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At least 397 records · Page 22Linked to original sources
PubMed1989

Pharmacokinetics of a radioiodinated monoclonal antibody F(ab')2 fragment in a xenograft model with circulating antigen.

The pharmacokinetics of 131I-labeled OC 125 F(ab')2 antibody fragment were investigated in athymic mice bearing OVCAR-3 ovarian carcinoma xenografts, a model in which the CA 125 antigen is present in serum. Nine antibody doses between 0.1 and 650 micrograms were studied. Optimal tumor to normal tissue ratios were obtained at 100-200 micrograms of F(ab')2. At most antibody doses, the pre-injection level of circulating CA 125 appeared to influence the localization of 131I activity in tumor, liver and spleen.

Animals↗
PubMed1990

Reduction of beta-adrenoceptor function by oxidative stress in the heart.

The effect of oxidative stress on beta-adrenoceptor function in the heart was determined. To this end ventricle membranes, field-stimulated rat left atria and field-stimulated rat right ventricle strips were exposed to 0.1 mM cumene hydroperoxide for 20 min. It was found that oxidative stress increased beta-adrenoceptor number and reduced c-AMP formation in the ventricle membranes. In the rat left atria and rat right ventricle strips the efficacy of beta-adrenoceptor agonists was reduced to approximately 30% of the control value, whereas maximal beta-adrenoceptor-mediated response was reduced to 50%. Using membranes from control atria and from atria exposed to oxidative stress, it was found that oxidative stress had no effect on beta-adrenoceptor density, nor on the affinity of (-)isoproterenol for the receptor. c-AMP production in membranes prepared from atria exposed to oxidative stress was reduced to approximately 30% of the c-AMP production in membranes prepared of control atria. In addition, it was found that the shape of the function that transduces the stimulus which is generated by receptor activation into an effect, is not altered by oxidative stress. It was concluded that the reduction of the efficacy of beta-adrenoceptor agonists by oxidative stress is probably caused by the reduction of c-AMP formation. Because the efficacy of forskolin and of dibutyryl c-AMP was not affected by oxidative stress, the reduced c-AMP formation is probably caused by an impaired coupling between the receptor and adenylate cyclase. The reduction of maximal beta-adrenoceptor-mediated response might be the result of cytotoxic aldehydes that are produced during oxidative stress. In ischemia, catecholamine release and subsequent beta-adrenoceptor hyperstimulation lead to cardiotoxicity. As shown in the present study, oxidative stress reduces beta-adrenoceptor function. This might represent a protective physiological feedback mechanism that protects the heart against excessive beta-adrenoceptor stimulation.

Adrenergic beta-Agonists↗
PubMed1990

Oxygen radicals in lung pathology.

Pulmonary tissue can be damaged in different ways, for instance by xenobiotics (paraquat, butylated hydroxytoluene, bleomycin), during inflammation, ischemia reperfusion, or exposure to mineral dust or to normobaric pure oxygen levels. Reactive oxygen species are partly responsible for the observed pulmonary tissue damage. Several mechanisms leading to toxicity are described in this review. The reactive oxygen species induce bronchoconstriction, elevate mucus secretion, and cause microvascular leakage, which leads to edema formation. Reactive oxygen species even induce an autonomic imbalance between muscarinic receptor-mediated contraction and the beta-adrenergic-mediated relaxation of the pulmonary smooth muscle. Vitamin E and selenium have a regulatory role in this balance between these two receptor responses. The autonomic imbalance might be involved in the development of bronchial hyperresponsiveness, occurring in lung inflammation. Finally, several antioxidants are discussed which may be beneficial as therapeutics in several lung diseases.

Animals↗
PubMed1992

Role of reactive oxygen species in intestinal diseases.

It is well known that reactive oxygen metabolites are generated during several pathologies, and that they are able to disturb many cellular processes and eventually lead to cellular injury. After intestinal ischemia, reactive oxygen species are produced when the ischemic tissue is reperfused. The enzyme xanthine oxidase is thought to play a key role in this process. As a result of this oxygen radical production, the permeability of the endothelium and the mucosa increases, allowing infiltration of inflammatory leukocytes into the ischemic area. Moreover, reactive oxygen species are also indirectly involved in leukocyte activation. In turn, these inflammatory cells respond with the production of oxygen radicals, which play an important role in the development of tissue injury. Thus, intestinal ischemia and reperfusion evokes an inflammatory response. Also during chronic intestinal inflammatory diseases, reactive oxygen metabolites are proposed to play an important role in the pathology. Scavenging of reactive oxygen species will thus be beneficial in these disorders.

Animals↗
PubMed1993

Molecular pharmacology of vitamin E: structural aspects of antioxidant activity.

In this review, the involvement of vitamin E in free radical physiology and antioxidant mechanisms is discussed. Moreover, structure-activity relationship (SAR) studies on vitamin E analogues are presented. A molecular explanation for the antioxidant activity often is based on molecular parameters, such as Hammett sigma and Brown sigma +. These parameters correlate with the activity. Using semiempirical calculations, we have found other molecular parameters related to electron distribution and structure (such as the difference in heat of formation between the compound and its radical or the energy of the highest occupied molecular orbital, HOMO) which correlate with the antioxidant action of vitamin E and its derivatives.

Antioxidants↗
PubMed1995

Differential sensitivity to hydrogen peroxide of dopaminergic and noradrenergic neurotransmission in rat brain slices.

Oxidative stress, induced by hydrogen peroxide, has been implicated in the pathogenesis of Parkinson's disease. Only scarce information is available if and how hydrogen peroxide, a side product of catecholamine (CA) breakdown, interferes with CAergic neurotransmission. Therefore, we investigated the effect of hydrogen peroxide on the release of [3H]dopamine (DA) and [3H]noradrenaline (NA) from rat striatal and cortical tissue slices, respectively. Hydrogen peroxide (0.01-1 mM) stimulated the spontaneous release of [3H]DA from striatal slices. Its effect on [3H]NA release from cortical slices, however, was much smaller than on DA release and occurred only in concentrations above 0.1 mM. Furthermore, only in concentrations of 1 mM or higher did a stimulation of spontaneous release of radioactivity from striatal slices incubated with [3H]choline occur. Omission of calcium significantly enhanced the effect on DA release, and an increase of calcium significantly reduced it. Blockade of vesicular storage with reserpine (0.3 microM) almost completely abolished [3H]DA release induced by hydrogen peroxide. Following incubation of striatal slices with [3H]NA in the presence of the NA (re)uptake blocker desmethylimipramine (0.3 microM), NA release was observed at a concentration (0.1 mM) at which no effect occurred in cortical slices. Moreover, under these conditions [3]NA and [3H]DA release from striatal slices reached comparable levels. Our results show that hydrogen peroxide induces a nonexocytotic release of DA and NA by interfering with the vesicular uptake and/or storage of these CAs. However, the striatal DA storage system, irrespective of the presence of either DA or NA, appeared to be substantially more sensitive to this effect than its cortical equivalent for storage of NA.

Animals↗
PubMed1996

Structural aspects of antioxidant activity of flavonoids.

Flavonoids, a group of naturally occurring antioxidants and iron chelators, might be used as cardioprotective agents in doxorubicin-induced cardiotoxicity, which is believed to be caused by the formation of oxygen free radicals. To investigate the underlying molecular mechanism, we tested a large group of flavonoids from all major structural subclasses on their ability to inhibit doxorubicin (enzymatically)-induced and Fe2+/ascorbate (nonenzymatically)-induced microsomal lipid peroxidation (LPO) and to chelate Fe2+. In addition, we measured half peak oxidation potentials (Ep/2). LPO inhibition data gave a good qualitative correlation with the oxidation potentials. Most flavonoids tested chelated Fe2+, but there were large differences in the chelating capacity. For good scavenging activity, a catechol moiety on ring B is required. The 3-OH moiety can function as a chelation site and can also be oxidized. The 3-OH group in combination with a C2 C3 double bond, increases the scavenging activity. Fe2+ chelation only plays a role in the LPO inhibition by less active scavengers. Chelation can then raise the activity to the level of the most active scavengers, possibly by site-specific scavenging. It can be concluded that Ep/2 values and iron chelating activity can almost completely describe the LPO inhibiting behaviour of the flavonoids.

Animals↗
PubMed1992

Desensitization of histamine H1 receptor-mediated cyclic GMP production in guinea-pig lung.

Histamine H1 receptor-mediated production of cGMP in guinea-pig lung tissue becomes rapidly desensitized after previous exposure to histamine. This desensitization is clearly concentration dependent and appears to be homologous. Responses to histamine are also inhibited by previous treatment with phorbol 12,13-dibutyrate. Yet, the time course of the inhibition is considerably slower and the maximal inhibition is significantly less compared to receptor desensitization. Moreover, the effects of the phorbol ester are not confined to H1 receptor responses. Since the effects of receptor desensitization are also not prevented by several protein kinase C inhibitors, the development of homologous H1 receptor desensitization is not dependent upon protein kinase C activation, but is caused by a yet unidentified mechanism.

Animals↗
PubMed1992

Atypical molecular pharmacology of a new long-acting beta 2-adrenoceptor agonist, TA 2005.

The molecular pharmacology of a new putative long-acting bronchodilator TA 2005 (8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxy-phenyl)- 1-methylethyl]amino]ethyl]carbostyril hydrochloride) has been compared with that of the reference compounds isoprenaline and salbutamol in both methacholine (3 x 10(-6) M) precontracted guinea pig tracheal smooth muscle relaxation and in bovine trapezium muscle binding experiments. TA 2005 appeared very potent compared with isoprenaline and salbutamol (pD2 values of 9.29 vs. 7.65 and 7.10 respectively). For isoprenaline and salbutamol a shallow displacement curve was observed and addition of the non-hydrolysable GTP analogue guanylyl-imidodiphosphate (GppNHp) gave a rightward shift (pKd,high and pKd,low values of 7.3 and 6.1 vs. 7.0 and 5.4 respectively). For TA 2005 a steep displacement curve was found with only one binding state even without GppNHp (pKd,high value of 8.2). The long duration of action of TA 2005 might be explained by tight binding of this compound to the beta 2-adrenoceptor. The extent of tight binding for TA 2005 was extremely large. The molecular basis of the tight agonist binding phenomenon for TA 2005 seems to be of different origin than for isoprenaline. It is hypothesized that a different mechanism of activation of the beta 2-adrenoceptor may be involved for TA 2005.

Adrenergic beta-Agonists↗
PubMed1993

Extracellular ATP elevates cytoplasmatic free Ca2+ in HeLa cells by the interaction with a 5'-nucleotide receptor.

In the present study we have characterized the effects of ATP and several other nucleotides on the intracellular Ca2+ levels of HeLa cells. Using fura-2 microscopy fluorescence measurements, the ATP-mediated increase in intracellular Ca2+ was shown to consist of a rapid rise which decreased after a few seconds to a sustained elevated level. In the absence of extracellular Ca2+ or in the presence of 10 microM La3+, only a transient elevation of the Ca2+ concentration was observed. The ATP responses were not altered after treatment of HeLa cells with cholera toxin or pertussis toxin. Pharmacological analysis of this calcium response revealed that this effect was not mediated by the classical P2y purinoceptor but by a 5'-nucleotide receptor.

Adenosine Triphosphate↗
PubMed1994

Rapid desensitization of the histamine H2 receptor on the human monocytic cell line U937.

In the present study we have subjected the histamine H2 receptor on the monocytic cell line U937 to a thorough pharmacological characterization using a series of selective histamine H1, H2 and H3 receptor agonists and antagonists. Recent reports have demonstrated the existence of a histamine H2 receptor on HL-60 and HGT-1 cells with a pharmacological profile distinct from the commonly described histamine H2 receptor. U937 cells, however, seem to express classical histamine H2 receptors. Histamine and dimaprit dose dependently induce the formation of cAMP, whereas dimaprit's inactive analogues, nordimaprit and homodimaprit, show reduced potencies. Histamine H1 and H3 receptor agonists do not show histamine H2 receptor activity. Various histamine H2 receptor antagonists are able to block the histamine induced production of cAMP with an antagonistic profile comparable to that observed in the guinea-pig right atrium. Furthermore, endogenous histamine H2 receptors in U937 cells are found to be susceptible to receptor desensitization, a mechanism which may become apparent under pathophysiological conditions or during drug therapy. A 30-min pre-exposure of U937 cells to histamine (100 microM) results in a 50% attenuation of the production of cAMP to a subsequent application of an agonist. Desensitization of the histamine H2 receptor in U937 cells is found to be homologous as the beta-adrenoceptor mediated response remained unaffected.

Cells, Cultured↗
PubMed1994

Structural characteristics of histamine H2 receptor antagonists that scavenge hypochlorous acid.

Gastric and duodenal ulcers are characterized by hypersecretion of gastric acid and pepsin, inflammation of the mucosa and an influx of neutrophils. These cells can produce reactive oxygen species after stimulation. Particularly hydroxyl radicals and hypochlorous acid (HOCl) can be cytotoxic and damage the gastroduodenal mucosa. It has been shown that histamine H2 receptor antagonists such as cimetidine, ranitidine and famotidine are good hydroxyl radical scavengers. This study was undertaken to investigate whether these agents were able to scavenge the cytotoxic HOCl, and if so, which part of the molecule could be responsible for this action. It appears that the sulfur atom in the compound is of importance for scavenging HOCl. This finding should be taken into consideration in the development of new anti ulcer drugs, as HOCl is a detrimental factor in the pathophysiology of gastroduodenal ulcers.

Cimetidine↗
PubMed1995

Anti-oxidant actions of oxymethazoline and xylomethazoline.

Anti-oxidant actions of oxymethazoline and xylomethazoline were investigated by measuring inhibition of microsomal lipid peroxidation and hydroxyl radical scavenging activity. Oxymethazoline was shown to be a potent inhibitor of lipid peroxidation (IC50 = 4.9 microM at t = 15 min, IC50 = 8.1 microM at t = 30 min), in contrast to xylomethazoline. Both compounds were excellent hydroxyl radical scavengers. Their rate constants (ks = 1.1 x 10(12) M-1 s-1 for oxymethazoline and ks = 4.7 x 10(10) M-1 s-1 for xylomethazoline) exceeded the rate constant of a known powerful scavenger cimetidine (ks = 1.8 x 10(10) M-1 s-1). The difference in inhibiting lipid peroxidation might be explained by the fact that only oxymethazoline has a hydroxy group which can donate a hydrogen atom and terminate the chain reaction of lipid peroxidation. The mechanism of hydroxyl radical scavenging activity is still unclear. Moreover oxymethazoline seems to have a different mode of action in scavenging hydroxyl radicals than xylomethazoline and cimetidine which results in an extremely high rate constant. Because oxidants play a role in tissue damage in inflammation, it was hypothesized that especially oxymethazoline and to a lesser extent xylomethazoline may have an additional beneficial effect, due to their anti-oxidant properties, in the topical treatment of nasal inflammation.

Animals↗
PubMed1995

Antioxidant-related parameters in patients treated for cancer chemoprevention with N-acetylcysteine.

N-acetylcysteine (NAC) is an antioxidant, possibly effective in the early steps of carcinogenesis, and is applied to prevent second primary tumours in the upper aerodigestive tract and the lungs. In this study, we evaluated the pharmacodynamic profile of 600 mg NAC treatment, given daily for 3 months. Treatment caused a significant increase of the non-protein-SH concentration in blood plasma (38%) and erythrocytes (31%). Glutathione levels in exfoliated buccal mucosa cells appeared not to be influenced by treatment. The total radical-trapping ability parameter (TRAP) of blood plasma showed no change. In vitro, the addition of glutathione, but not of NAC did increase the TRAP value. In addition, when peroxyl radicals were generated in vitro, NAC was shown to be consumed more rapidly than glutathione. This suggests that NAC prevents early damage, while glutathione functions over a longer time period.

Aged↗
PubMed1994

Differential expression of the 67-kD laminin receptor and 31-kD human laminin-binding protein in human ovarian carcinomas.

The expression of the 67-kD laminin receptor (67LR) and the 31-kD human laminin-binding protein (HLBP31), two proteins involved in cancer cell laminin interaction, was evaluated on 30 ovarian cancer specimens. Expression of the 67LR was increased (up to 2.5-fold, in 87% of the patients), while HLBP31 expression was downregulated in cancer cells compared with the normal tissue, as detected by northern blotting and immunohistochemistry. The immunohistochemical study demonstrated that the 67LR was significantly overexpressed (P < 0.05) in the group of patients whose cytoreductive surgery was suboptimal, and those with poor clinical outcome. No correlation was observed between HLBP31 expression and clinicopathological features. Increased expression of the 67LR appears to correlate with the invasive phenotype of ovarian cancer cells and suggests a role of the latter in ovarian cancer invasion.

Carrier Proteins↗
PubMed1996

Relationship between the tumour tissue pharmacokinetics and the antiproliferative effects of anthracyclines and their metabolites.

The intrinsic activity of anthracyclines and their metabolites was measured in order to determine whether the tumour exposure to the compounds reflects the difference in their ability to inhibit tumour growth. (Dox), 4'-epidoxorubicin (Epi-Dox), daunorubicin (Dauno), N-1-leucyl-doxorubicin (Leu-Dox) and their metabolites were analysed for their antiproliferative effects in three human malignant cell lines: MCF7, RPMI 8226 and A2780. The antitumour efficacy of equitoxic, maximum tolerated doses of the present drugs was assessed in nude mice bearing subcutaneous (s.c.) well-established A2780 doses of the parent drugs was assessed in nude mice bearing subcutaneous (s.c.) well-established A2780 human ovarian cancer xenografts. The same doses were given to tumour-bearing mice to determine the distribution of the anthracyclines and their metabolites in A2780 tumour tissue during the first 48 h after injection. In vitro antiproliferative effects of the anthracyclines and their metabolites revealed a comparable activity for the parent drugs and daunorubicinol, whereas the other metabolites were at least 10-fold less active. The growth inhibition obtained in A2780 xenografts was 87% for Dox, 82% for Epi-Dox, 74% for Dauno and 97% for Leu-Dox. In vivo, the exposure of tumour tissue to the drug, calculated as the area under the concentration-time curve (AUC), was related to the extent of growth inhibition after correction of the AUC values for the intrinsic activity of the anthracycline. For each of the anthracyclines, the sum of the corrected AUC values (nmol/g/min) of the active compounds was calculated as 8812 for Dauno; 9320 for Epi-Dox; 10 986 for Dox and 15 163 for Leu-Dox. The sequence of increasing AUC values corresponded with the sequence of increasing growth inhibition by the four anthracyclines observed in A2780 xenografts.

Animals↗
PubMed1993

Use of telemetry to record electrocardiogram and heart rate in freely moving mice.

This paper describes for the first time the possibility to record the electrocardiogram (ECG) and heart rate (HR) with a commercially available telemetry and data acquisition system in freely moving mice. The system comprises a telemetry transmitter implanted in the peritoneal cavity and a receiver, placed underneath the home cage, an A/D converter (MacLab) and a Macintosh LC II 4/80 computer with software (MacLab, Chart/Scope). The raw analog ECG data are digitized within the MacLab and can be converted to HR data additionally. The effects of surgery for implanting the transmitter, handling and anesthesia by either Nembutal or a mixture of Hypnorm, Dormicum, and water, on the changes in ECG and HR were examined. The telemetry system for recording the ECG and HR provides an accurate and reliable method for monitoring the direct effects of handling on HR. By using this telemetry system, we maintain that measurements in freely moving animals are more efficient, reliable, and less labor-intensive than the measurement techniques described in the literature thus far.

Animals↗
PubMed1994

A new radioligand binding assay for cytochrome P450IID1 (CYP2D1) in rat liver microsomes: a tool to predict sparteine/debrisoquine type polymorphism of drugs.

[3H]-Mepyramine ([3H]-pyrilamine) has a high affinity for cytochrome P450IID1 (CYP2D1) in rat liver microsomes, the isoenzyme involved in the oxidative metabolism of debrisoquine. Drugs known to interact with this enzyme, as either substrate or inhibitor, displaced [3H]-mepyramine. Compounds specific for other P450 isoenzymes did not displace [3H]-mepyramine. Drugs that are positive in this binding assay can be either substrates or inhibitors of CYP2D1 and warrant further research to investigate possible polymorphism. Substrates could reach toxicological concentrations, and inhibitors can have drug interactions with known CYP2D6 substrates. Although care should be taken in the extrapolation from rat to human, since CYP2D1 and CYP2D6 have clear differences, this rapid, easy-to-perform and inexpensive assay has predictive value for the sparteine/debrisoquine type of polymorphic behavior of compounds and could be used at an early stage in drug development.

Animals↗