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P Ney

Publications and source records attributed to P Ney.

At least 19 recordsLinked to original sources
PubMed1998

Preclinical safety studies of the combination moexipril hydrochloride/hydrochlorothiazide.

The general pharmacological properties of a combination of the angiotensin converting enzyme (ACE) inhibitor moexipril hydrochloride (CAS 82586-52-5) and the thiazide diuretic hydrochlorothiazide (CAS 58-93-5, HCTZ), ratio 7.5 + 12.5, were studied in generally accepted models in vitro and in vivo. In vitro, the combination showed neither agonistic nor antagonistic activities on the isolated guinea pig trachea in concentrations up to 2 x 10(-4) g/ml. In mice, there was no effect on intestinal motility or the thiopental-induced sleeping time up to 1000 mg/kg. The only activity observed in mice was an inhibition of spontaneous motility after oral dosing with 300 and 1000 mg/kg, respectively. Both HCTZ (1-10 mg/kg) alone and the combination moexipril/HCTZ (1.6 or 4.8 mg/kg) produced dose-related increases in diuresis and electrolyte excretion in rats, however, without any potentiating effects for the drug combination. On the cardiovascular system of anaesthetised dogs, the effects observed were as expected, e.g. dose-related decrease in blood pressure. Repeated dose toxicity studies in rats and dogs revealed the kidney as target organ. This effect, based on highly exaggerated pharmacological activity, is well-known for other ACE inhibitors. No potential for teratogenic effects could be observed for the drug combination. In summary, the preclinical data indicate that the combination of moexipril and HCTZ (ratio 7.5 + 12.5) represents a safe drug without relevant side effects or gross toxicity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Pharmacological and toxicological studies of the new angiotensin converting enzyme inhibitor moexipril hydrochloride.

The pharmacodynamic and toxicological profile of the new angiotensin converting enzyme (ACE) inhibitor moexipril (CAS 82586-52-5) and its active diacid metabolite moexiprilat were studied in vitro as well as in vivo. In vitro, moexiprilat was a potent inhibitor of ACE in guinea pig serum as well as on purified ACE from rabbit lung with IC50 values of 2.6 and 4.9 nmol/l, respectively. Both, moexipril and moexiprilat inhibited the angiotensin I (ANG I)-induced contractions of rabbit aorta concentration-dependently, whereas contractions by other agents were not affected, indicating a high selectivity of both compounds for ACE. Similar results were obtained in vivo in experiments investigating the blood pressure increasing response to intravenous injection of ANG I or ANG II in conscious normotensive rats and dogs after oral or intravenous application of moexipril or moexiprilat, respectively. The antihypertensive effects of the oral application of moexipril were studied in models of hypertension in the rat as well as in renal hypertensive dogs. In renal hypertensive rats, moexipril (0.03-10 mg/kg p.o.) caused a dose-dependent decrease in blood pressure with a threshold dose of 0.3 mg/kg. Once daily treatment of the animals with 3 mg/kg/d for 5 days lowered mean blood pressure by about 70 mmHg and blood pressure was maintained on this low level for the experimental period. In spontaneously hypertensive rats, oral administration of moexipril (30 mg/kg/d) for 5 days caused a progressive lowering of mean blood pressure from pre-treatment values of 180 +/- 7 mmHg to a trough on day 4 of 127 +/- 4 mmHg. In perinephritic hypertensive dogs, oral administration of moexipril (10 mg/kg) in combination with hydrochlorothiazide (10 mg/kg) caused a drop of mean blood pressure by 25 mmHg from pre-treatment control, which persisted for 24 h. In all these models, the action was characterized by a rapid onset and a long duration of action. After cessation of treatment, a gradual return to baseline values was observed. In contrast, only slight blood pressure lowering effects were seen in normotensive rats at high doses (100 mg/kg p.o.). The general pharmacological properties of moexipril were also studied in generally accepted models in vitro and in vivo. In doses or concentrations more than 100 times higher than those causing ACE inhibition, no effects were observed on the central nervous system, on isolated smooth muscle preparations, the digestive system, the kidney or the lung. Additionally, moexipril is devoid of anti-inflammatory properties and has no effect on platelet function. On the cardiovascular system, the effects observed can be attributed to ACE inhibition by moexipril. Repeated dose toxicity studies in rats and dogs revealed the heart and kidneys as target organs. These effects, based on highly exaggerated pharmacological activity, are comparable to other ACE-inhibitors. No potential for mutagenic or carcinogenic activity and no evidence of reproductive toxicity was apparent for meoxipril. The preclinical data indicate that moexipril possesses a high degree of specifity as an ACE-inhibitor without relevant side effects or gross toxicity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

The RN-BSN student: developing a model of empowerment.

Nursing practice is being redefined. Today's graduating nurse is practicing in a tomorrow full of unknowns. The relevancy of traditional nursing education is being questioned in today's health care climate of crisis. In an attempt to prepare the graduating RN-BSN student to cope with these changes, nurse educators developed a process of empowerment. The framework for this effort was derived from the curriculum revolution, adult learning theory and empowerment research. The faculty defined empowerment as both an interpersonal process and an outcome. A graphic model has been created consisting of the four elements of empowerment: collegiality, communication, autonomy and accountability. Learning experiences are selected based upon these four elements. Teaching strategies are identified. Positive changes in student behavior have been reported anecdotally. The faculty are beginning the next phase: designing a research project to investigate behavior changes related to this empowerment model.

Communication↗
PubMed1995

Identification of two novel regulatory elements within the 5'-untranslated region of the human A gamma-globin gene.

Interaction between the stage selector element (SSE) in the proximal gamma-globin promoter and hypersensitivity site 2 in the locus control region partly mediates the competitive silencing of the beta-globin promoter in the fetal developmental stage. We have now demonstrated that a second SSE-like element in the 5'-untranslated region of the gamma-gene also contributes to this competitive silencing of the beta-gene. Utilizing transient transfection assays in the fetal erythroid cell line, K562, we have shown that the core enhancer of hypersensitivity site 2 can preferentially interact with the proximal gamma-promoter in the absence of the SSE, completely silencing a linked beta-promoter. Mutation of a 20-base pair sequence of the gamma-gene 5'-untranslated region (UTR) led to derepression of beta-promoter activity. A marked activation of gamma-promoter activity was also observed with this mutation, suggesting the presence of a repressor. Fine mutagenesis dissected these activities to different regions of the 5'-UTR. The stage selector activity was localized to a region centered on nucleotides +13 to +15. Electromobility shift assays utilizing this sequence demonstrated binding of a fetal and erythroid-specific protein. The repressor activity of the 5'-UTR was localized to tandem GATA-like sites, which appear to bind a complex of two proteins, one of which is the erythroid transcription factor GATA-1. These results indicate that the 5'-UTR of the gamma-gene contains sequences that may be important for its transcriptional and developmental regulation.

Base Sequence↗
PubMed1995

Effects of prostaglandin E1, prostaglandin E0 and SPM 206 on isolated human coronary arteries.

The effects of PGE1, PGE0 and the stable PGE1-analogue SPM 206 on human epicardial coronary arteries were studied in vitro. The tension of the isolated arterial rings was measured isometrically. After precontraction, concentration-response curves with the compounds were performed. PGE1 and SPM 206 elicited concentration-dependent relaxations which are counteracted by a contractile action in higher concentrations. In PGE0, the contractile action occurred even in lower concentrations. This contraction was antagonized by the selective thromboxane A2 antagonist SQ 29,548, resulting in an equipotent relaxation for all three compounds.

Alprostadil↗
PubMed1995

Vasodilator effects of PGE1 in the coronary and systemic circulation of the rat are mediated by ATP-sensitive potassium (K+) channels.

This study was undertaken to investigate the possible involvement of K+ channels in PGE1-mediated vasodilatation. The increase in coronary flow elicited by PGE1 in isolated working rat hearts was attenuated by phentolamine and glibenclamide, inhibitors of ATP-regulated K+ channels, whereas apamin and charybdotoxin, inhibitors of calcium-activated K+ channels, were ineffective. In the anaesthetized rat, the duration of the hypotensive action of PGE1 was markedly attenuated by glibenclamide. It is concluded that the vasodilatory action of PGE1 in the coronary and systemic circulation of the rat is, at least in part, mediated via an opening of ATP-sensitive K+ channels.

Adenosine Triphosphate↗
PubMed1995

The induction of cyclooxygenase-2 elicited by endotoxin in endothelial cells and macrophages is inhibited by prostaglandin E1 and 13,14-dihydro prostaglandin E1.

The effects of PGE1 or 13,14-dihydro PGE1 (PGE0) on the expression of COX-2 protein and COX activity elicited by LPS (1 microgram/ml for 24 h) in bovine aortic endothelial cells (BAEC) and J774.2 macrophages were investigated. PGE1 or PGE0 (0.001 to 10 micrograms/ml) caused a dose-dependent decrease of COX activity elicited by LPS in both cell types. Western blot analysis showed that PGE1 or PGE0 (1 microgram/ml) inhibited the expression of COX-2 protein in LPS-activated BAEC and J774.2 macrophages. Thus, PGE1 or (its metabolite) PGE0 decrease the formation of COX metabolites by inhibiting the induction of COX-2 protein by LPS.

Alprostadil↗
PubMed1995

Reduction by prostaglandin E1 or prostaglandin E0 of myocardial infarct size in the rabbit by activation of ATP-sensitive potassium channels.

1. This study examined whether pretreatment of rabbits with infusions of prostaglandin E1 (PGE1) or prostaglandin E0 (PGE0) (which were terminated prior to the onset of ischaemia) reduce myocardial infarct size arising from coronary artery occlusion (60 min) and reperfusion (120 min). In addition, we investigated whether the observed cardioprotective effects of these two prostaglandins were due to the activation of ATP-sensitive potassium (KATP) channels. 2. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 2 h of reperfusion was 59 +/- 4% (n = 10). PGE1 or PGE0 treatment (1.0 micrograms kg-1 min-1), administered as 1 h pretreatments (0.05 ml min-1, i.v.), significantly reduced infarct size to 44 +/- 6% (n = 6) or 42 +/- 1% (n = 6), respectively. PGE1 or PGE0 pretreatment resulted in a significant reduction in mean arterial blood pressure, which returned to baseline within 15 min of discontinuation of the infusion (i.e. prior to LAL ligation). 3. The reduction in infarct size afforded by PGE1 was abolished by pretreatment of rabbits with the KATP channel blockers, glibenclamide (60 +/- 4%; n = 8) or 5-hydroxydecanoate (58 +/- 6%; n = 6). Similarly, glibenclamide also largely attenuated the reduction in infarct size afforded by PGE0 (52 +/- 3%; n = 8). 4. We propose that a 1 h pretreatment of PGE1 or PGE0 reduces infarct size by activating protein kinase C resulting in the opening of KATP channels.

Adenosine Triphosphate↗
PubMed1991

PGD2 and its mimetic ZK 110.841 are potent inhibitors of receptor-mediated activation of human neutrophils.

The action of PGD2 and its mimetic ZK 110.841 ((5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15- dihydroxy-16,17,18,19, 20-pentanor-5,13-prostadienoic acid) was compared to PGE1 in vitro on superoxide anion generation, degranulation, leukotriene (LT) B4 release and Ca++ fluxes in human polymorphonuclear leukocytes (PMN). All compounds were potent inhibitors of formyl-methionyl-leucyl-phenylalanine (FMLP)- and platelet-activating factor (PAF)-induced superoxide anion generation, beta-glucuronidase release and Ca++ influx. The PAF-induced release of LTB4 in the presence of 10 mumoles/l arachidonic acid was significantly attenuated by these prostaglandins. This inhibition of PMN function was paralleled by an increase in cellular cAMP levels. The molar potency of the prostaglandins used was comparable, although the D-type compounds appeared slightly more potent in some PMN function tests. None of the substances affected PMN activation induced by the calcium inophore calcimycin (A23187). The data demonstrate an effective inhibition of receptor-mediated (FMLP, PAF) PMN activation by PGD2 and its mimetic ZK 110.841, suggesting either an inhibitory PGD2 receptor on human PMN or action of PGD2 at the PGE receptor. PGD2 is a labile compound in vivo and is rapidly metabolized into a number of products with different biological properties. Since ZK 110.841 lacks this instability, this compound may serve as an important tool to classify PGD2-mediated reactions.

Alprostadil↗
PubMed1991

Antiplatelet, antineutrophil and vasodilating properties of 13,14-dihydro-PGE1 (PGE0)--an in vivo metabolite of PGE1 in man.

The actions of the in vivo metabolite of PGE1, 13,14-dihydro-PGE1 (PGE0), on platelet and neutrophil (PMN) function and vessel tone were studied in vitro. PGE0 inhibited aggregation, ATP release and thromboxane generation by human platelets (IC50 10-100 nmoles/l). The compound also inhibited superoxide anion generation and lysosomal enzyme release from human PMN. PGE0 was equipotent to PGE1 in both systems, while 15-keto-PGE1 was ineffective in platelets but produced some inhibition in PMN. These inhibitory effects of PGE0 and PGE1 were paralleled by concentration-dependent increases in cyclic AMP in platelets and PMN. Both compounds were also potent relaxants of several arterial preparations in the rabbit at comparable concentrations. In general, the vasorelaxing properties of PGE0 were somewhat lower and the contractile effects somewhat stronger in comparison to PGE1. These data demonstrate a significant and concentration-dependent inhibition of receptor-mediated activation of human platelets and PMN by PGE0. The molar potency of the compound is comparable to that of PGE1. Generation of PGE0 from infused PGE1 may contribute to the clinical efficacy of PGE1 in treatment of severe peripheral arterial occlusive disease.

Alprostadil↗
PubMed1991

[The pharmacology of 13,14-dihydro-PGE1 in comparison with PGE1].

This study investigates the effects of 13,14-Dihydro-PGE1 (PGE0) in comparison to PGE1 on human platelets, human polymorphonuclear granulocytes (PMN) and a number of vessel preparations of different species. The potency of PGE0 in inhibition of platelet and neutrophil activation is similar to PGE1. The vascular action differs. At a comparable molar potency, PGE0 showed stronger contractile and less relaxing effects than PGE1. The biological activities of PGE0 may contribute to the in vivo effects of PGE1 in treatment of peripheral arterial occlusive disease, in particular at high-dose i.v. administration.

Alprostadil↗
PubMed1990

Cyclic GMP mediates SIN-1-induced inhibition of human polymorphonuclear leukocytes.

Different nitrovasodilators were used to assess the role of cyclic GMP in the regulation of polymorphonuclear leukocyte (PMN) function. Molsidomine and its metabolites, 3-morpholinosydnonimine (SIN-1) and N-nitroso-N-morpholinoaminoacetonitrile (SIN-1A) at 0.01-1 mM, inhibited lysosomal enzyme release from PMN stimulated by 30 nM formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP). At 1 mM, molsidomine, SIN-1 and SIN-1A decreased beta-glucuronidase release by 19, 37 and 46% of the control, respectively. Glyceryl trinitrate (GTN) and sodium nitroprusside (SNP) showed no effect on beta-glucuronidase release from PMN. At 1 mM, SIN-1A, SIN-1 and SNP in the presence of 0.5 mM isobutylmethylxanthine (IBMX) stimulated cyclic GMP 21-, 9- and 14-fold, respectively, demonstrating a relation between cyclic GMP stimulation and neutrophil inhibition by the molsidomine metabolites. GTN and unmetabolized molsidomine were without effect on cyclic GMP levels. The hypothesis of an inhibitory effect of cyclic GMP on neutrophil function was further supported by the attenuation of SIN-1-induced inhibition of enzyme release by methylene blue (10 microM), an inhibitor of soluble guanylate cyclase. Moreover, 8-bromo cyclic GMP and dibutyryl cyclic GMP, 1 mM, decreased beta-glucuronidase release from FMLP-stimulated PMN by 12 and 44% of the control, respectively. These data demonstrate that cyclic GMP is an inhibitory second messenger in human PMN and suggest that this action of SIN-1 may be of considerable interest under conditions of platelet/PMN activation, e.g. during myocardial ischemia.

1-Methyl-3-isobutylxanthine↗
PubMed1990

A 46 base pair enhancer sequence within the locus activating region is required for induced expression of the gamma-globin gene during erythroid differentiation.

The locus activating region (LAR), contained within 30 kb of chromatin flanking the human beta-globin gene cluster, has recently been shown to be essential for high level beta-globin gene expression. To determine the effect of fragments containing LAR sequences on globin gene expression, mRNA from a marked gamma-globin gene linked to LAR fragments was assayed in stably transfected K562 erythroleukemia cells. DNaseI hypersensitive site II (HS II), located 10.9 kb upstream of the epsilon-globin gene, was required for high level gamma-globin gene expression. We also showed that a 46 bp enhancer element within HS II was necessary and sufficient for the increased gamma-globin gene expression observed with hemin induced erythroid maturation of K562 cells. These results localize a distant regulatory element important for activation of globin genes during human erythroid cell maturation.

Base Sequence↗
PubMed1990

Cytotoxic enzyme release and oxygen centered radical formation in human neutrophils are selectively inhibited by E-type prostaglandins but not by PGI2.

The action of PGE1, PGE2, PGI2 and iloprost on superoxide anion generation, lysosomal enzyme release, and changes of Ca2+ fluxes in human polymorphonuclear leukocytes (PMN) was studied in vitro. Both PGE-type compounds were equipotent inhibitors of FMLP-and PAF-stimulated superoxide anion generation, beta-glucuronidase release (IC50 3-5 mumol/l) and Ca2+ influx while PGI2 and iloprost were ineffective at concentrations up to 10 mumol/l. These inhibitory actions of PGE1 and PGE2 were paralleled by an increase in cAMP level of the PMN while no change occurred with PGI2 and iloprost. None of the prostaglandins affected the initial intracellular Ca2+ liberation after challenge with FMLP or PAF. Preincubation of PMN with PGE1 and PGE2 but not with iloprost resulted in subsequent desensitization against a second administration of these compounds. None of the compounds affected PMN activation produced by arachidonic acid or calcimycin (A 23187). These data demonstrate that PGE-type compounds are effective inhibitors of receptor-mediated (PAF, FMLP) activation of human PMN while prostacyclins are considerably less potent. This suggests that the inhibitory prostaglandin receptor on human PMN belongs to the E-type being functionally different from the inhibitory prostaglandin receptor on human platelets. These results suggest that compounds, such as PGE1 and PGE2 might be superior to prostacyclins to prevent PMN-associated generation of reactive oxygen species and lysosomal enzyme release in situations with endogenous PMN activation, i.e. inflammatory reactions.

Arachidonic Acid↗
PubMed1990

Nitrovasodilator-induced inhibition of LTB4 release from human PMN may be mediated by cyclic GMP.

This study investigates the action of nitrovasodilators on f-metleu-phe (FMLP)-stimulated LTB4 release and intracellular cyclic nucleotide levels in human polymorphonuclear leukocytes (PMN). Sodium nitroprusside, and the molsidomine (MOL) metabolites SIN-1 and SIN-1A potently inhibited LTB4 release and increased cGMP levels. No significant effects on LTB4 release or cGMP accumulation were observed in the presence of molsidomine or glyceryl trinitrate. None of the compounds tested affected cAMP levels. It is suggested that nitrovasodilators (i) inhibit LTB4 release from human PMN via enhanced cGMP and (ii) that this inhibition requires the presence of an active metabolite, probably nitric oxide.

Cyclic GMP↗
PubMed1989

E-type prostaglandins but not iloprost inhibit platelet activating factor-induced generation of leukotriene B4 by human polymorphonuclear leukocytes.

1. Platelet-activating factor (Paf) was found to stimulate leukotriene B4 release from human polymorphonuclear leukocytes (PMN). This stimulation was considerably enhanced in the presence of small amounts of exogenous arachidonic acid. 2. Prostaglandin E2 (PGE2) and PGE1 (0.1-10 microM) inhibited this reaction dose-dependently. No inhibition was seen with iloprost at these concentrations. 3. The data suggest that E prostaglandins are potent inhibitors of Paf-induced leukotriene generation by human PMNs and thus may serve as local factors controlling Paf-mediated inflammatory reactions.

Arachidonic Acids↗