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PubMed1990

Initial steps in the degradation of benzene sulfonic acid, 4-toluene sulfonic acids, and orthanilic acid in Alcaligenes sp. strain O-1.

Alcaligenes sp. strain O-1 grew with benzene sulfonate (BS) as sole carbon source for growth with either NH4+ or NH4+ plus orthanilate (2-aminobenzene sulfonate, OS) as the source(s) of nitrogen. The intracellular desulfonative enzyme did not degrade 3- or 4-aminobenzene sulfonates in the medium, although the enzyme in cell extracts degraded these compounds. We deduce the presence of a selective permeability barrier to sulfonates and conclude that the first step in sulfonate metabolism is transport into the cell. Cell-free desulfonation of BS in standard reaction mixtures required 2 mol of O2 per mol. One mol of O2 was required for a catechol 2,3-dioxygenase. When meta ring cleavage was inhibited with 3-chlorocatechol in desalted extracts, about 1 mol each of O2 and of NAD(P)H per mol of BS were required for the reaction, and SO3(2-) and catechol were recovered in high yield. Catechol was shown to be formed by dioxygenation in an experiment involving 18O2. 4-Toluene sulfonate was subject to NAD(P)H-dependent dioxygenation to yield SO3(2-) and 4-methylcatechol, which was subject to meta cleavage. OS also required 2 mol of O2 per mol and NAD(P)H for degradation, and SO3(2-) and NH4+ were recovered quantitatively. Inhibition of ring cleavage with 3-chlorocatechol reduced the oxygen requirement to 1 mol per mol of OS SO3(2-) (1 mol) and an unidentified organic intermediate, but no NH4+, were observed.

Alcaligenes↗
PubMed1992

Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy.

The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model. One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin (20 mg/kg per os). Three hours after indomethacin, the extent of macroscopically visible gastric damage was determined, and gastric LTB4 synthesis was determined. The compounds tested were PF-5901, A-64077, nordihydroguaiaretic acid, and L-698,037. Each compound produced dose-related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin-induced damage. The antioxidant properties of these compounds was assessed using an in vitro assay. There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin-induced gastric damage. In the second part of the study, the effects of intravenous, administration of LTD4 and LTB4 receptor antagonists on indomethacin-induced gastric epithelial damage (measured by permeability to [51Cr]EDTA) were assessed. The two LTD4 receptor antagonists (MK-571 and ICI-204,219) significantly reduced the permeability changes induced by indomethacin, while the two LTB4 antagonists (SC-41930 and LY-255,283) were without significant effect. Despite the reduction of gastric epithelial injury, blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury. These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs. However, it remains unclear to what extent leukotrienes are involved in the initiation of the injury, as opposed to its amplification.

5-Lipoxygenase-Activating Proteins↗
PubMedDate not supplied

Leukotriene receptor antagonists and related compounds.

Leukotrienes (LTs), lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past year and a half, the development of three new drugs that modulate the LT pathway has been completed. The first subclass of these drugs, leukotriene receptor antagonists (LTRA) (zafirlukast and montelukast), blocks the interaction of the cysteinyl form of the LTs with the cell type bearing the receptor. The second subclass, the 5-lipoxygenase (5-LO) inhibitors (zileuton) inhibits the 5-LO enzyme, which prevents the formation of both cysteinyl LTs and LTB4. The LT modulators have shown efficacy in inhibiting the physiological changes occurring after allergen, acetylsalicylic acid and exercise challenge in asthmatics. In addition, they have shown efficacy in improving symptoms, beta-agonist use and forced expiratory volume in 1 s (FEV1) in chronic, 'day-to-day' asthma in patients with mild disease. Comparison studies with low doses of inhaled corticosteroids suggest that LT modulators may have similar effects on symptom scores and beta-agonist use, but have lesser effects on FEV1. Finally, emerging data suggest that these drugs are beneficial in decreasing the dose of inhaled corticosteroids necessary to control more moderate to severe asthma. While long term studies will be helpful in determining the 'disease modifying' effects of these drugs, data suggest that these drugs are useful in the treatment of a broad range of asthmatic patients.

Acetates↗
PubMed2000

Zinc in the extracellular area of the central nervous system is necessary for the development of kainic acid-induced persistent hyperalgesia in mice.

Kainic acid produces a persistent hyperalgesia when injected intraperitoneally (i.p.) in the rat or mouse. At higher doses than those needed to influence nociception, kainic acid induces seizures and translocation of histologically reactive zinc in the hippocampus. We tested the hypothesis that zinc, localized in a population of small diameter primary afferent neurons, plays a role in kainic acid-induced hyperalgesia similar to that in the hippocampus where zinc translocation accompanies kainic acid-induced seizures. The importance of zinc in the extracellular area was assessed by the influence of compounds that chelate divalent cations (disodium calcium ethylene diaminetetraacetate (CaEDTA)) or zinc (dipicolinic acid (DPA)) on kainic acid-induced hyperalgesia. When measured using the tail flick assay, thermal hyperalgesia was blocked by pretreatment intrathecally (i.t.) with either 10 nmol of NaCaEDTA or 1 nmol of DPA, drugs whose distribution is limited to the extracellular area. Injection of 10 ng zinc chloride i.t. had no long-term effect on nociception or on kainic acid-induced hyperalgesia. Whether zinc is translocated in response to a hyperalgesic dose of kainic acid was determined using the zinc-selective dye, N-(6-methoxy-8-quinolyl)-para-toluenensulfonamide (TSQ), which produces a delicate stain in the neuropil of the mouse spinal cord as well as a dense stain in the hippocampus. Injection of a hyperalgesic dose of kainic acid failed to alter TSQ fluorescence in either the spinal cord or hippocampus, in contrast to the distinct bleaching of TSQ in the hippocampus 24 h after a convulsant dose of kainic acid. Together these data suggest that, while not translocated, zinc in the extracellular area is necessary but not sufficient for the development of kainic acid-induced hyperalgesia.

Aminoquinolines↗
PubMed2001

Fluorescent detection of Zn(2+)-rich vesicles with Zinquin: mechanism of action in lipid environments.

High concentrations of free Zn2+ ions are found in certain glutamatergic synaptic vesicles in the mammalian brain. These terminals can be visualized histochemically with quinoline sulfonamide compounds that form fluorescent complexes with Zn2+. The present study was undertaken to examine the interaction of the water-soluble quinoline sulfonamide probe, Zinquin (2-methyl-8-(toluene-p-sulfonamido)-6-quinolyloxyacetic acid) with the complex heterogeneous cellular environment. Experiments on rat hippocampal and neocortical slices gave indications that Zinquin in its free acid form was able to diffuse across the plasma and synaptic vesicle membranes. Further experiments were undertaken on unilamellar liposomes to study the interaction of Zinquin and its metal complexes in membranes. These experiments confirmed that Zinquin is able to diffuse across lipid bilayers. Steady-state and time-resolved fluorimetric studies showed that Zinquin in aqueous solution mainly forms a 1:2 (metal:ligand) complex with small amounts of a 1:1 complex. Formation of the 1:1 complex was favored by the presence of lipid, suggesting that it partitions into membranes. Evidence is presented that Zinquin can act as a Zn(2+)-ionophore, exchanging Zn2+ for two protons. The presence of a pH gradient across vesicles traps the Zn(2+)-probe complex within the vesicles. Zinquin is useful as a qualitative probe for detecting the presence of vesicular Zn2+; however, its tendency to partition into membranes and to serve as an ionophore should be borne in mind.

Animals↗
PubMed2003

Validation of the chloramine-T induced oxidation of human serum albumin as a model for oxidative damage in vivo.

PURPOSE: The validity of using chloramine-T as a model compound for mimicing oxidative stress was examined using human serum albumin (HSA) as a model. Important sites of oxidation were studied by mild treatment with chloramine-T and by mutating 34Cys for a serine (C34S). METHODS: High-performance liquid chromatography (HPLC) combined with fluorescence detection to confirm the validity of chloramine-T as an oxidizing agent was used. Oxidized amino acid residues were detected by reaction with 5,5'-dithiobis(2-nitro benzoic acid), digestion with cyanogen bromide, followed by capillary electrophoresis. Protein conformation was examined by spectroscopic techniques. RESULTS: From the HPLC analysis of human serum, the validity of using chloramine-T as an oxidizing agent was confirmed. At low chloramine-T concentrations (CT0.1-HSA, CT1-HSA), 34Cys and Met residues were oxidized, at medium concentrations (CT10-HSA), the tryptophan residue also appeared to be oxidized, and at the highest concentration (CT50-HSA), the net charge of Site II of HSA was found to be more negative. The two highest levels of oxidation of HSA (CT10-HSA, CT50-HSA) resulted in conformational changes with an increased exposure of hydrophobic regions, decreased high-affinity bindings of warfarin and ketoprofen and a reduced esterase-like activity. The latter protein also has a shorter plasma half-life and an increased liver clearance. CONCLUSIONS: We succeeded in imitating oxidative damage to HSA using chloramine-T and the findings show that Site II is more affected than Site I and 34Cys, when HSA is exposed to oxidative stress.

Animals↗
PubMed2001

Comparative efficacy of inhaled corticosteroids and antileukotriene drugs in asthma.

Asthma is an inflammatory disease of the airways that is best treated by minimising exposure to factors that provoke the inflammation (e.g. allergens) and by administering drugs that reduce the inflammatory response. The cornerstone of asthma treatment is inhaled corticosteroids. Their effectiveness is a result of their potent and broad anti-inflammatory properties. Antileukotriene drugs (leukotriene modifiers) provide an alternative and novel approach to the treatment of asthma. The novelty of these new compounds is that their effectiveness is firmly based on the pathophysiology of asthma, specifically the role played by the cysteinyl leukotrienes. At the same time, the availability of the antileukotriene drugs has stirred debate over when they should be used and how they compare to inhaled corticosteroids. Although the answers are not fully known at this time, the currently available published and presented data are adequate for us to draw some conclusions about their relative effectiveness and role in asthma treatment. The antileukotriene drugs are more effective than placebo, but they are not as effective as inhaled corticosteroids in improving lung function [measured as the forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow rate (PEFR)], reducing beta(2)-agonist use, and decreasing symptom-free days. In contrast, they may have similar beneficial effects on reducing asthma exacerbations and decreasing peripheral blood eosinophil counts. In the absence of knowing a priori the response of an individual patient to treatment with either therapy, the data favour initiating treatment with an inhaled corticosteroid. However, for patients with mild to moderate disease there are a number of circumstances that support using an antileukotriene drug first. A few examples are aspirin intolerance, predominantly exercise-induced symptoms and problems with using an inhaler or the adverse effects of inhaled corticosteroids such as dysphonia and thrush. For patients with more severe disease, inhaled corticosteroids remain the treatment of choice. Antileukotriene drugs should be considered as add-on therapy, especially in view of their possible complementary effects on reducing airway inflammation.

Administration, Inhalation↗
PubMed1998

A risk-benefit assessment of antileukotrienes in asthma.

The antileukotriene drugs are the first new therapeutic agents approved for the treatment of asthma in more than 20 years. The currently available compounds are orally active and either prevent the cysteinyl leukotrienes from binding to and activating the cysLT-1 receptor in the lung (leukotriene receptor antagonists) or inhibit leukotriene synthesis (leukotriene synthesis inhibitors). Studies performed in individuals without asthma and patients with asthma reveal that antileukotrienes prevent the bronchoconstriction produced by exercise, cold-air, allergen, aspirin (acetylsalicylic acid) and sulphur dioxide. Except for the setting of aspirin sensitivity where the antileukotrienes are nearly uniformly effective, individual responses to them are variable with complete protection in some, no protection in others and a modest degree of protection in the majority. The antileukotrienes bronchodilate the airways of patients with baseline bronchoconstriction, although usually not as well as beta-agonists. When given for weeks to months they rapidly improve pulmonary function and symptoms in patients with mild-to-moderate asthma, and probably in patients with more severe asthma as well, and these improvements persist for the duration of treatment. Here too, their beneficial effects are variable and not predictable based on clinical criteria. Recent studies suggest they can reduce asthma-induced airway inflammation and are equal or more effective than sodium cromoglycate, but equal or less effective than low-to-moderate dosages of inhaled corticosteroids. Initial experience with the antileukotrienes reveals limited toxicity and what appears to be a favourable therapeutic-to-toxic ratio. However, exposure of more patients with differing characteristics for longer periods of time is needed to substantiate this initial impression. The exact role of the antileukotrienes in the treatment of asthma remains to be determined, as does the relative potency of the various agents.

Anti-Asthmatic Agents↗
PubMed1994

Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation.

The effect of modulators of protein phosphorylation on the transcriptional activity of the androgen receptor (AR) was studied under transient expression conditions. Activators of protein kinase-A [8-bromo-cAMP (8-Br-cAMP)] and protein kinase-C (phorbol 12-myristate 13-acetate) or an inhibitor of protein phosphatase-1 and -2A (okadaic acid) influenced minimally pMMTV-chloramphenicol acetyl-transferase (CAT) activity in CV-1 cells cotransfected with an AR expression plasmid in the absence of androgen. In the presence of testosterone, however, all compounds enhanced AR-mediated transactivation by 2- to 4-fold. A nonsteroidal antiandrogen, Casodex, behaved as a pure antagonist; it blunted the action of testosterone and was not rendered agonistic by activators of protein kinase-A. A reporter plasmid containing two androgen response elements (AREs) in front of the thymidine kinase promoter (pARE2tk-CAT) was also used to examine promoter specificity. It was activated by 8-Br-cAMP, forskolin, or okadaic acid even without AR or androgen. However, when forskolin or okadaic acid was used together with androgen and AR, the resulting AR-dependent transactivation of pARE2tk-CAT was more than additive. Intact DNA- and ligand-binding domains, but not the N-terminal amino acid residues 40-147, of the receptor were mandatory for the synergism between protein kinase-A activators and androgen. Immunoreactive AR content in transfected COS-1 cells was not influenced by exposure to 8-Br-cAMP. Similar results were obtained by ligand binding assays. Quantitative or qualitative differences were not observed in DNA-binding characteristics between receptors extracted from cells treated with testosterone with or without protein kinase-A activator. Collectively, the synergistic stimulation of AR-dependent transactivation by androgen and protein kinase activators is not due to changes in cellular AR content or affinity of the receptor for the cognate DNA element; rather, this phenomenon seems to result from altered interaction of ligand-activated AR with other proteins in the transcription machinery.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system.

Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the nonsteroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention.

Androgen Antagonists↗
PubMed1997

Comparison of in vitro effects of the pure antiandrogens OH-flutamide, Casodex, and nilutamide on androgen-sensitive parameters.

OBJECTIVES: A combination of flutamide (Eulexin) or nilutamide (Anandron) with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy is the only therapy demonstrated to prolong life in prostate cancer. Recently, the low 50-mg daily dose of Casodex, an analogue of the pure antiandrogen flutamide, was chosen for clinical studies on the basis that the compound was 5 to 10 times more potent than flutamide, as suggested by data obtained in the inappropriate intact rat model. The present study was designed to compare the in vitro antiandrogenic activity of OH-flutamide (OH-FLU), the active metabolite of flutamide, Casodex, and nilutamide. METHODS: The effect of the antiandrogens was tested on two androgen-sensitive parameters, namely proliferation of the SEM-107 clone of Shionogi mouse mammary tumor cells and secretion of the GCDFP-15 (gross cystic disease fluid protein 15 kDa) in T-47D and ZR-75-1 human breast cancer cells. RESULTS: The twofold stimulation of Shionogi cell proliferation caused by a 10-day exposure to 1 nM testosterone was competitively reversed by incubation with OH-FLU, Casodex, or nilutamide, at the respective IC50 values of 72, 243, and 412 nM. Moreover, the marked increase in GCDFP-15 release induced by 1 nM testosterone was blocked by OH-FLU. Casodex, or nilutamide at respective IC50 values of 29, 180, and 87 nM in T-47D cells and at 35, 142, and 75 nM in ZR-75-1 cells. Similar data were detected in 4-androstenedione-induced Shionogi cell proliferation and in dihydrotestosterone-induced GCDFP-15 secretion in T-47D cells. CONCLUSIONS: OH-FLU is 3.1- to 7.8-fold more potent than Casodex, as measured on two in vitro androgen-sensitive parameters, in agreement with our recent in vivo data obtained in the model of castrated rats supplemented with 4-androstenedione implants, in which threefold greater potency of flutamide was observed. The present data, as well as other data from the literature, strongly indicate the need to choose a more appropriate dose of Casodex for the treatment of prostate cancer.

Androgen Antagonists↗
PubMed2000

Characteristics of a novel deep red/infrared fluorescent cell-permeant DNA probe, DRAQ5, in intact human cells analyzed by flow cytometry, confocal and multiphoton microscopy.

BACKGROUND: The multiparameter fluorometric analysis of intact and fixed cells often requires the use of a nuclear DNA discrimination signal with spectral separation from visible range fluorochromes. We have developed a novel deep red fluorescing bisalkylaminoanthraquinone, DRAQ5 (Ex(lambdamax) 646 nm; Em(lambdamax) 681 nm; Em(lambdarange) 665->800 nm), with high affinity for DNA and a high capacity to enter living cells. We describe here the spectral characteristics and applications of this synthetic compound, particularly in relation to cytometric analysis of the cell cycle. METHODS: Cultured human tumor cells were examined for the ability to nuclear locate DRAQ5 using single and multiphoton laser scanning microscopy (LSM) and multiparameter flow cytometry. RESULTS: Multiparameter flow cytometry shows that the dye can rapidly report the cellular DNA content of live and fixed cells at a resolution level adequate for cell cycle analysis and the cycle-specific expression of cellular proteins (e.g., cyclin B1). The preferential excitation of DRAQ5 by laser red lines (633/647 nm) was found to offer a means of fluorescence signal discrimination by selective excitation, with greatly reduced emission overlap with UV-excitable and visible range fluophors as compared with propidium iodide. LSM reveals nuclear architecture and clearly defines chromosomal elements in live cells. DRAQ5 was found to permit multiphoton imaging of nuclei using a 1,047-nm emitting mode-locked YLF laser. The unusual spectral properties of DRAQ5 also permit live cell DNA analysis using conventional 488 nm excitation and the single-photon imaging of nuclear fluorescence using laser excitation between 488 nm and low infrared (IR; 780 nm) wavelengths. Single and multiphoton microscopy studies revealed the ability of DRAQ5 to report three-dimensional nuclear structure and location in live cells expressing endoplasmic reticulum targeted-GFP, MitoTracker-stained mitochondria, or a vital cell probe for free zinc (Zinquin). CONCLUSION: The fluorescence excitation and emission characteristics of DRAQ5 in living and fixed cells permit the incorporation of the measurement of cellular DNA content into a variety of multiparameter cytometric analyses.

Anthraquinones↗
PubMed1996

The development of Casodex (bicalutamide): preclinical studies.

Casodex (bicalutamide, Zeneca Limited) was developed for the treatment of prostate cancer from a series of nonsteroidal compounds related to flutamide. Casodex is a selective antiandrogen that binds to rat, dog and human prostate androgen receptors, and has approximately a 4-fold higher affinity for the rat androgen receptor than hydroxyflutamide, the active metabolite of flutamide. Casodex also binds to androgen receptors found in the LNCaP human prostate tumour and the Shionogi S115 mouse mammary tumour cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, Casodex behaves as a 'pure' antiandrogen and inhibits gene expression and cell growth stimulated by androgens. Studies in vivo show that Casodex is a potent antiandrogen in the rat. In contrast to flutamide, which produces dose-related, marked increases in serum luteinising hormone (LH) and testosterone, Casodex has little effect on serum LH and testosterone; that is, it is peripherally selective. The peripheral selectivity of Casodex has now been shown to be due to poor penetration across the blood-brain barrier. In dogs, Casodex has exquisite potency and causes dose-related atrophy of the prostate gland and epididymis; with an oral ED50 of 0.1 mg/kg, it is about 50 times as potent as flutamide in this species. Casodex is also peripherally selective in the dog. In addition, magnetic resonance imaging studies have shown that Casodex is a potent antiandrogen in the monkey. Casodex, at a daily oral dose of 25 mg/kg effected a highly significant reduction in the growth of Dunning R3327H transplantable rat prostate tumours that was equivalent to that achieved by either surgical or medical castration with the LH-releasing hormone agonist Zoladex (goserelin). In a comparative study, flutamide was shown to be both less potent and less active than Casodex. In these preclinical studies, Casodex was well tolerated. The preclinical properties of Casodex give it advantages, with respect to potency, tolerability and the maintenance of effective antiandrogen serum concentrations, over other available antiandrogens. Moreover, it has a half-life that is compatible with once-daily administration.

Androgen Antagonists↗
PubMed1999

The chemical cell biology of zinc: structure and intracellular fluorescence of a zinc-quinolinesulfonamide complex.

Fluorescent cell-permeant compounds based on 6-methoxy-8-p-toluenesulfonamido-quinoline, TSQ, are potentially powerful probes of intracellular zinc chemistry; however, the structure, thermodynamics, and stoichiometry of the metal complexes, and the molecular basis of Zn(II) recognition, remain open issues. To address these, we report the first structural characterization of a Zn(II) complex of a TSQ derivative, namely 2-methyl-6-methoxy-8-p-toluenesulfonamido-quinoline (3) and describe its unusual coordination chemistry. The crystal structure of the fluorescent complex of 3 with zinc reveals a 2:1 stoichiometry wherein bidentate coordination of two nitrogens from each ligand gives rise to a highly distorted tetrahedral Zn(II) center. Both sulfonamido groups in the zinc complex are tilted away from zinc to make room for coordination of the amide nitrogens. Zn-O(2) and Zn-O(4) distances are essentially nonbonding (3.06 and 3.10 A, respectively). The bond angles [N(1)-Zn-N(2) 83.5 degrees and N(3)-Zn-N(4) 83.0 degrees] are quite small relative to the 109 degrees angle of an ideal tetrahedral center. This result provides an insight into the zinc-binding mode of the TSQ derivative zinquin, in which a methyl group replaces the hydrogen in the 2-position of the quinoline ring. The methyl group and sulfonamide oxygen atoms clearly hinder formation of both square planar and octahedral complexes. We also show here that the Zn(II) complex of 3 in DMSO-water (80/20 w/w) exhibits an overall binding stability (log beta 2 = 18.24 +/- 0.02) similar to zinquin. Fluorescence microscopy suggests that each of these members of this family demarks a similar set of Zn(II)-enriched compartments that are common to all eukaryotic cells examined to date, and further shows that the ester function is not required for observation of these ubiquitous Zn-loaded compartments. The combined structural, thermodynamic, and physiological results provide a basis for design of other Zn(II)-specific membrane permeant probes with a range of Zn(II) affinities and photophysical properties.

3T3 Cells↗
PubMed1996

The preclinical development of bicalutamide: pharmacodynamics and mechanism of action.

OBJECTIVES. To describe the preclinical development of bicalutamide and clarify its pharmacodynamics and mechanisms of action. Bicalutamide was developed from a series of nonsteroidal compounds related to flutamide that showed a range of pharmacologic activity from full androgen agonist to pure antiandrogen, including progestational and antiprogestational properties. METHODS AND RESULTS. Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5 alpha-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growth stimulated by androgen. Studies with the LNCaP cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr-->Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide): both these antiandrogens act as agonists in this cell line and stimulate proliferation. Studies in vivo show that bicalutamide is a potent antiandrogen in the rat. In immature, castrated male rats treated daily with testosterone propionate, bicalutamide produces a profound inhibition of accessory sex organ (ventral prostate and seminal vesicles) growth at oral doses as low as 0.25 mg/kg; it is more active in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide. In contrast to flutamide, which produces dose-related, marked increases in serum luteinizing hormone (LH) and testosterone as a consequence of the central inhibition of the negative feedback effects of androgens on the hypothalamic-pituitary-tests axis, bicalutamide has little effect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to differences between the prostate versus hypothalamic or pituitary receptors, as bicalutamide reverses the suppressive effect of testosterone on luteinizing hormone-releasing hormone (LHRH) secretion from hypothalamic slices in vitro and is as effective as flutamide at sensitizing the pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due to poor penetration across the blood-brain barrier: tissue distribution studies with [3H]bicalutamide show that although it is concentrated in the organs of metabolism and secretion as well as in the prostate, the pituitary glands, and the seminal vesicles, levels in the hypothalamus and the central nervous system (CNS) are much lower than in blood. Indeed, it is probable that levels found in the CNS reflect levels of blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; with an oral ED50 of 0.1 mg/kg, it is around 50 times as potent as flutamide in this species and also more potent than the steroidal antiandrogen WIN49596 and the 5 alpha-reductase inhibitor MK-906. Even at substantial multiples of the active dose (up to 100 mg/kg orally), bicalutamide failed to increase serum testosterone, so it is also peripherally selective in the dog.

Androgen Antagonists↗
PubMed1996

Leukotrienes in asthma. The potential therapeutic role of antileukotriene agents.

Recent advances in research have led to the identification of an inflammatory component to asthma. Although many endogenous mediators are involved in inflammation, leukotrienes appear to play an especially important role in asthma. The leukotrienes produce tissue edema, mucus secretion, and smooth-muscle proliferation, along with a powerful bronchoconstriction. In addition, antileukotriene drugs have emerged as potential therapeutic agents for asthma. This study was designed to review the current information on these new agents. In this review, full-length articles of antileukotriene agents are examined. These articles were found through MEDLINE under the following medical headings: asthma, inflammation, leukotriene, leukotriene-receptor antagonist, and leukotriene-synthesis inhibitor. Most clinical studies cited are placebo-controlled trials involving healthy individuals and patients with asthma. These studies indicate that antileukotriene agents improve lung function and reduce the symptoms of asthma and the need for additional medication. Drugs that inhibit leukotriene-receptor binding and leukotriene synthesis hold promise as new additions to the armamentarium of clinicians who treat asthma. Furthermore, these drugs have already helped to elucidate some details of the pathophysiological features of asthma.

Animals↗
PubMedDate not supplied

A drug interaction between zafirlukast and theophylline.

The apparent low adverse effect profile of the new drug zafirlukast has made it an attractive choice in the treatment of asthma. We present the first case (to our knowledge) of a potentially serious drug-drug interaction between zafirlukast and theophylline. A 15-year-old white girl with asthma had been taking theophylline (Slo-bid, Rhone-Poulenc Rorer Pharmaceuticals Inc, Collegeville, Pa) (300 mg twice daily), with drug levels of approximately 61 micromol/L (11.0 microg/mL) for several years. Recently, her serum theophylline levels had increased to the toxic range (133.2 micromol/L [24 microg/mL]) shortly after the addition of zafirlukast (Accolate, Zeneca Pharmaceuticals, Wilmington, Del) to her regimen. Attempts were made to stop and then restart the theophylline therapy at progressively lower doses; however, with each attempt, the patient's reaction to the drug became more toxic, with serum theophylline levels ranging between 99.9 and 149.9 micromol/L (18 and 27 microg/mL). So this potential drug-drug interaction could be investigated, the patient stopped taking both drugs for 1 week. Then, she again started taking theophylline (75 mg twice daily), and over 2 days reached a steady state serum theophylline level of 12.8 to 14.4 micromol/L (2.3-2.6 microg/mL). On the third day, zafirlukast (20 mg twice daily) was reintroduced to the regimen, and the theophylline therapy was continued. By the fifth day, a dramatic 7-fold increase was seen in the serum theophylline level (101.6 micromol/L [18.3 microg/mL]). The areas under the curve for theophylline alone and theophylline with zafirlukast were 29.3 and 197 (mg x h)/L, respectively. One explanation for the noted increase in the theophylline level is that metabolism occurs mainly by cytochrome P450 (CYP 1A2), an enzyme that is known to be inhibited with high concentrations of zafirlukast. Although the current metabolism of the 2 drugs in combination is poorly understood, the potential for serious interactions seems to exist in the rapidly growing population of persons with asthma, for whom they may be prescribed. The noted increase in the theophylline level after zafirlukast administration is in contrast to the original reports by the manufacturer. Therefore, we recommend that physicians evaluate serum theophylline levels closely when prescribing the 2 drugs in combination.

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