Coordination-driven self-assembly of ruthenium(ii) architectures: synthesis, characterization and cytotoxicity studies.

Coordination-driven self-assembly of organometallic η6-arene ruthenium(ii) supramolecular architectures (MA1-MA4) was carried out by employing dinuclear ruthenium acceptors [Ru2(µ-η4-C2O4)(CH3OH)2(η6-p-cymene)2](CF3SO3)2 (Rua), [Ru2(µ-η4-C6H2O4)(CH3OH)2(η6-p-cymene)2](CF3SO3)2 (Rub), [Ru2(dhnq)(H2O)2(η6-p-cymene)2](CF3SO3)2 (Ruc) and [Ru2(dhtq)(H2O)2(η6-p-cymene)2](CF3SO3)2 (Rud) separately with a new tetratopic donor (TD) in methanol at room temperature [TD = N,N,N',N'-tetra(pyridin-4-yl)-[1,1'-biphenyl]-4,4'-diamine]. All the coordination architectures were characterized by using spectroscopic techniques. The potency of these self-assembled architectures against human cervical cancer HeLa and human lung adenocarcinoma A549 cell lines is explored in vitro using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), annexin V-FITC/PI and 2',7'-dichlorofluorescein-diacetate assays.

Acetaminophen and Metamizole Induce Apoptosis in HT 29 and SW 480 Colon Carcinoma Cell Lines In Vitro.

BACKGROUND/AIM: The perioperative phase is supposed to be a period with high vulnerability for cancer dissemination. Acetaminophen and metamizole are common analgesics administered during this phase. We investigated the effect of acetaminophen, metamizole and 4-methylaminoantipyrine (MAA) on proliferation and apoptosis of colon carcinoma cell lines (SW 480 and HT 29). MATERIALS AND METHODS: Proliferation was detected by cell proliferation ELISA BrdU, and apoptosis by Annexin V staining. Cytochrome c and caspase 3, 8 and 9 expression levels were detected by western blot. RESULTS: Acetaminophen, metamizole or MAA caused slight changes in proliferation. Acetaminophen, metamizole or the combination increased apoptosis in both cell lines. All agents decreased caspase 3 and 8 expression in SW480. Acetaminophen decreased caspase 9 expression in both cell lines. CONCLUSION: In clinically relevant doses, acetaminophen and/or metamizole induce apoptosis in both colon cancer cell lines. Both mitochondrial and death receptor pathways might be involved in acetaminophen-induced apoptosis.

Efficacy of the non-adenosine analogue A1 adenosine receptor agonist (BR-4935) on cardiovascular function after cardiopulmonary bypass.

BACKGROUND: We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass. METHODS: Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined. RESULTS: Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group. CONCLUSION: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

Allergic cholestatic hepatitis and exanthema induced by metamizole: verification by lymphocyte transformation test.

We report about a 66-year-old-male patient who was hospitalized with generalized exanthema and increase of liver enzymes after intake of metamizole because of flue-like symptoms. Despite initial high dose steroids, disease activity persisted, and therefore liver biopsy was performed. Histology revealed acute hepatitis with perivenular non-bridging confluent necrosis and granuloma formation consistent with drug-induced hepatitis. A metamizole-induced process was suspected. Lymphocyte transformation test confirmed the sensitization of the patient's lymphocytes to metamizole and three of its four metabolites (4-methylaminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine). Other drugs could be excluded with high probability. In the follow-up, the general condition of the patient improved, and liver enzymes decreased under treatment with steroids. Thus, we conclude that in this patient metamizole has induced an allergic reaction not only of the skin but also of the liver. To our knowledge, an allergic cholestatic hepatitis caused by metamizole has been reported only once in literature.

[Postoperative pain therapy with 1-methadone and metamizole. A randomized study within the scope of intravenous on-demand analgesia]. / Postoperative Schmerztherapie mit 1-Methadon und Metamizol. Eine randomisierte Untersuchung im Rahmen der intravenösen On-Demand Analgesie.

Methadone, a potent long-acting opioid analgesic, is only seldom prescribed for postoperative pain relief in Germany. It was the aim of the present investigation to evaluate its efficacy and to establish an adequate dose range using intravenous patient-controlled analgesia (PCA), as well as to determine possible drug interactions with the antipyretic analgesic metamizol (dipyrone). 120 patients recovering from elective major abdominal, gynaecological or orthopaedic surgery under standardized balanced anaesthesia were randomly allocated to three groups to self-administer intravenous 1-methadone. Demand doses were 0.573 mg (group LD), 1.145 mg (group HD) or 0.573 mg to which 50 mg metamizol (dipyrone) were added (group LM). Infusion rate was set to 0.137 mg 1-methadone/h in every group, lockout time was 1 min. Hourly maximum dose was set to 5.95 mg 1-methadone/h. During an average PCA duration of 21 hours patients demanded mean dosages of 16.4 mg (LD), 18.7 mg (HD) or 13.4 mg (LM) 1-methadone. Although individual variation in drug consumption was high, effective pain relief was possible in all cases. Cardiovascular and respiratory status during the observation period was always normal. 88-93% of patients preferred PCA in comparison with earlier experienced conventional postoperative pain treatment. It is concluded that patients are able to control adequate drug consumption, i.e. to avoid overdosage, by adjusting demand frequency if variable demand dosages are offered. Thus 13-19 mg 1-methadone per day can be recommended as reasonable dose range for pain relief during the early postoperative period.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo response of mitoxantrone and doxorubicin with dipyrone in parental and doxorubicin-resistant P388 leukemia.

The efficacy of dipyrone to modulate antitumor activity of mitoxantrone (MTN) and doxorubicin (DOX) was studied in vivo in mice bearing P388 murine lymphocytic leukemia sensitive (P388/S) and resistant P388/DOX) to DOX. P388/DOX-bearing mice demonstrated marginally higher sensitivity to dipyrone at 200 mg/kg when compared to P388/S-bearing mice. However, dipyrone could significantly enhance the antitumor activity of MTN and DOX in both P388/S and P388/DOX-tumor-bearing mice. MTN was cross-resistant to P388/DOX.

Agranulocytosis associated with "Mexican aspirin" (dipyrone): evidence for an autoimmune mechanism affecting multipotential hematopoietic progenitors.

A case of acute, transient agranulocytosis and thrombocytopenia associated with ingestion of dipyrone is reported. This once widely used analgesic, which is now banned in the United States, was obtained by the patient as "aspirin" while traveling in Mexico. Studies of the effects of this patient's serum on purified CD34+ marrow cells, which were highly enriched for hematopoietic progenitors, showed not only a drug-dependent suppression of the in vitro growth of myeloid progenitors, as has been reported previously, but also a drug-dependent suppression of primitive multipotential progenitors (CFU-Mix) and erythroid progenitors (BFU-E). These findings indicate that autoimmune, antibody-hapten interactions which have been reported to occur in dipyrone- and aminopyrine-induced agranulocytosis are not restricted to the neutrophil lineage.

[Importance of endogenous opioids and prostaglandins in the action of analgin (metamizole) and verapamil]. / Znachenie éndogennykh opioidov i prostaglandinov v deistvii anal'gina (metamizola) i verapamila.

The effects of a non-narcotic analgetic methamizole and the calcium channel blocker verapamil on carrageenan hyperalgesia, release of beta-endorphin and synthesis of prostaglandin E2 (PGE2) were studied. It was found that a combined administration of analgin and verapamil prolonged the analgesic effect. Analgin stimulated release of beta-endorphin with the maximum coinciding in time with the peak of the analgesic effect. Against the background of the action of calcium ionophore A 23187 the combination of analgin with verapamil inhibited PGE2 synthesis more distinctly. The combination of these pharmacological agents is suggested to exert the effect both at different levels, central and peripheral, and on various cellular mechanisms involved in pain modulation.

Quiescent Q fever endocarditis exacerbated by cardiac surgery and corticosteroid therapy.

Q fever endocarditis occurs in up to 11% of patients infected by Coxiella burnetti. Major clues for the diagnosis are culture-negative endocarditis, hepatic involvement, rash, and thrombocytopenia. Characteristically, the diagnosis is delayed. In our patient, Q fever endocarditis occurred without previously recorded signs of infection. Fever, rash, and hepatic involvement all occurred following aortic valve replacement. The histologic picture of the excised valve was consistent with endocarditis, and serologic tests disclosed elevated IgA and IgG antiphase 1 antibody titers against C burnetti, compatible with Q fever endocarditis. It is assumed that the exacerbation of quiescent Q fever endocarditis was caused by cardiac surgery and steroid therapy.

A new mechanism of action of dipyrone: blockade of the release of a nociceptive factor from macrophages.

Rat macrophage monolayers pre-treated with endotoxin release into the incubating fluid a factor (MW greater than 10,000) capable of inducing writhing in mice (MNF). This release was inhibited by dipyrone (3.5-35 micrograms/ml) but not by indomethacin (0.5-2 micrograms/ml). Writhing in mice induced by the factor is blocked by dipyrone (0.5-50 mg/kg) and indomethacin (0.5-2 mg/kg). These results indicate that in addition to the previously described direct blockade of hyperalgesia by dipyrone, this drug may also affect the release of MNF, which induces in vivo nociception through the release of prostaglandin-like substances.

[Infusion therapy of acute vertebragenic pain syndrome]. / Infusionstherapie akuter vertebragener Schmerz-syndrome.

In the course of a double blind study 67 patients with acute vertebragenic pain syndromes have been treated with 3 infusion solutions, which only differed from each other by the analgetic component. Nefopam as an analgeticum showed a clearly prolonged effect and a quicker analgetic effect. As far as pains which occurred during a resting period and pains which occurred during a movement were concerned no differences in the effect were observed. Patients treated with Nefo-Dolpasse showed a smaller rate of side effects than those treated with comparable solutions.

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.

Restoration of doxorubicin responsiveness in doxorubicin-resistant P388 murine leukaemia cells by dipyrone.

The effect of dipyrone along with doxorubicin and mitoxantrone was studied alone and in combination on the 3H-thymidine (3H-TdR) incorporation in P388 leukaemia sensitive (P388/S) and resistant (P388/ADR) to doxorubicin. Dipyrone 10(-4) M demonstrated minimal inhibitory effect on DNA biosynthesis in both the sensitive and resistant cells. Doxorubicin and mitoxantrone at equimolar concentrations, indicated time and dose-dependent inhibition in 3H-TdR incorporation in the sensitive cells. The inhibition was more at the higher drug concentrations at 4 h drug exposure. Mitoxantrone showed cross-resistance in P388/ADR compared to P388/S. Both the drugs along with 10(-4) M dipyrone in the incubating medium revealed synergistic inhibitory activity in P388/S and P388/ADR. Observations indicate circumvention of doxorubicin and mitoxantrone resistance in P388/ADR by dipyrone.

Dipyrone-containing analgesics.

Analgesics containing dipyrone continue to be available throughout Africa, including South Africa and Zimbabwe. Although an effective analgesic and antipyretic, dipyrone may cause severe side-effects, including agranulocytosis. The mechanism of this hypersensitivity reaction has been well documented, and many reports of agranulocytosis associated with dipyrone use have been published. Use of this drug has been prohibited or restricted in several countries. Dipyrone is known by a variety of official names, which may contribute to confusion in deciding whether a particular preparation contains this drug. The prescribing information contained in the Monthly Index of Medical Specialities (MIMS) (South Africa) and the MIMS Desk Reference is inadequate for some of the products available, although the package inserts do provide more detailed information. The continued use of these products is difficult to justify when safer alternatives are available.

Effects of co-administration of monomethylaminoantipyrine with diethylaminoethyl 2,2-diphenylvalerate (SKF 525-A) on gamma-glutamyltranspeptidase, glutathione S-transferase and hepatic drug metabolizing enzyme activities in rats.

4-Monomethylaminoantipyrine (MAA)-induced increase of hepatic drug metabolizing enzymes was suppressed by SKF 525-A. This may be due to the partial binding of SKF 525-A to a portion of cytochrome P-450. On the other hand, glutathione S-transferase and gamma-glutamyltranspeptidase (gamma-GTP) activities of rat liver were both induced by repeated administration of MAA in combination with SKF 525-A. In addition, under the same condition, glutathione level in rat liver was significantly decreased.

The effects of acidic and nonacidic pyrazoles on arachidonic acid metabolism in mouse peritoneal macrophages.

The effects of acidic and nonacidic pyrazole derivatives and their metabolites on arachidonic acid metabolism have been investigated in mouse peritoneal macrophages stimulated with the calcium ionophore A 23 187 (10(-6) Mol/l). In the group of the acidic compounds with anti-inflammatory properties, phenylbutazone and butyl malonic acid mono (1-phenylhydrazide), the hydrolysis product of mofebutazone, inhibited prostaglandin production in a dose-dependent manner (10(-4)-10(-6) Mol/l). In contrast, mofebutazone itself and its hydroxylation product, 4-OH-mofebutazone, failed to show any activity. Similarly, in the case of bumadizone, an anti-inflammatory drug structurally related to phenylbutazone, no inhibitory effect on prostaglandin release was found either. The nonacidic pyrazole derivatives with antipyretic and anti-inflammatory activity, antipyrine, isopropylaminophenazone, as well as metamizol and its active metabolites 4-methylaminophenazone and 4-aminophenazone, also inhibited prostaglandin release dose-dependently. This was found to be paralleled by an increased leukotriene C4 production. Neither of the main excretory metabolites of metamizol, acetyl- and formylaminophenazone, showed any effect. The concentration levels at which the nonacidic compounds affected arachidonic acid metabolism (approx. 10(-4) Mol/l) were high enough to elicit anti-inflammatory effects. They were far higher, though, than the plasma levels producing antipyretic and analgesic effects that are reached after therapeutic doses.

Investigations on the carcinogenicity of dipyrone in rats.

A carcinogenicity study with dipyrone (metamizol methanesulfonate) was conducted in male and female Wistar rats. The compound was administered with the feed for a period of 24 months in doses of 0, 1000, or 3000 ppm, followed by a 6-month recovery period (without compound administration). The rats in the high-dose group, especially the females, showed a statistically significant body weight gain retardation which was not correlated with reduced feed consumption. The chronic administration of dipyrone did not influence the survival of the rats. No treatment-related changes in clinical signs and hematological parameters occurred. The absolute and relative weights of thyroids and pituitaries in the high-dose males were increased statistically significantly but were still within the normal range of the rat strain used. Histological examination of the animals which died intercurrently or were killed in extremis or at the end of the recovery period did not reveal any nonneoplastic or neoplastic changes which were compound related under the test conditions used. All of the tumors in all groups of animals were considered spontaneous in nature. Dipyrone did not show carcinogenic potential in rats in this study.