Phase II trial of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl and doxorubicin chemotherapy in metastatic breast cancer: A National Cancer Institute of Canada clinical trials group study.
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PURPOSE: This multicenter phase II trial investigated the efficacy and toxicity of a combination of the novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE), and doxorubicin in patients with anthracycline-naive metastatic breast cancer. Preclinical models and early single institutional studies suggested DPPE could potentiate the cytotoxicity of doxorubicin. PATIENTS AND METHODS: Forty-two women, 32 to 77 years old (median, 59 years), with anthracycline-naive metastatic breast cancer were treated. Patients may have had one previous regimen of nonanthracycline chemotherapy, either in the adjuvant or metastatic disease treatment setting. DPPE (6 mg/kg) was administered as an 80 minute intravenous infusion with doxorubicin (60 mg/m(2)) given intravenously over the last 20 minutes of the DPPE infusion. Patients were premedicated with an antiemetic and sedating regimen. The DPPE/doxorubicin treatment was given every 21 days for a maximum of seven cycles. RESULTS: All 42 patients were assessable. Overall, toxicity was comparable to that expected with doxorubicin alone, with the exception of DPPE-related motion sickness, mild hallucinations, and cerebellar signs at the time of the infusion. These CNS side effects were manageable in an ambulatory care setting, improved with subsequent cycles of treatment, and did not usually require hospitalization. Four patients developed febrile neutropenia. Thirty-five patients received four or more cycles of chemotherapy. The overall response rate was 52.5% (95% confidence interval, 36% to 68%), with 9.5% complete responses (n = 4), 43% partial responses (n = 18), and 38% of patients with stable disease (n = 16). CONCLUSION: The antitumour effects of DPPE/doxorubicin the 52.5% response rate seems encouraging, particularly in consideration of the fact that a recently reported randomized National Cancer Institute of Canada Clinical Trials Group trial using single-agent doxorubicin 60 mg/m(2) in one of the treatment arms achieved a 31% response rate. Thus, a randomized phase III trial of doxorubicin versus doxorubicin plus DPPE is being conducted in this clinical setting. (+info)
Characterization of the binding of [3H]-clobenpropit to histamine H3-receptors in guinea-pig cerebral cortex membranes.
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1 We have investigated the binding of a novel histamine H3-receptor antagonist radioligand, [3H]- clobenpropit ([3H]-VUF9153), to guinea-pig cerebral cortex membranes. 2 Saturation isotherms for [3H]-clobenpropit appeared biphasic. Scatchard plots were curvilinear and Hill plot slopes were significantly less than unity (0.63+/-0.03; n = 12+/-s.e.mean). The radioligand appeared to label two sites in guinea-pig cerebral cortex membranes with apparent affinities (pKD') of 10.91+/-0.12 (Bmax = 5.34+/-0.85 fmol mg(-1) original wet weight) and 9.17+/-0.16 (Bmax = 23.20+/-6.70 fmol mg(-1)). 3 In the presence of metyrapone (3 mM) or sodium chloride (100 mM), [3H]-clobenpropit appeared to label a homogeneous receptor population (Bmax=3.41+/-0.46 fmol mg-1 and 3.49+/-0.44 fmol mg(-1), pKD' = 10.59+/-0.17 and 10.77+/-0.02, respectively). Scatchard plots were linear and Hill slopes were not significantly different from unity (0.91+/-0.04 and 0.99+/-0.02, respectively). Granisetron (1 microM), rilmenidine (3 microM), idazoxan (0.3 microM), pentazocine (3 microM) and 1,3-di-(2-tolyl)guanidine (0.3 microM) had no effect on the binding of [3H]-clobenpropit. 4 The specific binding of [3H]-clobenpropit appeared to reach equilibrium after 25 min at 21+/-3 degrees C and remained constant for >180 min. The estimated pKD' (10.27+/-0.27; n = 3+/-s.e.mean) was not significantly different from that estimated by saturation analysis in the presence of metyrapone. 5 A series of histamine H3-receptor ligands expressed affinity values for sites labelled with [3H]-clobenpropit which were not significantly different from those estimated when [3H]-R-alpha-MH was used to label histamine H3-receptors in guinea-pig cerebral cortex membranes. (+info)
Sensitization of visceral afferents to bradykinin in rat jejunum in vitro.
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1. We have investigated the effects of inflammatory mediators on visceral afferent discharge and afferent responses to bradykinin (BK) in rat jejunum using a novel in vitro technique. 2. Prostaglandin E2 (1 microM) augmented responses to BK without affecting basal firing, while histamine (100 microM) and adenosine (100 microM) activated basal discharge and enhanced BK responses. In contrast, 5-HT (100 microM) increased basal discharge without influencing responses to BK. 3. Afferent discharge induced by histamine was inhibited by both H1 (pyrilamine) and H3 (thioperamide) but not H2 (ranitidine) receptor antagonists at 10 microM. In contrast, sensitization to BK induced by histamine was inhibited by ranitidine (10 microM). 4. Afferent discharge induced by adenosine was blocked by the A1 receptor antagonist DPCPX (10 microM) but remained unaffected by A2A receptor blockade with ZM241385 (10 microM). In contrast, sensitization of BK responses by adenosine was unaffected by both antagonists. Basal discharge and BK-induced responses were unaffected by the A3 receptor agonist IB-MECA (1 microM). While involvement of A2B receptors is not excluded, adenosine may activate afferent discharge through A1 receptors, while sensitization to BK could involve a receptor other than A1, A2A or A3, possibly the A2B receptor. 5. Inhibition of cyclo-oxygenase with naproxen (10 microM) prevented sensitization after histamine but not adenosine. 6. Sensitization was mimicked by dibutyryl cAMP. This occurred without changes in basal firing and was unaffected by naproxen. 7. In conclusion, afferent discharge induced by BK is augmented by histamine, adenosine and PGE2, but not by 5-HT. Evidence suggests that sensitization involves separate mechanisms from afferent activation. Sensitization may be mediated by increases in cAMP following direct activation by mediators at the nerve terminal or through indirect pathways such as the release of prostaglandins. (+info)
Nalpha-methyl histamine and histamine stimulate gastrin release from rabbit G-cells via histamine H2-receptors.
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BACKGROUND: Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine. AIM: To determine the direct effects of histamine receptor agonists on isolated gastrin cells. METHODS: Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates. RESULTS: NalphaMH (10-6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/- 0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2-antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M) increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10-5 M) (P < 0.01). CONCLUSION: NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia. (+info)
Cysteinyl leukotrienes mediate histamine hypersensitivity ex vivo by increasing histamine receptor numbers.
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BACKGROUND: Hyperresponsiveness to histamine is a key feature of a variety of pathological conditions, including bronchial asthma, food allergy, colitis ulcerosa, and topical allergic disorders. Cells isolated from hyperresponsive individuals do not display exaggerated histamine responses ex vivo and thus the molecular mechanisms underlying histamine responsiveness remain obscure. Importantly, several in vivo observations implicate cysteinyl leukotrienes as possible mediators of increased histamine responses. We decided to investigate whether cysteinyl leukotrienes enhance the cellular reaction to histamine in cell types involved in pathological and immunological histamine hyperresponsiveness, as this might provide an in vitro system for studying histamine responsiveness and could shed light on the underlying molecular mechanisms. MATERIALS AND METHODS: Histamine responsiveness was determined by measuring histamine-induced prostaglandin E(2) production. Scatchard analysis was performed to determine the number of histamine H(1) receptors. Mouse macrophages, primary isolated human peripheral blood monocytes, and human umbilical smooth muscle cells were investigated before and after cysteinyl leukotriene stimulation. RESULTS: In all three cell types tested, cysteinyl leukotrienes instantaneously enhanced histamine-induced prostaglandin E(2) production. This increase in prostaglandin E(2) production coincided with the immediate and transient appearance of additional H(1) receptors on the plasma membrane. CONCLUSIONS: Cysteinyl leukotrienes prime histamine responses by recruiting additional histamine receptors in immunologically relevant cell types in vitro. (+info)
Bronchial vasodilation evoked by increased lower airway osmolarity in dogs.
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Hyperosmotic saline solutions stimulate lower airway sensory nerves. To determine whether airway hyperosmolarity evokes neurally mediated changes in bronchial artery blood flow (Qbr), we measured the effect of injection of small volumes (1 ml) of hyperosmotic saline into a right lobar bronchus on Qbr of anesthetized, artificially ventilated dogs. In 14 dogs, hyperosmotic saline (1,200 and 2,400 mmol/l) increased Qbr by 58 +/- 12 (SE) and 118 +/- 12%, respectively, from a baseline of 8 +/- 2 ml/min. Qbr increased within 6-8 s of the injections, peaked at 20 s, and returned to control over 2-3 min. Isosmotic saline had minimal effects. In contrast, hyperosmotic saline decreased flow in an intercostal artery that did not supply the airways. The bronchial vasodilation was decreased by 72 +/- 11% after combined blockade of alpha-adrenoceptors and muscarinic cholinergic receptors and by 66 +/- 6% when the cervical vagus nerves were cooled to 0 degrees C. Blockade of H(1) and H(2) histamine receptors did not reduce the nonvagal response. We conclude that hyperosmolarity of the lower airways evokes bronchial vasodilation by both a centrally mediated reflex that includes cholinergic and adrenergic efferent pathways and by unidentified local mechanisms. (+info)
Histamine H(3) receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves.
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1. The present study investigates whether presynaptic histamine receptors regulate noradrenaline release from intestinal sympathetic nerves. The experiments were performed on longitudinal muscle-myenteric plexus preparations of guinea-pig ileum, preincubated with [(3)H]-noradrenaline. 2. In the presence of rauwolscine, electrically-induced [(3)H]-noradrenaline release was inhibited by histamine or R-alpha-methylhistamine, whereas it was unaffected by pyridylethylamine, impromidine, pyrilamine, cimetidine, thioperamide or clobenpropit. The inhibitory effects of histamine or R-alpha-methylhistamine were antagonized by thioperamide or clobenpropit, but not by pyrilamine or cimetidine. In the absence of rauwolscine, none of these drugs modified the release of [(3)H]-noradrenaline. 3. The modulatory action of histamine was attenuated by pertussis toxin and abolished by N-ethylmaleimide. Tetraethylammonium or 4-aminopyridine enhanced the evoked tritium outflow and counteracted the inhibitory effect of histamine. However, the blocking effects of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by reduction of Ca(2+) concentration in the superfusion medium. 4. Histamine-induced inhibition of tritium output was enhanced by omega-conotoxin or low Ca(2+) concentration, whereas it was not modified by nifedipine, forskolin, rolipram, phorbol myristate acetate, H7 or lavendustin A. 5. The present results indicate that presynaptic H(3) receptors, located on sympathetic nerve endings, mediate an inhibitory control on intestinal noradrenergic neurotransmission. It is suggested that these receptors are coupled to G(i)/G(o) proteins which modulate the activity of N-type Ca(2+) channels through a direct link, thus reducing the availability of extracellular Ca(2+) at the level of noradrenergic nerve terminals. (+info)
Orosomucoid has a cAMP-dependent effect on human endothelial cells and inhibits the action of histamine.
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The plasma protein orosomucoid (alpha(1)-acid glycoprotein) has previously been shown to constitute a critical component of the capillary barrier. The protein has also been suggested to act as an anti-inflammatory mediator in a diversity of experimental situations. Recently we reported that orosomucoid is synthesized by the microvascular endothelial cells per se. In the present study, the effects of orosomucoid on primary cultures of human umbilical vein endothelial cells (HUVEC) were studied using the Cytosensor microphysiometer. We found that 1) orosomucoid (0.01 g/l) increased the metabolic activity of HUVEC as reflected by the increased acidification rate of +14 +/- 1%; 2) pretreatment with 0.5 mM 8-bromo-cAMP for 20 min markedly and reversibly inhibited the effect of orosomucoid, whereas 8-bromo-cGMP did not; 3) histamine elicited a dose-dependent response that was abolished by pretreatment with either cAMP or cGMP; and finally, 4) pretreatment of HUVEC for 6 min with orosomucoid (0.01 g/l) inhibited the action of histamine. In summary, this is the first report demonstrating that orosomucoid affects human endothelial cells and that it does so by using cAMP as a second messenger. This provides an explanation for previous findings of anti-inflammatory effects of the protein and shows that orosomucoid affects the endothelium during both normal and pathophysiological conditions. (+info)