BMC Pharmacology[JOURNAL]
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200 papers
Cloning and expression of the rabbit prostaglandin EP2 receptor.
Guan Y, Stillman BA, Zhang Y … +6 more , Schneider A, Saito O, Davis LS, Redha R, Breyer RM, Breyer MD
BMC Pharmacol · 2002 Jun · PMID 12097143 · Full text
BACKGROUND: Prostaglandin E2 (PGE2) has multiple physiologic roles mediated by G protein coupled receptors designated E-prostanoid, or "EP" receptors. Evidence supports an important role for the EP2 receptor in regulatin...
BACKGROUND: Prostaglandin E2 (PGE2) has multiple physiologic roles mediated by G protein coupled receptors designated E-prostanoid, or "EP" receptors. Evidence supports an important role for the EP2 receptor in regulating fertility, vascular tone and renal function. RESULTS: The full-length rabbit EP2 receptor cDNA was cloned. The encoded polypeptide contains 361 amino acid residues with seven hydrophobic domains. COS-1 cells expressing the cloned rabbit EP2 exhibited specific [3H]PGE2 binding with a Kd of 19.1 +/- 1.7 nM. [3H]PGE2 was displaced by unlabeled ligands in the following order: PGE2>>PGD2=PGF2alpha=iloprost. Binding of [3H]PGE2 was also displaced by EP receptor subtype selective agonists with a rank order of affinity consistent with the EP2 receptor (butaprost>AH13205>misoprostol>sulprostone). Butaprost free acid produced a concentration-dependent increase in cAMP accumulation in rabbit EP2 transfected COS-1 cells with a half-maximal effective concentration of 480 nM. RNase protection assay revealed high expression in the ileum, spleen, and liver with lower expression in the kidney, lung, heart, uterus, adrenal gland and skeletal muscle. In situ hybridization localized EP2 mRNA to the uterine endometrium, but showed no distinct localization in the kidney. EP2 mRNA expression along the nephron was determined by RT-PCR and its expression was present in glomeruli, MCD, tDL and CCD. In cultured cells EP2 receptor was not detected in collecting ducts but was detected in renal interstitial cells and vascular smooth muscle cells. EP2 mRNA was also detected in arteries, veins, and preglomerular vessels of the kidney. CONCLUSION: EP2 expression pattern is consistent with the known functional roles for cAMP coupled PGE2 effects in reproductive and vascular tissues and renal interstitial cells. It remains uncertain whether it is also expressed in renal tubules.
In vitro susceptibility to pentavalent antimony in Leishmania infantum strains is not modified during in vitro or in vivo passages but is modified after host treatment with meglumine antimoniate.
Carrió J, Portús M
BMC Pharmacol · 2002 May · PMID 12019027 · Full text
BACKGROUND: Leishmaniasis is a common parasitic disease in Southern Europe, caused by Leishmania infantum. The failures of current treatment with pentavalent antimonials are partially attributable to the emergence of ant...
BACKGROUND: Leishmaniasis is a common parasitic disease in Southern Europe, caused by Leishmania infantum. The failures of current treatment with pentavalent antimonials are partially attributable to the emergence of antimony-resistant Leishmania strains. This study analyses the in vitro susceptibility to pentavalent antimony of intracellular amastigotes from a range of L. infantum strains, derived from the same infected animal, during in vitro and in vivo passages and after host treatment with meglumine antimoniate. RESULTS: SbV-IC50 values for strains from two distinct isolates from the same host and one stock after two years of culture in NNN medium and posterior passage to hamster were similar (5.0 +/- 0.2; 4.9 +/- 0.2 and 4.4 +/- 0.1 mgSbV/L, respectively). In contrast, a significant difference (P < 0.01, t test) was observed between the mean SbV-IC50 values in the stocks obtained before and after treatment of hosts with meglumine antimoniate (4.7 +/- 0.4 mgSbV/L vs. 7.7 +/- 1.5 mgSbV/L). Drug-resistance after drug pressure in experimentally infected dogs increased over repeated drug administration (6.4 +/- 0.5 mgSbV/L after first treatment vs. 8.6 +/- 1.4 mgSbV/L after the second) (P < 0.01, t test). CONCLUSIONS: These results confirm previous observations on strains from Leishmania/HIV co-infected patients and indicate the effect of the increasing use of antimony derivatives for treatment of canine leishmaniasis in endemic areas on the emergence of Leishmania antimony-resistant strains.
Seed germination, phenology, and antiedematogenic activity of Peperomia pellucida (L.) H. B. K.
Arrigoni-Blank Mde F, Oliveira RL, Mendes SS … +5 more , Silva Pde A, Antoniolli AR, Vilar JC, Cavalcanti SC, Blank AF
BMC Pharmacol · 2002 May · PMID 12019026 · Full text
BACKGROUND: Peperomia pellucida is popularly known as coraçãozinho in the Brazilian northeast and is used in the treatment of abscesses, furuncles, and conjunctivitis. Our work aimed to determine the term of the developm...
BACKGROUND: Peperomia pellucida is popularly known as coraçãozinho in the Brazilian northeast and is used in the treatment of abscesses, furuncles, and conjunctivitis. Our work aimed to determine the term of the development stages and the species cycle in the four seasons of the year (complete development, beginning of bloom, complete bloom, and seed set), verifying the plant's therapeutic profile during the four distinct development phases in order to detect differences in its potency. Pharmacological tests were performed to observe the anti-inflammatory activity. RESULTS: Phenological observations were accessed for a 12 month-period, from the Brazilian summer of 1999/2000 to fall 2000. On average the plantules' emergence occurred 15 days after seeding. All plantules grew in a similar manner up to 25 days after transplantation in all seasons. Starting on the 25th day, we observed faster growth during spring, with plants reaching a height of about 60 cm after 100 days of transplantation, unlike other seasons, in which plants reached heights of 40, 40, and 35 cm during winter, summer, and fall, respectively. The P. pellucida aqueous extract showed significant anti-inflammatory activity during phenophases 1 and 2 of winter and spring. Depending on the plant's phenophase there was variation in the potency of edema inhibition. CONCLUSION: P. pellucida has a phenological cycle of approximately 100 days. It is recommended that the P. pellucida aqueous extract is used as an antiedematogenic only during phenophases 1 and 2 of winter and spring.
Selective alteration of gene expression in response to natural and synthetic retinoids.
Brand C, Ségard P, Plouvier P … +3 more , Formstecher P, Danzé PM, Lefebvre P
BMC Pharmacol · 2002 May · PMID 12019025 · Full text
BACKGROUND: Retinoids are very potent inducers of cellular differentiation and apoptosis, and are efficient anti-tumoral agents. Synthetic retinoids are designed to restrict their toxicity and side effects, mostly by inc...
BACKGROUND: Retinoids are very potent inducers of cellular differentiation and apoptosis, and are efficient anti-tumoral agents. Synthetic retinoids are designed to restrict their toxicity and side effects, mostly by increasing their selectivity toward each isotype of retinoic acids receptors (RARalpha,beta, gamma and RXRalpha, beta, gamma). We however previously showed that retinoids displayed very different abilities to activate retinoid-inducible reporter genes, and that these differential properties were correlated to the ability of a given ligand to promote SRC-1 recruitment by DNA-bound RXR:RAR heterodimers. This suggested that gene-selective modulation could be achieved by structurally distinct retinoids. RESULTS: Using the differential display mRNA technique, we identified several genes on the basis of their differential induction by natural or synthetic retinoids in human cervix adenocarcinoma cells. Furthermore, this differential ability to regulate promoter activities was also observed in murine P19 cells for the RARbeta2 and CRABPII gene, showing conclusively that retinoid structure has a dramatic impact on the regulation of endogenous genes. CONCLUSIONS: Our findings therefore show that some degree of selective induction or repression of gene expression may be achieved when using appropriately designed ligands for retinoic acid receptors, extending the concept of selective modulators from estrogen and peroxisome proliferator activated receptors to the class of retinoid receptors.
Activation of the peroxisome proliferator-activated receptor alpha protects against myocardial ischaemic injury and improves endothelial vasodilatation.
Tabernero A, Schoonjans K, Jesel L … +3 more , Carpusca I, Auwerx J, Andriantsitohaina R
BMC Pharmacol · 2002 Apr · PMID 11940253 · Full text
BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the metabolism of lipoproteins and fatty acids, and seems to protect against the development of atherosclerosis. To...
BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the metabolism of lipoproteins and fatty acids, and seems to protect against the development of atherosclerosis. To evaluate the possible protective role of PPARalpha on cardiovascular function, the effect of the PPARalpha agonist, fenofibrate was assessed with respect to ischaemia/reperfusion injury and endothelial function in mice. RESULTS: Fenofibrate treatment reduces myocardial infarction size and improves post-ischaemic contractile dysfunction. Hearts from PPARalpha null mice exhibit increased susceptibility to ischaemic damages and were refractory to protection by fenofibrate treatment suggesting that the beneficial effects of fenofibrate were mediated via PPARalpha. Furthermore, fenofibrate improves endothelium- and nitric oxide-mediated vasodilatation in aorta and mesenteric vascular bed. A decreased inhibitory effect of reactive oxygen species in the vessel wall accounts for enhanced endothelial vasodilatation. However, the latter cannot be explained by an increase in nitric oxide synthase expression nor by an increase sensitivity of the arteries to nitric oxide. CONCLUSIONS: Altogether the present data suggest that fenofibrate exerts cardioprotective effect against ischaemia and improves nitric oxide-mediated response probably by enhancing antioxidant capacity of the vessel wall. These data underscore new therapeutic perspectives for PPARalpha agonists in ischaemic myocardial injury and in cardiovascular diseases associated with endothelial dysfunction.
The farnesyl transferase inhibitor RPR-130401 does not alter radiation susceptibility in human tumor cells with a K-Ras mutation in spite of large changes in ploidy and lamin B distribution.
Mégnin-Chanet F, Lavelle F, Favaudon V
BMC Pharmacol · 2002 · PMID 11929613 · Full text
BACKGROUND: Growth inhibition by RPR-130401, a non-peptidomimetic farnesyltransferase inhibitor, was investigated without or with combined exposure to ionizing radiation in three human tumor cell lines (HCT-116, MiAPaCa-...
BACKGROUND: Growth inhibition by RPR-130401, a non-peptidomimetic farnesyltransferase inhibitor, was investigated without or with combined exposure to ionizing radiation in three human tumor cell lines (HCT-116, MiAPaCa-2 and A-549) bearing a point mutation in the K-Ras gene. RESULTS: RPR-130401 inhibited cell growth with an IC50 of 50 nM (HCT-116), 120 nM (MiAPaCa-2) and 710 nM (A-549), with a poor incidence of apoptosis. The drug brought about G1 and S phase depletion together with arrest of cells in G2 phase and induced a significant accumulation of hyperploid cells showing active S phase DNA synthesis, with HCT-116 and A-549 cells being the most and least responsive, respectively. The drug also produced dramatic changes of the nuclear lamin B pattern, without lamin B cleavage and perturbation of the actin cytoskeleton. On the other hand, RPR-130401 elicited strictly additive interaction in combined treatment with ionizing radiation with regard to cell kill, altered cell cycle progression and induced hyperploidy. CONCLUSIONS: The data suggest that disruption of orderly progression through mitosis and cytokinesis, is a major outcome of drug action and that this effect proceeds from inhibition of lamin B farnesylation. It is anticipated from the strict additivity of RPR-130401 and radiation that neither induced radiation resistance nor acute or late complications of radiotherapy, should occur in combined treatment with RPR-130401.
Down-regulation of the alpha-2C adrenergic receptor: involvement of a serine/threonine motif in the third cytoplasmic loop.
Deupree JD, Borgeson CD, Bylund DB
BMC Pharmacol · 2002 Apr · PMID 11926967 · Full text
BACKGROUND: The mechanisms by which alpha-2 adrenergic receptors are down-regulated following chronic exposure to agonist are not well understood. Interestingly, the human alpha-2C receptor does not down-regulate, wherea...
BACKGROUND: The mechanisms by which alpha-2 adrenergic receptors are down-regulated following chronic exposure to agonist are not well understood. Interestingly, the human alpha-2C receptor does not down-regulate, whereas the opossum alpha-2C receptor does down-regulate. A comparison of the amino acid sequence of the third intracellular loop of these two receptors shows that the opossum alpha-2C receptor contains a potential G protein-coupled receptor kinase (GRK)phosphorylation motif (EESSTSE) with four hydroxyl residues, whereas the human alpha-2C receptor motif only contains two hydroxyl residues (DESSAAAAE). Because a similar acidic serine-rich motif (EESSSSD) in the human alpha-2 adrenergic receptor has been demonstrated to be phosphorylated by GRK and all four serines are required for desensitization of the receptor, we sought to determine whether the EESSTSE sequence was involved in the down-regulation of the alpha-2C adrenergic receptor. RESULTS: Site-directed mutagenesis was used to mutate the opossum alpha-2C receptor to SSVA and AAVA in place of the SSTS wild-type sequence. Down-regulation experiments on CHO cells transfected with the receptors demonstrated that neither of the mutated receptors down-regulated following 24 h exposure to norepinephrine, whereas the wild-type receptor down-regulated to 65 +/- 10% of the control. CONCLUSIONS: These results indicate that a motif with four hydroxyl amino acid residues in an acidic environment is important for down-regulation of the opossum alpha-2C adrenergic receptor. Because these are potential GRK phosphorylation sites, we suggest that GRK phosphorylation may be involved in alpha-2C adrenergic receptor down-regulation.
An MCASE approach to the search of a cure for Parkinson's Disease.
Klopman G, Sedykh A
BMC Pharmacol · 2002 Apr · PMID 11926966 · Full text
BACKGROUND: Parkinson's disease is caused by a dopamine deficiency state in the fore brain area. Dopamine receptor agonists, MAO-B inhibitors, and N-Methyl-D-Aspartate (NMDA) receptor antagonists are known to have antipa...
BACKGROUND: Parkinson's disease is caused by a dopamine deficiency state in the fore brain area. Dopamine receptor agonists, MAO-B inhibitors, and N-Methyl-D-Aspartate (NMDA) receptor antagonists are known to have antiparkinson effect. Levodopa, a dopamine structural analog, is the best currently available medication for the treatment of Parkinsons disease. Unfortunately, it also induces side effects upon long administration time. Thus, multidrug therapy is often used, in which various adjuvants alleviate side effects of levodopa and enhance its antiparkinsonian action. RESULTS: Computer models have been created for three known antiparkinson mechanisms using the MCASE methodology. New drugs for Parkinsons disease can be designed on the basis of these models. We also speculate that the presence of biophores belonging to different groups can be beneficial and designed some potential drugs along this line. The proposed compounds bear pharmacophores of MAO-B inhibitors, dopamine agonists and NMDA antagonists, which could synergistically enhance their antiparkinson effect. CONCLUSIONS: The methodology could readily be expanded to other endpoints where drugs with multiple activity mechanisms would be desirable.
Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice.
Hosseinzadeh H, Younesi HM
BMC Pharmacol · 2002 Mar · PMID 11914135 · Full text
BACKGROUND: Crocus sativus L. (saffron) is used in folk medicine, for example as an antiedematogenic agent. We aimed to evaluate the antinociceptive and anti-inflammatory activity of saffron extracts in mice. RESULTS: We...
BACKGROUND: Crocus sativus L. (saffron) is used in folk medicine, for example as an antiedematogenic agent. We aimed to evaluate the antinociceptive and anti-inflammatory activity of saffron extracts in mice. RESULTS: We used aqueous and ethanolic maceration extracts of Crocus sativus L. stigma and petals. Antinociceptive activity was examined using the hot plate and writhing tests. The effect of extracts against acute inflammation was studied using xylene induced ear edema in mice. The activity of the extracts against chronic inflammation was assessed by formalin-induced edema in the rat paw. In the hot plate tests, intraperitoneal injection of both extracts showed no significant antinociceptive activity in mice. The extracts exhibited antinociceptive activity against acetic acid induced writhing. Naloxone partially blocked only the antinociceptive activity of the stigma aqueous extract. Only the stigma extracts showed weak to moderate effect against acute inflammation. In chronic inflammation, both aqueous and ethanolic stigma extracts, as well as ethanolic petal extract, exerted anti-inflammatory effects. CONCLUSIONS: We conclude that aqueous and ethanolic extracts of saffron stigma and petal have an antinociceptive effect, as well as acute and/or chronic anti-inflammatory activity.
Delta opioid activation of the mitogen-activated protein kinase cascade does not require transphosphorylation of receptor tyrosine kinases.
Kramer HK, Onoprishvili I, Andria ML … +4 more , Hanna K, Sheinkman K, Haddad LB, Simon EJ
BMC Pharmacol · 2002 · PMID 11897012 · Full text
BACKGROUND: In this study, we investigated the mechanism(s) by which delta opioids induce their potent activation of extracellular signal-regulated protein kinases (ERKs) in different cell lines expressing the cloned del...
BACKGROUND: In this study, we investigated the mechanism(s) by which delta opioids induce their potent activation of extracellular signal-regulated protein kinases (ERKs) in different cell lines expressing the cloned delta-opioid receptor (delta-OR). While it has been known for some time that OR stimulation leads to the phosphorylation of both ERK isoforms, the exact progression of events has remained elusive. RESULTS: Our results indicate that the transphosphorylation of an endogenous epidermal growth factor receptor (EGFR) in the human embryonic kidney (HEK-293) cell line does not occur when co-expressed delta-ORs are stimulated by the delta-opioid agonist, D-Ser-Leu-enkephalin-Thr (DSLET). Moreover, neither pre-incubation of cultures with the selective EGFR antagonist, AG1478, nor down-regulation of the EGFR to a point where EGF could no longer activate ERKs had an inhibitory effect on ERK activation by DSLET. These results appear to rule out any structural or catalytic role for the EGFR in the delta-opioid-mediated MAPK cascade. To confirm these results, we used C6 glioma cells, a cell line devoid of the EGFR. In delta-OR-expressing C6 glioma cells, opioids produce a robust phosphorylation of ERK 1 and 2, whereas EGF has no stimulatory effect. Furthermore, antagonists to the RTKs that are endogenously expressed in C6 glioma cells (insulin receptor (IR) and platelet-derived growth factor receptor (PDGFR)) were unable to reduce opioid-mediated ERK activation. CONCLUSION: Taken together, these data suggest that the transactivation of resident RTKs does not appear to be required for OR-mediated ERK phosphorylation and that the tyrosine-phosphorylated delta-OR, itself, is likely to act as its own signalling scaffold.
Central effects of clozapine in regulating micturition in anesthetized rats.
Vera PL, Miranda-Sousa AJ, Ordorica RC … +1 more , Nadelhaft I
BMC Pharmacol · 2002 · PMID 11884246 · Full text
BACKGROUND: We previously showed that systemic administration of the atypical neuroleptic clozapine in the rat altered a number of urodynamic variables and inhibited the external urethral sphincter. Since clozapine acts...
BACKGROUND: We previously showed that systemic administration of the atypical neuroleptic clozapine in the rat altered a number of urodynamic variables and inhibited the external urethral sphincter. Since clozapine acts at several receptor types both at the periphery and the central nervous system, the site of action remained uncertain. Therefore, the purpose of this study was to determine the effects of central administration of clozapine on the bladder and the external urethral sphincter during cystometry and to examine differences in spinal versus supraspinal administration. We extended our observations by delivering clozapine centrally in anesthetized rats instrumented with either an intrathecal (L6-S1 spinal segment) or an intracerebroventricular (lateral ventricle) catheter. RESULTS: Clozapine decreased micturition volume and increased residual volume possibly by acting at a supraspinal site. Expulsion time and amplitude of the high frequency oscillations were reduced by clozapine possibly by acting at a spinal site. Bladder capacity was increased after central clozapine but probably due to a peripheral effect. Clozapine acting at spinal and supraspinal sites increased pressure threshold. Contraction time and peak pressure were not affected by clozapine. The EMG from the external urethral sphincter was also reduced following clozapine centrally and suggests a spinal and a supraspinal site of action. CONCLUSIONS: The results from the present study suggest that spinal and supraspinal central sites mediate clozapine's action in inhibiting expulsion parameters and the external urethral sphincter of the rat. Therefore, the reduction in the voiding efficiency observed after clozapine appears to be mediated by spinal and supraspinal sites.
4-(N,N-dipropylamino)benzaldehyde inhibits the oxidation of all-trans retinal to all-trans retinoic acid by ALDH1A1, but not the differentiation of HL-60 promyelocytic leukemia cells exposed to all-trans retinal.
Russo J, Barnes A, Berger K … +4 more , Desgrosellier J, Henderson J, Kanters A, Merkov L
BMC Pharmacol · 2002 · PMID 11872149 · Full text
BACKGROUND: The signal transduction pathways mediated by retinoic acid play a critical role in the regulation of cell growth and differentiation during embryogenesis and hematopoiesis as well as in a variety of tumor cel...
BACKGROUND: The signal transduction pathways mediated by retinoic acid play a critical role in the regulation of cell growth and differentiation during embryogenesis and hematopoiesis as well as in a variety of tumor cell lines in culture. Following the reports that two members of the superfamily of aldehyde dehydrogenase (ALDH) enzymes, ALDH1A1 and ALDH1A2, were capable of catalyzing the oxidation of all-trans retinal to all-trans retinoic acid with submicromolar Km values, we initiated an investigation of the ability of 4-(N,N-dipropylamino)benzaldehyde (DPAB) to inhibit the oxidation of retinal by purified mouse and human ALDH1A1. RESULTS: Our results show that DPAB potently inhibits retinal oxidation, with IC50 values of 0.11 and 0.13 microM for purified mouse and human ALDH1A1, respectively. Since the HL-60 human myeloid leukemic cell line has been used extensively to study the retinoic acid induced differentiation of HL-60 cells to granulocytes, and ALDH1A1 activity had previously been reported in HL-60 cells, we investigated the ability of DPAB to block differentiation of HL-60 promyelocytic leukemia cells exposed to retinal in culture. In HL-60 cells coincubated with 1 microM retinal and 50 microM DPAB for 144 hours, cell differentiation was inhibited only 30%. Furthermore, the NAD-dependent oxidation of propanal or retinal was less than 0.05 nmoles NADH formed/min-10(7) cells in spectrophotometric assays using HL-60 cell extracts. CONCLUSION: Although ALDH1A1 may be the major catalytic activity for retinal oxidation in some retinoid-dependent mouse and Xenopus embryonic tissues and in adult human and mouse hematopoietic stem cells, another catalytic activity appears to synthesize the retinoic acid ligand necessary to stimulate the differentiation of HL-60 cells to end stage granulocytes.
Low molecular mass dinitrosyl nonheme-iron complexes up-regulate noradrenaline release in the rat tail artery.
Kleschyov AL, Hubert G, Munzel T … +2 more , Stoclet JC, Bucher B
BMC Pharmacol · 2002 · PMID 11872148 · Full text
BACKGROUND: Dinitrosyl nonheme-iron complexes can appear in cells and tissues overproducing nitric oxide. It is believed that due to their chemical nature these species may be implicated in certain pathophysiological eve...
BACKGROUND: Dinitrosyl nonheme-iron complexes can appear in cells and tissues overproducing nitric oxide. It is believed that due to their chemical nature these species may be implicated in certain pathophysiological events. We studied the possible role of low molecular mass dinitrosyl iron complexes in the control of noradrenaline release in electrically stimulated rat tail artery. RESULTS: A model complex, dinitrosyl-iron-thiosulfate (at 1-10 microM) produced a concentration-dependent enhancement of electrical field stimulated [3H]noradrenaline release (up to 2 fold). At the same time, dinitrosyl-iron-thiosulfate inhibited neurogenic vasoconstriction, consistent with its nitric oxide donor properties. A specific inhibitor of cyclic GMP dependent protein kinase, Rp-8pCPT-cGMPS, partially inhibited the effect of dinitrosyl-iron-thiosulfate on neurogenic vasoconstriction, but not on [3H]noradrenaline release. Another model complex, dinitrosyl-iron-cysteine (at 3 microM) elicited similar responses as dinitrosyl-iron-thiosulfate. Conventional NO and NO+ donors such as sodium nitroprusside, S-nitroso-L-cysteine or S-nitroso-glutathione (at 10 microM) had no effect on [3H]noradrenaline release, though they potently decreased electrically-induced vasoconstriction. The "false complex", iron(II)-thiosulfate showed no activity. CONCLUSIONS: Low molecular mass iron dinitrosyl complexes can up-regulate the stimulation-evoked release of vascular [3H]noradrenaline, apparently independently of their NO donor properties. This finding may have important implications in inflammatory tissues.
Pharmacokinetics of artesunate after single oral administration to rats.
Olliaro PL, Nair NK, Sathasivam K … +2 more , Mansor SM, Navaratnam V
BMC Pharmacol · 2001 · PMID 11835690 · Full text
BACKGROUND: Artesunate is a commonly used antimalarial drug derived from artemisinin. It is rapidly converted to dihydroartemisinin. Little is known on this conversion in the GI tract and blood, and how this influences a...
BACKGROUND: Artesunate is a commonly used antimalarial drug derived from artemisinin. It is rapidly converted to dihydroartemisinin. Little is known on this conversion in the GI tract and blood, and how this influences absorption. In order to study the absorption phase of the kinetics of artesunate following oral administration in rats, samples were collected at baseline, and then 0.5, 2, 5, 10, 15, 30, 45, 60 and 120 minutes after a single dose of 150 mg. RESULTS: Peak concentration of parent artesunate and dihydroartemisinin was achieved within 5 and 37.5 +/- 8.7 min, respectively of start of administration through gavage. The half lives of absorption were 2.73 +/- 0.85 and 12.49 +/- 2.49 min, respectively. CONCLUSIONS: These times were considerably shorter for artesunate than those found in studies which start sampling later. The profiles of parent compound and metabolite result from a complex equation dictated by the pH-dependent rates of hydroxylation of artesunate to dihydroartemisinin, the different rates at which either compounds are absorbed, and the catalytic hydroxylation by esterases. The rate of chemical oxidation of artesunate is pH dependent; this explains its rapid conversion to dihydroartemisinin in the stomach, as compared to its greater stability in other compartments at higher pH and in plasma. We propose that variable proportions of absorption take place in the stomach, and conclude that parent artesunate reaches an early peak within minutes of dosing, and that the early dihydroartemisinin levels result primarily from the absorption of the metabolite as such.
In vivo models of lung neutrophil activation. Comparison of mice and hamsters.
Corteling R, Wyss D, Trifilieff A
BMC Pharmacol · 2002 · PMID 11806755 · Full text
BACKGROUND: Evidence suggests that both the migration and activation of neutrophils into the airway is of importance in pathological conditions such as pulmonary emphysema. In the present study, we describe in vivo model...
BACKGROUND: Evidence suggests that both the migration and activation of neutrophils into the airway is of importance in pathological conditions such as pulmonary emphysema. In the present study, we describe in vivo models of lung neutrophil infiltration and activation in mice and hamsters. RESULTS: BALB/c and C57BL/6 mice were intranasally treated with lipopolysaccharide (0.3 mg/kg). Twenty-four hours after, animals were treated intranasally with N-Formyl-Met-Leu-Phe (0 to 5 mg/kg). Golden Syrian hamsters were treated intratracheally with 0.5 mg/kg of lipopolysaccharide. Twenty-four hours after, animals were treated intratracheally with 0.25 mg/kg of N-Formyl-Met-Leu-Phe. Both mice and hamster were sacrificed two hours after the N-Formyl-Met-Leu-Phe application. In both BALB/c and C57BL/6 mice, a neutrophil infiltration was observed after the sequential application of lipopolysaccharide and N-Formyl-Met-Leu-Phe. However, 5 times less neutrophil was found in C57BL/6 mice when compared to BALB/c mice. This was reflected in the neutrophil activation parameters measured (myeloperoxidase and elastase activities). Despite the presence of neutrophil and their activation status, no lung haemorrhage could be detected in both strains of mice. When compared with mice, the lung inflammation induced by the sequential application of lipopolysaccharide and N-Formyl-Met-Leu-Phe was much greater in the hamster. In parallel with this lung inflammation, a significant lung haemorrhage was also observed. CONCLUSIONS: Both mouse and hamster can be used for pharmacological studies of new drugs or other therapeutics agents that aimed to interfere with neutrophil activation. However, only the hamster model seems to be suitable for studying the haemorrhagic lung injury process.
NO-independent regulatory site of direct sGC stimulators like YC-1 and BAY 41-2272.
Becker EM, Alonso-Alija C, Apeler H … +10 more , Gerzer R, Minuth T, Pleiss U, Schmidt P, Schramm M, Schröder H, Schroeder W, Steinke W, Straub A, Stasch JP
BMC Pharmacol · 2001 · PMID 11801189 · Full text
BACKGROUND: The most important receptor for nitric oxide is the soluble guanylate cyclase (sGC), a heme containing heterodimer. Recently, a pyrazolopyridine derivative BAY 41-2272, structurally related to YC-1, was ident...
BACKGROUND: The most important receptor for nitric oxide is the soluble guanylate cyclase (sGC), a heme containing heterodimer. Recently, a pyrazolopyridine derivative BAY 41-2272, structurally related to YC-1, was identified stimulating soluble guanylate cyclase in an NO-independent manner, which results in vasodilatation and antiplatelet activity. The study described here addresses the identification of the NO-independent site on soluble guanylate cyclase. RESULTS: We developed a photoaffinity label (3H-meta-PAL) for the direct and NO-independent soluble guanylate cyclase (sGC) stimulator BAY 41-2272 by introducing an azido-group into the tritium labeled compound. The synthesized photoaffinitylabel directly stimulates the purified sGC and shows in combination with NO a synergistic effect on sGC activity. Irradiation with UV light of 3H-meta-PAL together with the highly purified sGC leads to a covalent binding to the alpha1-subunit of the enzyme. This binding is blocked by unlabeled meta-PAL, YC-1 and BAY 41-2272. For further identification of the NO-independent regulatory site the 3H-meta-PAL labeled sGC was fragmented by CNBr digest. The 3H-meta-PAL binds to a CNBr fragment, consisting of the amino acids 236-290 of the alpha1-subunit. Determination of radioactivity of the single PTH-cycles from the sequencing of this CNBr fragment detected the cysteines 238 and 243 as binding residues of the 3H-meta-PAL. CONCLUSIONS: Our data demonstrate that the region surrounding the cysteines 238 and 243 in the alpha1-subunit of the sGC could play an important role in regulation of sGC activity and could be the target of this new type of sGC stimulators.
Receptorphin: a conserved peptide derived from the sequence of the opioid receptor, with opioid displacement activity and potent antiproliferative actions in tumor cells.
Kampa M, Loukas S, Tsapis A … +1 more , Castanas E
BMC Pharmacol · 2001 · PMID 11737867 · Full text
BACKGROUND: In addition to endogenous opioids, a number of peptide sequences, derived from endogenous (hemorphins, alphaS1-casomorphin), and exogenous proteins (casomorphins, exorphins) have been reported, possessing opi...
BACKGROUND: In addition to endogenous opioids, a number of peptide sequences, derived from endogenous (hemorphins, alphaS1-casomorphin), and exogenous proteins (casomorphins, exorphins) have been reported, possessing opioid activity. In the present work, we report the identification of a new peptide, receptorphin (Tyr-Ile-Phe-Asn-Leu), derived from the sequence of the second transmembrane loop of the opioid receptor. This sequence is unique for the opioid receptor, and conserved in all species and receptor-types. RESULTS AND DISCUSSION: Receptorphin competes for opioid binding, presenting a kappa-receptor interaction, while it binds equally to delta- and mu- opioid and somatostatin-binding sites, and inhibits the cell proliferation of a number of human cancer cell lines, in a dose-dependent and reversible manner, at the picomolar or the nanomolar range. Receptorphin shows a preferential action on prostate cancer cells. CONCLUSION: Our work identifies, for the first time a peptide, in a receptor sequence, possessing ligand-agonistic activities. A hypothesis, based on receptorphin liberation after cell death, is presented, which could tentatively explain the time-lag observed during opioid antiproliferative action.
Minipig cytochrome P450 3A, 2A and 2C enzymes have similar properties to human analogs.
Soucek P, Zuber R, Anzenbacherová E … +2 more , Anzenbacher P, Guengerich FP
BMC Pharmacol · 2001 · PMID 11737866 · Full text
BACKGROUND: The search for an optimal experimental model in pharmacology is recently focused on (mini)pigs as they seem not only to be an alternative source of cells and tissues for xenotherapy but also an alternative sp...
BACKGROUND: The search for an optimal experimental model in pharmacology is recently focused on (mini)pigs as they seem not only to be an alternative source of cells and tissues for xenotherapy but also an alternative species for studies on drug metabolism in man due to similarities between (mini) pig and human drug metabolizing systems. The purpose of this work is to characterize minipig liver microsomal cytochromes P450 (CYPs) by comparing their N-terminal sequences with corresponding human orthologs. RESULTS: The microsomal CYPs exhibit similar activities to their human orthologous enzymes (CYP3A4, nifedipine oxidation; 2A6, coumarin 7-hydroxylation; 2D6, bufuralol 1'-hydroxylation; 2E1, p-nitrophenol hydroxylation; and 2C9, tolbutamide hydroxylation). Specific minipig CYP (2A, 2C and 3A) enzymes were partially purified and proteins identified by immunostaining (using antibodies against the respective human CYPs) were used for N-terminal amino acid sequencing. From comparisons, it can be concluded that the sequence of the first 20 amino acids at the N-terminus of minipig CYP2A is highly similar to human CYP2A6 (70% identity). The N-terminal sequence of CYP2C shared about 50% similarity with human 2C9. The results on the minipig liver microsomal CYP3A yielded identical data with those obtained for amino acid sequences of the pig CYP3A29 showing 60% identity with human CYP3A4. CONCLUSIONS: Thus, our results further support the view that minipigs may serve as model animals in pharmacological/toxicological studies with substrates of human CYP enzymes, namely, of the CYP3A and CYP2A forms.
Peroxisome proliferator-activated receptor agonists prevent 25-OH-cholesterol induced c-jun activation and cell death.
Chang JY, Liu LZ
BMC Pharmacol · 2001 · PMID 11737865 · Full text
BACKGROUND: Cholesterol oxides, the oxygenated derivatives of cholesterol, have been shown to cause programmed cell death in a variety of cell types. Using N9 microglia, this study was designed to investigate the molecul...
BACKGROUND: Cholesterol oxides, the oxygenated derivatives of cholesterol, have been shown to cause programmed cell death in a variety of cell types. Using N9 microglia, this study was designed to investigate the molecular events induced by cholesterol oxides prior to the execution of programmed cell death. RESULTS: Microglia were very sensitive to 25-OH-cholesterol, such that a 2-day treatment of the cells with 5 microM 25-OH-cholesterol reduced cell viability to 5-10% of controls. There was a dose- and time-dependent increase in c-jun and phospho-c-jun levels in microglia prior to this 25-OH-cholesterol induced cell death. In contrast, 7-beta-OH-cholesterol, which was relatively non-toxic to microglia, did not increase phospho-c-jun levels. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that have important roles in atherogenesis. Results from this study indicate that PPAR agonists such as 15d-PGJ2, indomethacin and WY14643 can attenuate cholesterol oxide induced c-jun activation and cell death in microglia. CONCLUSIONS: Peroxisome proliferator-activated receptor agonists may be useful in future development of pharmacological agents against cholesterol oxide induced cytotoxicity.
Effect of a short-term in vitro exposure to the marine toxin domoic acid on viability, tumor necrosis factor-alpha, matrix metalloproteinase-9 and superoxide anion release by rat neonatal microglia.
Mayer AM, Hall M, Fay MJ … +8 more , Lamar P, Pearson C, Prozialeck WC, Lehmann VK, Jacobson PB, Romanic AM, Uz T, Manev H
BMC Pharmacol · 2001 · PMID 11686853 · Full text
BACKGROUND: The excitatory amino acid domoic acid, a glutamate and kainic acid analog, is the causative agent of amnesic shellfish poisoning in humans. No studies to our knowledge have investigated the potential contribu...
BACKGROUND: The excitatory amino acid domoic acid, a glutamate and kainic acid analog, is the causative agent of amnesic shellfish poisoning in humans. No studies to our knowledge have investigated the potential contribution to short-term neurotoxicity of the brain microglia, a cell type that constitutes circa 10% of the total glial population in the brain. We tested the hypothesis that a short-term in vitro exposure to domoic acid, might lead to the activation of rat neonatal microglia and the concomitant release of the putative neurotoxic mediators tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinases-2 and-9 (MMP-2 and -9) and superoxide anion (O2-). RESULTS: In vitro, domoic acid [10 microM-1 mM] was significantly neurotoxic to primary cerebellar granule neurons. Although neonatal rat microglia expressed ionotropic glutamate GluR4 receptors, exposure during 6 hours to domoic acid [10 microM-1 mM] had no significant effect on viability. By four hours, LPS (10 ng/mL) stimulated an increase in TNF-alpha mRNA and a 2,233 % increase in TNF-alpha protein In contrast, domoic acid (1 mM) induced a slight rise in TNF-alpha expression and a 53 % increase (p < 0.01) of immunoreactive TNF-alpha protein. Furthermore, though less potent than LPS, a 4-hour treatment with domoic acid (1 mM) yielded a 757% (p < 0.01) increase in MMP-9 release, but had no effect on MMP-2. Finally, while PMA (phorbol 12-myristate 13-acetate) stimulated O2- generation was elevated in 6 hour LPS-primed microglia, a similar pretreatment with domoic acid (1 mM) did not prime O2- release. CONCLUSIONS: To our knowledge this is the first experimental evidence that domoic acid, at in vitro concentrations that are toxic to neuronal cells, can trigger a release of statistically significant amounts of TNF-alpha and MMP-9 by brain microglia. These observations are of considerable pathophysiological significance because domoic acid activates rat microglia several days after in vivo administration.
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