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At least 739 records · Page 41Linked to original sources
PubMed1985

Pharmacologic modification of blood flow in the rabbit microvasculature with prostacyclin and related drugs.

The rabbit epigastric free flap was used to investigate the effect of prostacyclin and drugs modifying its synthesis in vivo on microvascular blood flow. Prostacyclin and its analogue carbacyclin caused an increase in flow with a maximal twofold increase at approximately 6.5 and 250 ng/ml, respectively, in the flap. Thromboxane synthetase inhibitors such as dazoxiben hydrochloride, UK-38,485, 7-IHA, and imidazole (up to 7 X 10(-4) M in the flap) as well as the prostaglandins 6-oxo-PGF1 alpha and PGE2 (up to 3.7 and 9.2 ng/ml, respectively, in the flap) all failed to modify the control flow rate in the cutaneous microcirculation. It is concluded that the vasodilatory properties of prostacyclin and carbacyclin, together with their known platelet antiaggregatory properties, warrant further study in problem areas of microsurgery such as flap ischemia. The use of thromboxane synthetase inhibitors had no demonstrable effect on the normal flap, and their effect on the ischemic flap remains to be investigated.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results.

Medical Review Officer interpretation of laboratory results is an important component of drug testing programs. The clinical evaluation of laboratory results to assess the possibility of appropriate medical use of a drug is a task with many different facets, depending on the drug class considered. This intercession prevents the reporting of positive results unless it is apparent that drugs were used illicitly. In addition to the commonly encountered prescribed drugs that yield positive drug testing results, other sources of positive results must be considered. This review describes a series of compounds referred to as "precursor" drugs that are metabolized by the body to amphetamine and/or methamphetamine. These compounds lead to positive results for amphetamines even though neither amphetamine nor methamphetamine were used, a possibility that must be considered in the review of laboratory results. Description of the drugs, their clinical indications, and results seen following administration are provided. This information allows for the informed evaluation of results with regard to the potential involvement of these drugs.

Amphetamine↗
PubMed2004

c-Jun N-terminal kinase mediates hepatic injury after rat liver transplantation.

BACKGROUND: Orthotopic liver transplantation (OLT) requires cold ischemic storage followed by warm reperfusion. Although c-Jun N-terminal kinase (JNK) is rapidly activated after OLT, the functional consequences of JNK activation are unknown. The aim of this study was to address the role of JNK after OLT using the selective JNK inhibitor CC-401. METHODS: Donors, recipients, or stored liver explants were treated with vehicle or JNK inhibitor before OLT by an arterialized two-cuff method with 40 hours of cold storage. Recipients were assessed for 30-day survival, and graft injury was assessed over time by hepatic histology, serum transaminases, caspase 3 activation, cytosolic cytochrome c, and lipid peroxidation. RESULTS: Survival after OLT increased after donor plus storage and storage only treatment with JNK inhibitor (P<0.05). Treatment of recipient only did not improve survival. Increased survival correlated with improved hepatic histology and serum aspartate aminotransferase levels. JNK inhibition significantly decreased nonparenchymal cell killing at 60 minutes after reperfusion (P<0.05) and pericentral necrosis at 8 hours after reperfusion (P<0.01). JNK inhibition decreased cytochrome c release, caspase 3 activation (P<0.05), and lipid peroxidation (P<0.05). JNK inhibition also transiently blocked phosphorylation of c-Jun at 60 minutes after reperfusion (P<0.05) without affecting other MAPK signaling, including p-38 and Erk activation. CONCLUSIONS: JNK inhibition decreases hepatic necrosis and apoptosis after OLT, suggesting that JNK activation promotes cell death by both pathways. Inhibition of JNK may be a new therapeutic strategy to prevent liver injury after transplantation.

Animals↗
PubMed1982

Interpretation of CO2 exhalation rate data from demethylation of aminopyrine and its metabolite monomethylaminoantipyrine.

1 Aminopyrine breath tests make use of the commercially available (N-dimethyl-[14C])-aminopyrine. A pharmacokinetic model has been proposed to relate 14CO2 exhalation rates (CER) to the demethylation of ([14C]-methyl)-aminopyrine (AP) and -monomethylaminoantipyrine (MAP). 2 computer simulations based on the model show that the shape of the CER-time profile is largely dependent on the ratio of the MAP to AP elimination rate constants. If this ratio equals 0.5 then the CERs decline in the monoexponential fashion. Ratios less than 0.5 result in concave biexponential curves whereas ratios greater than 0.5 result in convex curves. When demethylation is not complete for both compounds the transfer from biexponential to monoexponential behaviour will only occur at ratios greater than 0.5. 3 The resolution of concave biexponential CER-time profiles to give accurate estimates of AP and MAP elimination rate constants can only be achieved when the length of the experiment is adequate. The commonly employed 2 microCi tracer dose of aminopyrine is insufficient to monitor CER over the necessary time period to detect the proposed biexponential decline.

Aminopyridines↗
PubMed1987

Oral nafazatrom in man: effect on inhaled antigen challenge.

The effect of oral nafazatrom (Bay g6575, 2 X 3 g) or placebo on inhaled antigen challenge was assessed in a double-blind study. In four subjects antigen challenge resulted in an immediate fall of 93.2 +/- 3.36% in airflow at 40% of vital capacity (Vp40) and a 45.85 +/- 4.95% reduction in forced partial expiratory volume at one second (FEV1). Neither nafazatrom nor placebo had any effect on baseline lung function or that after challenge. Leukotriene B4 was generated by ex vivo stimulus of blood with ionophore A23187, and quantified by high performance liquid chromatography (h.p.l.c.)-radioimmunoassay. No inhibition of LTB4 formation occurred ex vivo following oral nafazatrom, although addition of 10(-5) M nafazatrom to blood in vitro significantly inhibited LTB4 release. Peak plasma nafazatrom levels during the study ranged from 3.3 X 10(-7) M to 1.47 X 10(-6) M which are below the concentration (10(-5) M) at which significant 5-lipoxygenase inhibition occurs in vitro. Oral nafazatrom is ineffective as a 5-lipoxygenase inhibitor in man, probably because of poor bioavailability after administration.

Adult↗
PubMed1984

Effect of dipyrone, acetylsalicylic acid and acetaminophen on human neutrophil chemotaxis.

Dipyrone metabolites 4-methylaminoantipyrine (MAA) and 4-formylaminoantipyrine (FAA) as well as acetylsalicylic acid inhibited neutrophil migration toward zymosan-activated serum. Inhibition was maximal (76.8 +/- 19.0; 79.2 +/- 12.5 and 80.0 +/- 4.4%, respectively, P less than 0.003) when suboptimal concentrations (0.3%) of the chemoattractant were used and could be demonstrated with drug concentrations comparable with plasma concentrations obtained in clinical use. Acetaminophen and other dipyrone metabolites 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA) lacked chemotactic inhibitory potential. Only MAA and FAA inhibited mildly neutrophil random migration (18.1 +/- 7.8 and 11.2 +/- 3.4%, respectively). We suggest that blocking neutrophil movement plays a role in the anti-inflammatory activity of dipyrone and acetylsalicylic acid, but their mechanism of inhibition remains obscure.

Acetaminophen↗
PubMed1997

Pharmacokinetic study of dipyrone metabolite 4-MAA in the horse and possible implications for doping control.

The pharmacokinetic behaviour of dipyrone metabolite 4-MAA in serum was determined in seven horses of different breeds after a single intravenous dose administration. A biexponential formula was fitted to the serum concentration vs. time data. The median half-life of the elimination phase (t1/2 beta) was 4.85 h (range 5.04 h), the median volume of distribution (Vd(area)) was 1.85 L/kg (range 3.2 L/kg) and median of total clearance was 4.0 mL/min/kg (range 2.3 mL/min/kg).

Animals↗
PubMed1982

A novel inhibitor of gamma-aminobutyrate aminotransferase with anorectic activity.

1-(n-decyl)-3-Pyrazolidinone (BW357U) is a potent, selective inhibitor of gamma-aminobutyrate aminotransferase (GABA-T) in vitro and in vivo. After acute or chronic, oral or intraperitoneal administration of BW357U to rats, brain GABA levels were elevated in a dose-dependent manner. When inhibition of brain GABA-T exceeded 50%, whole brain GABA levels were elevated approximately threefold, and an anorectic effect was observed in the absence of other symptoms. This compound, because of its potency and selectivity, may be useful in studies relating to the function of GABA-containing neurons in appetite regulation.

4-Aminobutyrate Transaminase↗
PubMed1985

Pharmacological modulation of responses of guinea-pig airways contracted with antigen and calcium ionophore A23187.

Ovalbumin (OA) and calcium ionophore A23187 were used to induce contractions of sensitized guinea-pig tracheal and lung parenchymal preparations in the presence and absence of indomethacin. This model was used to examine the properties of a series of compounds reported to inhibit 5-lipoxygenase or to antagonize lipoxygenase products at the receptor level. FPL55712 and piriprost appeared to act as pharmacological antagonists because they rapidly reduced tracheal tone established by OA. The prolonged phase (i.e. greater than 10 min post-challenge) of airways contractions induced by OA is assumed to be lipoxygenase-dependent and was inhibited by nordihydroguaiaretic acid (NDGA), FPL55712, nafazatrom and benoxaprofen, in order of potency. Piriprost had similar inhibitory effects on the trachea, but not on lung parenchyma. The inhibitory effects of NDGA and FPL55712 were reduced, and those of nafazatrom increased by indomethacin. Indomethacin decreased the inhibitory effect of piriprost on the trachea, but facilitated inhibition by this agent on the parenchyma. A roughly similar pattern was seen on A23187-induced contractions, but FPL55712 did not modify these contractions and benoxaprofen enhanced the response of the trachea. BW755C enhanced the overall contractile response of OA- and A23187-induced tracheal contractions (but not parenchymal contractions) in a bell-shaped manner, an effect not seen in the presence of indomethacin. This indicated that BW755C could be acting as a cyclo-oxygenase inhibitor. The results suggested that, although inhibitors of the lipoxygenase pathway were partially effective in inhibiting the contractions of the airways induced by OA or A23187, other mediators in addition to those of the lipoxygenase pathway contribute to these contractions.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

Pharmacological modulation of responses of guinea-pig airways contracted with arachidonic acid.

Arachidonic acid (AA) was used to induce contractions of guinea-pig tracheal and lung parenchymal preparations in the presence of indomethacin. Prior addition of FPL55712, nordihydroguaiaretic acid (NDGA), piriprost, benoxaprofen or nafazatrom, in order of potency, inhibited AA-induced contractions of trachea. Higher concentrations (2 - 3 fold) were necessary to inhibit contractions of parenchyma. FPL55712 and piriprost appeared to act as pharmacological antagonists of leukotrienes because they rapidly reduced the tone of the airways established by AA. Administration of exogenous AA to indomethacin-treated trachea appears to be a good model to examine leukotriene receptor antagonists and inhibitors of the lipoxygenase pathway.

Animals↗
PubMed1987

Effect of nafazatrom and indomethacin on pulmonary removal of prostaglandin E1 after endotoxin in rabbits.

1 We compared the effects of endotoxin on pulmonary prostaglandin E1 (PGE1) removal in groups of rabbits pretreated with the cyclo-oxygenase inhibitor, indomethacin, or nafazatrom (Bay g 6575), which has been shown to increase plasma prostacyclin concentrations. 2 In untreated animals, endotoxin transiently decreased pulmonary removal of [3H]-PGE1, caused pulmonary hypertension, systemic hypotension and increased plasma concentrations of PGE2 and 6-keto-PGF1 alpha. 3 Indomethacin pretreatment prevented the transient decrease in pulmonary removal of [3H]-PGE1 in response to endotoxin, prevented the haemodynamic effects and inhibited prostaglandin synthesis. Pretreatment with nafazatrom did not affect the decreased pulmonary removal of [3H]-PGE1, exacerbated the haemodynamic response, reduced survival and potentiated the increase in circulating 6-keto-PGF1 alpha. 4 We conclude that indomethacin acts to prevent the depression of pulmonary [3H]-PGE1 removal by eliminating surface area changes associated with endotoxin-induced pulmonary vasoconstriction. 5 These data suggest that nafazatrom treatment results in exacerbation of the endotoxin-induced systemic hypotension presumably due to its effect on increased plasma prostacyclin during the later phase of endotoxaemia.

Alprostadil↗
PubMed1985

A study of disturbances in granulocytopoiesis in humans using a diffusion chamber system.

Data are presented demonstrating that bone marrow granulocytic cells from normal persons continuously proliferate and mature during 5 d of cultivation in a diffusion chamber system (DC). Bone marrow granulocytopoiesis in 3 patients with different granulocytopoietic disorders was investigated using DC. In patient 1, with drug-induced agranulocytosis, bone marrow aspirated on the "day of recovery" revealed intensive proliferation in DC resulting in a highly significant increase of mature granulocytes. Patient 2 suffered from chronic neutropenia of unknown aetiology. After 5 d cultivation of bone marrow in DC an increase of metamyelocytes was observed, indicating delayed maturation of granulocytic cells. Patient 3 had neutropenia probably due to the splenic sequestration. Data obtained with DC suggest stimulated granulocytopoiesis in this patient. The results obtained using DC reflect the particular phase of the disease in which bone marrow was aspirated. It may be concluded that this method could provide additional data in quantitative and functional disorders of granulocytes.

Adolescent↗
PubMed2002

The oxidative biotransformation of losoxantrone (CI-941).

The oxidative biotransformation of the anticancer drug 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride (losoxantrone, CI-941) after incubation of primary cultures of rat hepatocytes has been investigated. The structures of twelve losoxantrone metabolites have been elucidated by means of high-performance liquid chromatography-mass spectometry, tandem mass spectrometry, and two-dimensional NMR. In these mammalian hepatocytes, the CI-941 biotransformation includes a monohydroxylation of the phenolic substructure of the CI-941-chromophore via cytochrome P450 catalysis, resulting in metabolites having an ortho- and para-hydroquinonoid substructure, respectively. The identification of a glutathione conjugate as a follow-up metabolite confirms the oxidative activation of the ortho-hydroxylated losoxantrone metabolite. The oxidative activation establishes the ability of CI-941 to form covalent bonds to intracellular nucleophilic targets. Furthermore, the CI-941 metabolism was shown to be extremely suppressed in rat hepatocytes incubated with metyrapone. In contrast to these results, human tumor HepG2 cells did not show any CI-941 biotransformation after incubation.

Animals↗
PubMed2001

DNA-interactive anticancer aza-anthrapyrazoles: biophysical and biochemical studies relevant to the mechanism of action.

The physicochemical and DNA-binding properties of anticancer 9-aza-anthrapyrazoles (9-aza-APs) were investigated and compared with the carbocyclic analogs losoxantrone (LX) and mitoxantrone (MX). Unlike their carbocyclic counterparts, the tested 9-aza-APs do not undergo self-aggregation phenomena. The pyridine nitrogen at position 9, missing in the carbocyclic derivatives, is involved in protonation equilibria at physiological pH. In addition, 9-aza-APs are electrochemically reduced at a potential intermediate between LX and MX. These data fully agree with quantum mechanical calculations. Binding to nucleic acids was examined by spectroscopic, chiroptical, and DNase I footprinting techniques as a function of ionic strength and base composition. The 9-aza-APs exhibit prominent affinity for DNA, with an important electrostatic contribution to the binding free energy. A very remarkable sequence preference pattern dramatically favors GC steps in double-helical DNA, whereas the carbocyclic reference compounds show a substantially lower selectivity for GC. A common DNA complexation geometry, considerably differing from that of MX, characterizes all anthrapyrazoles. Hence, bioisosteric substitution and ring-hydroxy deletion play an important role in defining the physicochemical properties and in modulating the affinity of anthrapyrazoles for the nucleic acid, the geometry of the intercalation complex, and the sequence specific contacts along the DNA chain. Drug stimulation of topoisomerase II-mediated DNA cleavage is remarkably attenuated in the aza-bioisosteric derivatives, suggesting that other non-enzyme-mediated cytotoxic mechanism(s), possibly connected with free radical production, are responsible for efficient cell killing. The biophysical and biochemical properties exhibited by 9-aza-APs contribute to clarifying the peculiar pharmacological profile of this family of compounds.

Animals↗