8b, the analogous thiolactams 4a and 4b, and the 4H-pyrido[2,3-d]-thieno[3,2-b]azepines 11 and 12 which represent a novel heterocyclic scaffold. The in vitro evaluation of 4a in a cell line based screening revealed a noteworthy antitumor activity and a remarkable selectivity for renal tumor cell lines. The cell line selectivity pattern of 4a differs distinctly from the pattern displayed by standard antitumor agents.

Animals↗
PubMed1999

Exploration of the effect of sterically demanding 3'-amido substitution of 3'-deoxyadenosines towards inhibition of cyclin-dependent kinase 1.

With focus on exploring the structural demands of adenosine triphosphate pockets of different target enzymes, the 3'-amido-3'-deoxyadenosines 1-7 were synthesized. The inhibitory activity of these compounds on a selected cyclin-dependent kinase as model target in anticancer research was evaluated in vitro. A starfish oocyte enzyme based assay revealed a decreased inhibitory activity in comparison to adenosine. Consequently, the introduction of spacefilling lipophilic 3'-amido substituents alters the enzyme inhibition in an unfavorable manner.

Animals↗
PubMed1998

Neutrophil adhesion and activation during systemic thrombolysis in acute myocardial infarction.

In a pilot study, alterations of polymorphonuclear neutrophil function during systemic thrombolysis in acute myocardial infarction have been investigated in humans. The following parameters of neutrophil function were measured before and at 15 and 45 minutes after initiation of systemic thrombolysis with a recombinant tissue-type plasminogen activator in 20 patients with acute myocardial infarction: (1) neutrophil adhesion and (2) neutrophil activation. During systemic thrombolysis a significant decrease was observed in neutrophil adhesion (5.5+/-6.4 to 3.2+/-3.3; p<0.05), in phagocyting neutrophil activation (39+/-18 to 25+/-14%; p<0.05), and in resting neutrophil activation (9+/-7 to 3+/-4%; p<0.05). Successful reperfusion coincided with a significantly higher reduction of phagocyting neutrophil activation (40+/-14 to 20+/-12% vs. 39+/-24 to 26+/-19% in unsuccessful reperfusion; p<0.05), and of neutrophil adhesion (6.2+/-5.7 to 2.7+/-3.0 vs. 4.1+/-3.8 to 3.5+/-4.0 in unsuccessful reperfusion; p<0.05) during thrombolysis. Systemic thrombolysis in acute myocardial infarction is accompanied by a reduction in neutrophil adhesion and activation dependent on thrombolytic success.

Acute Disease↗
PubMed1998

d-Fused [1]benzazepines with selective in vitro antitumor activity: synthesis and structure-activity relationships.

The synthesis of novel quinolino[3,2-d][1]benzazepines and pyrido[3,2-d][1]benzazepines is described. The in vitro antitumor activity of the compounds has been tested in the antitumor screening of the National Cancer Institute (NCI). Several 2,4-diarylpyrido[3, 2-d][1]benzazepin-6-ones and -thiones turned out to exhibit considerable cytotoxicity for tumor cells. For studies of SAR within these series, substituents were introduced into the aromatic rings of the parent systems. Compounds from the thiolactam series tended to show higher potency than the corresponding lactams. Prominent compounds with noteworthy activity and remarkable selectivity for renal cancer cell lines are the lactams 10c, 10g, and 10h and the corresponding thiolactams 11c, 11g, and 11h. Methylation of the azepine nitrogen leads to complete loss of activity, whereas annelation of a triazolo ring at the lactam site or transformation of the thiolactam function to a thiolactim ether results in decreased antitumor activity and selectivity. Consequently, the secondary lactam or thiolactam structure of the seven-membered ring has to be regarded as essential for selective antitumor activity.

Antineoplastic Agents↗