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At least 757 records · Page 42Linked to original sources
PubMed1985

Respiratory epithelium inhibits bronchial smooth muscle tone.

The aim of the present study was to determine whether or not the respiratory epithelium can modulate the responsiveness of bronchial smooth muscle. Paired rings of canine bronchi (4-6 mm OD), in some of which the epithelium had been removed mechanically (by rubbing the luminal surface), were mounted in physiological saline solution, gassed with 95% O2-5% CO2, and maintained at 37 degrees C. The presence or absence of the epithelium was confirmed by histological examination. Removal of the epithelium increased the contractile responses evoked by acetylcholine, histamine, and 5-hydroxytryptamine. Transmural nerve stimulation evoked similar peak responses in the presence and absence of epithelium. In unrubbed preparations, the peak response was followed by a gradual decrease when the stimulation was continued. This decrease, which persisted in the presence of propranolol, was not observed in epithelium-denuded preparations. In bronchial rings contracted with acetylcholine, isoproterenol produced concentration-dependent relaxations which were significantly greater in rings with epithelium compared with denuded rings. These results suggest that respiratory epithelial cells may generate an inhibitory signal to decrease the responsiveness of bronchial smooth muscle to contractile agonists and augment the effectiveness of inhibitory stimuli.

Acetylcholine↗
PubMed2001

A novel 9-aza-anthrapyrazole effective against human prostatic carcinoma xenografts.

OBJECTIVES: Systematic investigation of a novel series of intercalating agents, 9-aza-anthrapyrazoles, has led to the identification of a promising analogue, BBR 3438. This study describes the antitumour efficacy of the novel compound in human prostate carcinoma models and the molecular/cellular basis of its activity. METHODS AND RESULTS: The novel 9-aza-anthrapyrazole BBR 3438 was significantly more effective than doxorubicin and losoxantrone (DuP-941) in two of the three tested prostate carcinoma models. The superior activity was more evident in PC3 tumour, since BBR 3438 produced an appreciable rate of complete tumour regressions. Under these conditions, the drug-induced antiproliferative activity paralleled delayed apoptosis. Tumour response to in vivo drug treatment was associated with an early down-regulation of Bcl-2, which was somewhat more marked for the aza compound. In fact, the 9-aza-anthrapyrazole induced DNA cleavage in vitro with isolated DNA topoisomerase II (isoform alpha) and DNA strand breaks in prostatic carcinoma cells. Although the molecular effects of losoxantrone and the 9-aza analogue on the enzyme target were comparable, the cytotoxic effects of BBR 3438 could be enhanced by long-term exposure as a consequence of favourable cellular accumulation and prominent DNA-binding affinity. In addition, a lower reduction potential of the 9-aza-anthrapyrazole in comparison with classical anthrapyrazoles suggests an increased ability of the drug to induce oxidative stress following free radical production, which may be a contributing factor in determining the long-term response (i.e. delayed cell death) to genotoxic damage. CONCLUSIONS: BBR 3438 exhibited a unique profile of preclinical activity with a superior efficacy against prostatic carcinoma models compared to reference compounds (doxorubicin and losoxantrone). The antitumour efficacy of BBR 3438 against prostatic carcinoma could be the result of a combination of favourable events, including enhanced intracellular accumulation and an increased DNA-binding affinity favouring the accumulation of multiple sublethal or lethal damage. In spite of its enhanced cytotoxic potency, the 9-aza compound was better tolerated in vivo than losoxantrone, thus improving the therapeutic index. The preclinical profile of efficacy against prostatic carcinoma, a tumour resistant to conventional antitumour drugs, makes the novel 9-aza-anthrapyrazole BBR 3438 a promising candidate for clinical evaluation.

Adenocarcinoma↗
PubMed2002

Single-dose oral tolerance test with alternative compounds for the management of adverse reactions to drugs.

BACKGROUND: Adverse reactions to drugs are common in the clinical practice. Many outpatients are frequently referred to allergists in order to determine which drugs they can safely take in the future. OBJECTIVE: We set up an oral single-dose tolerance test procedure to find out for each patient one or more alternative drugs that can be taken when needed. METHODS: 452 outpatients (130 male, 322 female) with well-documented reactions (urticaria/angioedema, respiratory symptoms, laryngeal edema, anaphylaxis, exfoliative skin diseases) underwent the challenge. All tests were preceded by a single-blind placebo: if a reaction occurred, a second placebo was administered. Otherwise, a single dose (1/10 of the therapeutic one) of an alternative drug was given blindly and the patient was then observed for 6 h. The drugs used were different in structure from those suspected of having caused the adverse reaction. The patients were followed up at 4- to 6-month intervals, in order to detect any reaction that may have occurred with the tested drugs. RESULTS: 98 patients (89 women) had untoward reactions after the first placebo and 34 out of them reacted to the second placebo, too. During challenges the reaction rate ranged between 4.6 and 9.0%; these reactions were easily managed and none of them was severe. We followed up 407 patients: 87.2% of them were able to use one or more of the suggested drugs without reactions, 9.3% did not take the drugs and only 3.5% reported reactions to the previously tested drugs. CONCLUSION: The challenge procedure proved to be a simple tool for managing patients with adverse reactions to drugs. Its safety and reliability were validated by a long-term follow-up.

Administration, Oral↗
PubMed1986

Maitotoxin, a calcium channel activator, increases prolactin release from rat pituitary tumor 7315a cells by a mechanism that may involve leukotriene production.

Arachidonate and its metabolites may play an important role in the release of prolactin. In the present study, the effect of maitotoxin, a calcium channel activator, was measured on the release of arachidonate and its metabolites from the prolactin-secreting 7315a tumor. Maitotoxin increased the release of prolactin, arachidonate, prostaglandins E2 and F2 alpha (PGE2, PGF2 alpha) and leukotriene C4 (LTC4) from 7315a cells prelabeled with [3H]arachidonate. The magnitude of the increase of prolactin and arachidonate release was decreased in low-calcium medium. The release of arachidonate from cellular phospholipids is necessary for the effect of maitotoxin on prolactin release because quinacrine, an inhibitor of arachidonate hydrolysis from phospholipids, blocked the maitotoxin-induced release of prolactin. The ability of maitotoxin to induce prolactin release appears to require metabolic transformation of arachidonate to its metabolites because BW755c, an inhibitor of the conversion of arachidonate, blocked the maitotoxin-induced prolactin release. In particular, LTC4 may be an important component of the prolactin release process because nordihydroguaiaretic acid and nafazatrom, which block the production of leukotrienes and other lipoxygenase-generated products, decreased LTC4 and prolactin release without affecting arachidonate, PGE2 or PGF2 alpha production. In contrast, indomethacin, a prostaglandin synthesis inhibitor, decreased PGE2 and PGF2 alpha production without affecting LTC4 or prolactin release. These data indicate that release of LTC4 and prolactin are closely linked events in 7315a tumor cells.

Animals↗
PubMed1984

Asthma relieved by acetylsalicylic acid and nonsteroid anti-inflammatory drugs.

The authors report 2 typical asthmatic cases in whom the administration of acetylsalicylic acid (ASA) and nonsteroid anti-inflammatory drugs (NSAID) resulted in bronchodilatation. 500 mg of ASA were administered intravenously to 1 patient and the other was treated with ASA, indomethacin, noramidopyrine intravenously and acetaminophen orally during a bronchospastic attack. FEV1 and SRAW were measured before and after drug administration. The test was repeated with placebo (physiological saline). FEV1 increased rapidly after ASA and NSAID administration. Although the pathogenesis of asthma reversed by aspirin is not entirely clear, the authors suggest an alteration of sensitivity of the cyclo-oxygenase enzyme due to the inhibitory action of ASA and NSAID.

Anti-Inflammatory Agents↗
PubMed1981

Increased release of vascular prostacyclin-like activity after long-term treatment of diabetic rats with Bay g 6575.

10 male Wistar rats were made diabetic by an intravenous injection of streptozotocin. 10 sex and age-matched rats served as control animals. 5 of the diabetic and 5 of the control rats received Bay g 6575 (20 mg/kg orally) for 6 days each week throughout the whole study period (9-11 months). From these animals aorta was removed for prostacyclin bioassay based upon its platelet aggregation inhibitory effect. The diabetic rats treated with Bay g 6575 released significantly more prostacyclin than the controls (p less than 0.005). Our study suggests further experiments in other animal models more susceptible to diabetic vascular lesions than the rat model to evaluate the possible beneficial role of the treatment with Bay g 6575.

Adenoma↗
PubMed1983

Laser-induced thrombi in rat mesenteric vessels and antithrombotic drugs.

A method to induce microthrombi in small mesenteric arteries (phi 15-25 microns) has been developed to study platelet reactions and to investigate antithrombotic drugs. A high power water immersion interference contrast system, based on a Leitz Orthoplan microscope, was used. In Nembutal-anesthetized male Wistar rats and in fawn hooded bleeder rats, vascular lesions were produced with a Hadron-512-Ruby-bio-laser or with a Coherent CR-2 supergraphite ion laser (Argon laser). The ruby laser produced intravascular precipitates consisting of proteins and erythrocytes which usually stuck to the vessel wall and on which platelets immediately adhered, transformed with pseudopode formation and formed loose aggregates. The Argon laser induced vascular damage, usually without intravascular heat precipitates which also led to platelet adhesion, transformation and aggregation. Fibrin threads rarely formed in the early platelet thrombi. Thrombus formation was significantly reduced in this model by dipyridamole (10 mg/kg orally), by Ditazole (50 mg/kg orally), heparin (100 IU/kg i.v.), Molsidomine (50 mg/kg orally), Nafazatrom (Bay G 6575, 10 mg/kg i.v. and orally), Ticlopidine (100 and 200 mg/kg orally) and Tioxaprofen (EMD 26644, 10 mg/kg orally). Thrombus formation was also significantly reduced in fawn hooded bleeder rats.

Animals↗
PubMed1984

Platelet aggregation in arterioles of the hamster cheek pouch and in heart transplants: its tissue-dependent influencibility by acetylsalicylic acid and nafazatrom.

Different, tissue-dependent antiaggregatory properties of endothelial cells are suggested by in vitro findings, which show different spectra and amounts of arachidonic acid products to be synthesized by vessels of different type and origin. Platelet aggregation was assessed in vivo in native arterioles of the hamster cheek pouch and in arterioles of heart transplants by intravascular excitation of fluorescein isothiocyanate-dextran (FITC-d). The time to aggregate appearance (TAA) was determined, i.e. the interval from onset of FITC-d excitation until the first aggregate was seen to adhere to the vessel wall. Two groups were pretreated with 100 micrograms/kg nafazatrom and 100 mg/kg acetylsalicylic acid (ASA), both potent antithrombotic drugs. Nafazatrom has been shown to stimulate prostacyclin release from endothelial cells, whereas ASA blocks cyclooxygenase both in platelets and vessel walls. TAA was the same for native arterioles of both types. Nafazatrom was equally effective in both vessels, and about three orders of magnitude more potent than ASA in prolonging TAA. ASA was twice as effective in arterioles of the heart as it was in those of the skin type, indicating that tissue-dependent mechanisms achieve the antiaggregatory potency of the vessel walls. It is concluded that further in vivo studies on platelet aggregation and thrombus formation should be performed on cardiac vessels directly and not on vessels of different origin. The presented model may be a useful tool for investigating the mentioned tissue-dependent mechanisms of thrombus formation in vivo.

Animals↗
PubMed1984

Detection of drug-dependent IgG antibodies with antiplatelet activity by the antiglobulin consumption assay.

Drug-induced thrombocytopenia is a common acquired hemorrhagic disorder. In this study 32 patients with drug-induced thrombocytopenia were examined with the antiglobulin consumption assay. Platelet-associated IgG was elevated in 19 of 20 patients that were analyzed. An increase in serum platelet bindable IgG was observed in 24 subjects after the addition of various drugs (acetylsalicylic acid, noraminopyrine, antibiotics, sulfamides, digoxin, heparin and chenodeoxycholic acid). These findings are significant for the presence of drug-dependent platelet antibodies.

Adolescent↗
PubMed1985

Lymphocyte transformation test in drug-induced toxic epidermal necrolysis.

Lymphocyte transformation tests (LTT) to drugs remain widely used in drug reactions, despite controversies about their real usefulness. We tested the lymphocytes of 12 patients recovering from a drug-induced Toxic epidermal necrolysis (TEN). There was no difference between the amounts of thymidine incorporated when patients' lymphocytes were cultivated with culprit or innocent drugs. In both situations the lymphocytes from patients reacted like the lymphocytes from controls cultivated with the same panel of drugs. These negative results do not exclude that a hypersensitivity reaction may play a role in the physiopathology of TEN. Anyhow, they clearly indicate that testing lymphocyte transformation to drugs has no practical value in the diagnosis of TEN.

Adolescent↗
PubMed1985

Nafazatrom-induced salvage of ischemic myocardium in anesthetized dogs is mediated through inhibition of neutrophil function.

The effects of nafazatrom on leukocyte function in vitro and in vivo were related to its ability to salvage ischemic myocardium in an occlusion-reperfusion model of myocardial injury in the anesthetized dog. Nafazatrom (0.4-75 microM) produced dose-related inhibition in vitro of neutrophil aggregation, superoxide anion generation, arachidonic acid metabolism, and, to a lesser extent, the release of beta-glucuronidase. In contrast, nafazatrom (0.4-37.5 microM) did not substantially influence platelet aggregation or the platelet metabolism of arachidonic acid. In vivo nafazatrom (10 mg/kg, po) reduced infarct size from 58 +/- 3% of the risk area (mean +/- SEM, n = 9) in control dogs to 23 +/- 2% of the risk area (n = 9, P less than 0.01). Nafazatrom also reduced the incidence of accompanying arrhythmias. Nafazatrom-induced myocardial salvage was not associated with any hemodynamic changes; moreover, it was independent of platelets, since thrombocytopenia did not prevent nafazatrom from exerting a protective effect. Measurements of the neutrophil-specific myeloperoxidase enzyme in ischemic myocardium indicate that the smaller infarct size in dogs treated with nafazatrom is accompanied by diminished leukocyte infiltration. Thus, the ability of nafazatrom to inhibit neutrophil function in vitro and cell infiltration in vivo may underly its myocardial-protective effects.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2005

c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells.

Several primary murine and human B lymphomas and cell lines were found to constitutively express high levels of the activated form of c-jun N-terminal kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family. Proliferation of murine B lymphomas CH31, CH12.Lx, BKS-2, and WEHI-231 and the human B lymphomas BJAB, RAMOS, RAJI, OCI-Ly7, and OCI-Ly10 was strongly inhibited by SP600125, an anthrapyrazolone inhibitor of JNK, in a dose-dependent manner. The lymphoma cells underwent apoptosis and arrested at the G2/M phase of cell cycle. Furthermore, JNK-specific small interfering RNA (siRNA) inhibited the growth of both murine and human B lymphomas. Thus in the B-lymphoma model, JNK appears to have a unique prosurvival role. Survival signals provided by CD40 and interleukin-10 (IL-10) together reversed the growth inhibition induced by the JNK inhibitor. c-Myc protein levels were reduced in the presence of both SP600125 and JNK-specific siRNA, and CD40 ligation restored c-Myc levels. Moreover, Bcl-xL rescued WEHI-231 cells from apoptosis induced by the JNK inhibitor. The JNK inhibitor also reduced levels of early growth response gene-1 (Egr-1) protein, and overexpressing Egr-1 partially rescued lymphoma cells from apoptosis. Thus, JNK may act via c-Myc and Egr-1, which were shown to be important for B-lymphoma survival and growth.

Animals↗
PubMed1991

Anthrapyrazole CI941: a highly active new agent in the treatment of advanced breast cancer.

Thirty-one patients with advanced breast cancer were treated with CI941, an anthrapyrazole structurally related to mitoxantrone. Patients had not previously been treated with anthracyclines or mitoxantrone, and 15 patients had not received any previous cytotoxic chemotherapy. CI941 was given at a dose of 50 mg/m2 by intravenous bolus injection every 21 days. Thirty patients were assessable for response, and all were assessable for toxicity. Two patients (7%) had complete responses (CRs), and 17 (56%) achieved partial responses (PRs; overall response rate, 63%; 95% confidence interval, 46% to 81%). The response rates in patients with and without prior chemotherapy were 63% and 64%, respectively. The median response duration was 37 weeks from start of treatment, with a maximum response duration of greater than 70 weeks. Median survival has not yet been reached. Leukopenia was the most frequently encountered toxicity, with a World Health Organization (WHO) grade greater than 3 occurring in 74% of courses. Thrombocytopenia and anemia were negligible. Only 10 patients (32%) had alopecia severe enough to wear a wig. There were no cardiac symptoms or events in any patient, but a slight median fall in left ventricular ejection fraction (LVEF) of 6% (from +7 to -12) during stress and 6% (from +14 to -14) at rest occurred. Other toxicities were mild, and the drug was generally well tolerated. CI941 is a very active and well-tolerated new agent in the treatment of advanced breast cancer, with neutropenia being the main toxicity.

Adult↗
PubMed1983

Influence of phenobarbital and 3-methylcholanthrene on the metabolism of aminopyrine in isolated hepatocyte system.

The effect of phenobarbital (PB) and 3-methylcholanthrene (3-MC) on the metabolic behavior of aminopyrine (AM) was studied using an isolated hepatocyte system prepared from male Wistar rats. The formation of 4-formylaminoantipyrine (FAA) was increased after pretreatment with PB, but not 3-MC. However, the total amounts of AM and its main metabolites recovered from hepatocyte system after the incubation for 30 min were considerably reduced both by PB and 3-MC-pretreatment. Furthermore, when using 4-monomethylaminoantipyrine (MAA), the first metabolite of AM, as a substrate, 3-MC-pretreatment resulted in a more significant decrease in the total amounts of MAA and its further metabolites recovered than did PB. Present observation suggests the participation of cytochrome P-448 as well as cytochrome P-450 in the metabolism of AM.

Aminopyrine↗
PubMed1985

Product inhibition of aminopyrine N-demethylation in isolated hepatocytes.

The product inhibition of aminopyrine (AM) N-demethylation by 4-monomethylaminoantipyrine (MAA) was examined in vitro in preparations of isolated rat hepatocytes using gas chromatograph-mass spectrometer (GC-MS). The kinetic study for AM N-demethylation, which was determined by MAA formation, was studied at concentrations from 0.2 to 4.0 mM with or without various concentrations of D3-MAA. D3-MAA inhibited AM N-demethylation non-competitively at concentrations of 0.2 to 1.0 mM of AM (Ki = 0.81 mM), though it did competitively at concentrations of 1.0 to 4.0 mM of AM (Ki = 0.81 mM). From the present observation, it was suggested that the inhibition type of AM N-demethylation by D3-MAA was dependent on the substrate (AM) concentration.

Aminopyrine↗
PubMed1987

Effects of co-administration of monomethylaminoantipyrine and cobaltous chloride on hepatic glutathione level and glutathione-related enzyme activities in rats.

Concurrent administration of monomethylaminoantipyrine (MAA) and CoCl2 caused a significant decrease of hepatic reduced glutathione and oxidized glutathione levels. Furthermore, the increase of glutathione S-transferase activity by combined treatment resulted in the decrease of Se-dependent glutathione peroxidase activity.

Aminopyrine↗
PubMed2002

Metamizole use by Latino immigrants: a common and potentially harmful home remedy.

A 4-year-old boy presented with fever, septic arthritis, and persistent neutropenia. Bone marrow biopsy revealed no evidence of neoplasia. Additional history disclosed that the patient had been given metamizole for pain before onset of his illness. Metamizole, a nonsteroidal antiinflammatory agent, is prohibited in the United States because of the risk of agranulocytosis but is widely used in Mexico and other countries. The increasing number of Latinos in the United States and the extensive cross-border transfer of medicines raise concerns that metamizole use and associated complications may become more frequent. After identification of the index patient, additional inquiry revealed that the patient's mother was hospitalized previously for overwhelming sepsis associated with metamizole use. These cases prompted an investigation of metamizole use in an urban pediatric clinic, which revealed that 35% of Spanish-speaking Latino families had used metamizole; 25% of these families had purchased the medication in the United States. We conclude that metamizole use is common and may be underrecognized in immigrant Latino patients. Physicians in the United States, especially those who practice primary care, hematology/oncology, and infectious diseases, must be aware of the availability and use of metamizole in specific patient populations and its potential for harmful side effects.

Agranulocytosis↗