BMC Pharmacology[JOURNAL]
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200 papers
Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779.
Messina MP, Rauktys A, Lee L … +1 more , Dabora SL
BMC Pharmacol · 2007 Nov · PMID 17986349 · Full text
BACKGROUND: Tuberous Sclerosis Complex (TSC) is an autosomal dominant hamartoma disorder with variable expression for which treatment options are limited. TSC is caused by a mutation in either the TSC1 or TSC2 genes, who...
BACKGROUND: Tuberous Sclerosis Complex (TSC) is an autosomal dominant hamartoma disorder with variable expression for which treatment options are limited. TSC is caused by a mutation in either the TSC1 or TSC2 genes, whose products, hamartin and tuberin, function as negative regulators in the highly-conserved mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin (also known as sirolimus), an mTOR inhibitor, has been shown to reduce disease severity in rodent models of TSC and is currently being evaluated in clinical trials in human populations. The cytokine interferon-gamma (IFN-gamma) is also a potential therapeutic agent for TSC. A high-expressing IFN-gamma allele has been associated with reduced disease severity in human TSC patients and it has been shown in mouse models that treatment with exogenous IFN-gamma reduces disease severity. RESULTS: Here, we examine the effects of treating Tsc2+/- mice at different time points with a rapamycin analog (CCI-779) as a single agent or with a combination of CCI-779 and IFN-gamma. We observed that administering a short course of CCI-779 or CCI-779 plus IFN-gamma reduced the severity of kidney lesions if administered after such lesions develop. As long as treatment is given after lesions arise, altering the time period during which treatment was given did not significantly impact the effect of the treatment on disease severity. We did not observe a significant benefit of combination therapy relative to treatment with a rapamycin analog alone in Tsc2+/- mice. We also compared timing of treatment and two mTOR inhibitors (rapamycin and CCI-779) in nude mice bearing Tsc2-/- tumors. CONCLUSION: Preventing the genesis of TSC-related kidney lesions in Tsc2+/- mice is not an effective treatment strategy; rather, the presence of growing tumors appears to be the most important factor when determining an appropriate treatment schedule. Treatment with rapamycin was more effective in reducing tumor growth and improving survival in nude mice bearing Tsc2-/- tumors and also resulted in higher rapamycin levels in blood, brain, and kidney tissue than treatment with an equal milligram dose of CCI-779. We anticipate these results will influence future preclinical and clinical trials for TSC.
Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide.
Rezaï K, Lokiec F, Grandjean I … +7 more , Weill S, de Cremoux P, Bordier V, Ekue R, Garcia M, Poupon MF, Decaudin D
BMC Pharmacol · 2007 Oct · PMID 17963518 · Full text
BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore in...
BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy. METHODS: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection. RESULTS: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone. CONCLUSION: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.
Ciclesonide uptake and metabolism in human alveolar type II epithelial cells (A549).
Nonaka T, Nave R, McCracken N … +2 more , Kawashimo A, Katsuura Y
BMC Pharmacol · 2007 Sep · PMID 17900334 · Full text
BACKGROUND: Ciclesonide is a novel inhaled corticosteroid for the treatment of airway inflammation. In this study we investigated uptake and in vitro metabolism of ciclesonide in human alveolar type II epithelial cells (...
BACKGROUND: Ciclesonide is a novel inhaled corticosteroid for the treatment of airway inflammation. In this study we investigated uptake and in vitro metabolism of ciclesonide in human alveolar type II epithelial cells (A549). Ciclesonide uptake was compared with fluticasone propionate, an inhaled corticosteroid that is not metabolized in lung tissue. A549 cells were incubated with 2 x 10(-8) M ciclesonide or fluticasone propionate for 3 to 30 min to determine uptake; or with 2 x 10(-8) M ciclesonide for 1 h, followed by incubation with drug-free buffer for 3, 6, and 24 h to analyze in vitro metabolism. High performance liquid chromatography with tandem mass spectrometry was used to measure the concentrations of both corticosteroids and metabolites. RESULTS: At all time points the mean intracellular concentration was higher for ciclesonide when compared with fluticasone propionate. Activation of ciclesonide to desisobutyryl-ciclesonide (des-CIC) was confirmed and conjugates of des-CIC with fatty acids were detected. The intracellular concentration of ciclesonide decreased over time, whereas the concentration of des-CIC remained relatively stable: 2.27 to 3.19 pmol/dish between 3 and 24 h. The concentration of des-CIC fatty acid conjugates increased over time, with des-CIC-oleate being the main metabolite. CONCLUSION: Uptake of ciclesonide into A549 cells was more efficient than that of the less lipophilic fluticasone propionate. Intracellular concentrations of the pharmacologically active metabolite des-CIC were maintained for up to 24 h. The local anti-inflammatory activity of ciclesonide in the lung may be prolonged by the slow release of active drug from the depot of fatty acid esters.
Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7.
Gaube F, Wolfl S, Pusch L … +2 more , Kroll TC, Hamburger M
BMC Pharmacol · 2007 Sep · PMID 17880733 · Full text
BACKGROUND: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, th...
BACKGROUND: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic black cohosh rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7. RESULTS: Both extract and purified compounds clearly inhibited cellular proliferation. Gene expression profiling with the extract allowed us to identify 431 regulated genes with high significance. The extract induced expression pattern differed from those of 17beta-estradiol or the estrogen receptor antagonist tamoxifen. We observed a significant enrichment of genes in an anti-proliferative and apoptosis-sensitizing manner, as well as an increase of mRNAs coding for gene products involved in several stress response pathways. These functional groups were highly overrepresented among all regulated genes. Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1. In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated. Real-Time RT-PCR analysis of 13 selected genes was conducted after treatment with purified compounds - the cycloartane-type triterpene glycoside actein and triterpene aglycons - showing similar expression levels compared to the extract. CONCLUSION: No estrogenic but antiproliferative and proapoptotic gene expression was shown for black cohosh in MCF-7 cells at the transcriptional level. The effects may be results of the activation of different pathways. The cycloartane glycosides and - for the first time - their aglycons could be identified as an active principle in black cohosh.
An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data.
Sugaya N, Ikeda K, Tashiro T … +10 more , Takeda S, Otomo J, Ishida Y, Shiratori A, Toyoda A, Noguchi H, Takeda T, Kuhara S, Sakaki Y, Iwayanagi T
BMC Pharmacol · 2007 Aug · PMID 17705877 · Full text
BACKGROUND: Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the...
BACKGROUND: Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the recent development of high-throughput screening (HTS) technologies. Individual PPIs have been targeted by small drug-like chemicals (SDCs), however, interactome data have not been fully utilized for exploring drug targets due to the lack of comprehensive methodology for utilizing these data. Here we propose an integrative in silico approach for discovering candidates for drug-targetable PPIs in interactome data. RESULTS: Our novel in silico screening system comprises three independent assessment procedures: i) detection of protein domains responsible for PPIs, ii) finding SDC-binding pockets on protein surfaces, and iii) evaluating similarities in the assignment of Gene Ontology (GO) terms between specific partner proteins. We discovered six candidates for drug-targetable PPIs by applying our in silico approach to original human PPI data composed of 770 binary interactions produced by our HTS yeast two-hybrid (HTS-Y2H) assays. Among them, we further examined two candidates, RXRA/NRIP1 and CDK2/CDKN1A, with respect to their biological roles, PPI network around each candidate, and tertiary structures of the interacting domains. CONCLUSION: An integrative in silico approach for discovering candidates for drug-targetable PPIs was applied to original human PPIs data. The system excludes false positive interactions and selects reliable PPIs as drug targets. Its effectiveness was demonstrated by the discovery of the six promising candidate target PPIs. Inhibition or stabilization of the two interactions may have potential therapeutic effects against human diseases.
Abstracts of the 3rd International Conference on cGMP: Generators, Effectors and Therapeutic Implications, Dresden, Germany, 15-17 June 2007.
BMC Pharmacol · 2007 · PMID 17678523
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Sodium valproate stimulates potassium and chloride urinary excretion in rats: gender differences.
Jakutiene E, Grikiniene J, Vaitkevicius A … +3 more , Tschaika M, Didziapetriene J, Stakisaitis D
BMC Pharmacol · 2007 Aug · PMID 17683602 · Full text
BACKGROUND: The diuretic effect of valproates and its relation to urinary potassium (K+) and chloride (Cl-) excretion have not yet been investigated, so the aim of this study was to evaluate the influence of a single dos...
BACKGROUND: The diuretic effect of valproates and its relation to urinary potassium (K+) and chloride (Cl-) excretion have not yet been investigated, so the aim of this study was to evaluate the influence of a single dose of sodium valproate (NaVPA) on 24-h urinary K+ and Cl- excretion in young adult Wistar rats of both genders. For measurement of K+ in urine, the same animals and samples as in our earlier publication were used (Pharmacology 2005 Nov, 75:111-115). The authors propose a new approach to the pathophysiological mechanisms of NaVPA effect on K+ and Cl- metabolism. Twenty six Wistar rats were examined after a single intragastric administration of 300 mg/kg NaVPA (13 NaVPA-male and 13 NaVPA-female), 28 control intact Wistar rats (14 males and 14 females) were studied as a control group. The 24-h urinary K+, Cl-, creatinine and pH levels were measured. RESULTS: Total 24-h diuresis and 24-h diuresis per 100 g of body weight were found to be significantly higher in NaVPA-rats of both genders than in rats of the control group (p < 0.05). The data showed NaVPA to enhance 24-h K+ excretion in NaVPA-males and NaVPA-females with significant gender-related differences: 24-h K+ excretion in NaVPA-male rats was significantly higher than in control males (p = 0.003) and NaVPA-female rats (p < 0.001). Regarding the 24-h K+ excretion, NaVPA-female rats did not show a statistically significant difference versus females of the control group (p > 0.05). 24-h urinary K+ excretion per 100 g of body weight in NaVPA-male rats was significantly higher than in control males (p = 0.025). NaVPA enhanced Cl- urinary excretion: 24-h Cl- urinary excretion, 24-h urinary Cl- excretion per 100 g of body weight and the Cl-/creatinine ratio were significantly higher in NaVPA-male and NaVPA-female rats than in gender-matched controls (p < 0.05). 24-h chloriduretic response to NaVPA in male rats was significantly higher than in female rats (p < 0.05). CONCLUSION: NaVPA causes kaliuretic and chloriduretic effects with gender-related differences in rats. Further investigations are necessary to elucidate the mechanism of such pharmacological effects of NaVPA.
Structural and functional definition of the specificity of a novel caspase-3 inhibitor, Ac-DNLD-CHO.
Yoshimori A, Sakai J, Sunaga S … +5 more , Kobayashi T, Takahashi S, Okita N, Takasawa R, Tanuma S
BMC Pharmacol · 2007 Jun · PMID 17594508 · Full text
BACKGROUND: The rational design of peptide-based specific inhibitors of the caspase family members using their X-ray crystallographies is an important strategy for chemical knockdown to define the critical role of each e...
BACKGROUND: The rational design of peptide-based specific inhibitors of the caspase family members using their X-ray crystallographies is an important strategy for chemical knockdown to define the critical role of each enzyme in apoptosis and inflammation. Recently, we designed a novel potent peptide inhibitor, Ac-DNLD-CHO, for caspase-3 using a new computational screening system named the Amino acid Positional Fitness (APF) method (BMC Pharmacol. 2004, 4:7). Here, we report the specificity of the DNLD sequence against caspase-3 over other major caspase family members that participate in apoptosis by computational docking and site-directed mutagenesis studies. RESULTS: Ac-DNLD-CHO inhibits caspases-3, -7, -8, and -9 activities with Kiapp values of 0.68, 55.7, >200, and >200 nM, respectively. In contrast, a well-known caspase-3 inhibitor, Ac-DEVD-CHO, inhibits all these caspases with similar Kiapp values. The selective recognition of a DNLD sequence by caspase-3 was confirmed by substrate preference studies using fluorometric methylcoumarin-amide (MCA)-fused peptide substrates. The bases for its selectivity and potency were assessed on a notable interaction between the substrate Asn (N) and the caspase-3 residue Ser209 in the S3 subsite and the tight interaction between the substrate Leu (L) and the caspase-3 hydrophobic S2 subsite, respectively, in computational docking studies. Expectedly, the substitution of Ser209 with alanine resulted in loss of the cleavage activity on Ac-DNLD-MCA and had virtually no effect on cleaving Ac-DEVD-MCA. These findings suggest that N and L residues in Ac-DNLD-CHO are the determinants for the selective and potent inhibitory activity against caspase-3. CONCLUSION: On the basis of our results, we conclude that Ac-DNLD-CHO is a reliable, potent and selective inhibitor of caspase-3. The specific inhibitory effect on caspase-3 suggests that this inhibitor could become an important tool for investigations of the biological function of caspase-3. Furthermore, Ac-DNLD-CHO may be an attractive lead compound to generate novel effective non-peptidic pharmaceuticals for caspase-mediated apoptosis diseases, such as neurodegenerative disorders and viral infection diseases.
Uptake and metabolism of ciclesonide and retention of desisobutyryl-ciclesonide for up to 24 hours in rabbit nasal mucosa.
Sato H, Nave R, Nonaka T … +6 more , Yoshihisa N, Atsuhiro N, Mochizuki T, Takahama S, Kondo S, Wingertzahn M
BMC Pharmacol · 2007 Jun · PMID 17553148 · Full text
BACKGROUND: The nasal tissue uptake and metabolism of ciclesonide, a new-generation corticosteroid under investigation for treatment of allergic rhinitis, to its active metabolite, desisobutyryl-ciclesonide (des-CIC), wa...
BACKGROUND: The nasal tissue uptake and metabolism of ciclesonide, a new-generation corticosteroid under investigation for treatment of allergic rhinitis, to its active metabolite, desisobutyryl-ciclesonide (des-CIC), was evaluated when administered to rabbits in a hypotonic versus an isotonic ciclesonide suspension. Nasal mucosa extracts from normal Japanese white rabbits were evaluated by high-performance liquid chromatography with tandem mass spectrometry detection after a single 143-mug dose of ciclesonide. Retention and formation of fatty acid conjugates of des-CIC were also measured in nasal mucosa extracts postadministration of a hypotonic ciclesonide suspension (143-mug single dose). RESULTS: Versus an isotonic suspension, the hypotonic suspension achieved higher concentrations of des-CIC (5.6-fold, 11.4-fold, and 13.4-fold; p < 0.05 for all) and ciclesonide (25.3-fold, 34.2-fold [p = not significant], and 16-fold [p < 0.05]) at 30, 120, and 240 min postadministration. Additionally, when administered via a hypotonic suspension, des-CIC was retained up to 24 h postadministration (45.46 pmol/g tissue). Highest concentration of major fatty acid ester conjugate, des-CIC-oleate, was detected in nasal mucosa at 8 h postadministration. CONCLUSION: These data suggest that a hypotonic ciclesonide suspension provides higher intracellular concentrations of des-CIC up to 24 h, thereby providing a rationale for investigation of ciclesonide as a convenient once-daily nasal spray for treatment of allergic rhinitis.
Abstracts of the 2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications. Potsdam, Germany. June 10-12, 2005.
Abbey-Hosch SE, Smirnov D, Potter LR
BMC Pharmacol · 2005 · PMID 17477856 · Full text
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Clofibrate treatment in pigs: effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents.
Luci S, Giemsa B, Hause G … +2 more , Kluge H, Eder K
BMC Pharmacol · 2007 Apr · PMID 17437637 · Full text
BACKGROUND: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whe...
BACKGROUND: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species. RESULTS: Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05). CONCLUSION: The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis.
The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms.
Herbert MK, Weis R, Holzer P
BMC Pharmacol · 2007 Mar · PMID 17367519 · Full text
BACKGROUND: Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. Although tramadol is an opioid-like analgesic, its effect on gut motility is little known. Therefore, the effect of (+)-tramad...
BACKGROUND: Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. Although tramadol is an opioid-like analgesic, its effect on gut motility is little known. Therefore, the effect of (+)-tramadol, (-)-tramadol and the major metabolite O-desmethyltramadol on intestinal peristalsis in vitro and their mechanisms of action were examined. Distension-induced peristalsis was recorded in fluid-perfused segments of the guinea pig small intestine. The intraluminal peristaltic pressure threshold (PPT) was used to quantify the motor effects of extraserosally administered drugs. RESULTS: Racemic tramadol, its (+)- and (-)-enantiomers and the major metabolite O-desmethyltramadol (0.1-100 microM) concentration-dependently increased PPT until peristalsis was transiently or persistently abolished. The rank order of potency was (-)-tramadol < (+)-tramadol <O-desmethyltramadol. The peristaltic motor inhibition caused by (+)- and (-)-tramadol was markedly and that of O-desmethyltramadol nearly completely prevented by naloxone, but left unaltered by the 5-hydroxytryptamine receptor antagonists methysergide plus tropisetron. The adrenoceptor antagonists prazosin plus yohimbine reduced the effect of (+)- and (-)-tramadol but not that of O-desmethyltramadol. CONCLUSION: The results show that the metabolite O-desmethyltramadol is more potent in inhibiting peristalsis than its parent compound. The action of all tramadol forms depends on opioid receptors, and that of (+)- and (-)-tramadol also involves adrenoceptors.
In rats, oral oleoyl-DHEA is rapidly hydrolysed and converted to DHEA-sulphate.
Serrano M, Grasa Mdel M, Fernández-López JA … +1 more , Alemany M
BMC Pharmacol · 2007 Mar · PMID 17346356 · Full text
BACKGROUND: Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and ha...
BACKGROUND: Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and has antiglucocorticoid activity. DHEA has been used for the treatment of a number of diseases, including obesity; its pharmacological effects depend on large oral doses, which effect rapidly wanes in part because of its short half-life in plasma. Since steroid hormone esters circulate for longer periods, we have studied here whether the administration of DHEA oleoyl ester may extend its pharmacologic availability by keeping high circulating levels. RESULTS: Tritium-labelled oleoyl-DHEA was given to Wistar male and female rats by gastric tube. The kinetics of appearance of the label in plasma was unrelated to sex; the pattern being largely coincident with the levels of DHEA-sulfate only in females, and after 2 h undistinguishable from the results obtained using labelled DHEA gavages; in the short term, practically no lipophilic DHEA label was found in plasma. After 24 h only a small fraction of the label remained in the rat organs, with a different sex-related distribution pattern coincident for oleoyl- and free- DHEA gavages. The rapid conversion of oleoyl-DHEA into circulating DHEA-sulfate was investigated using stomach, liver and intestine homogenates; which hydrolysed oleoyl-DHEA optimally near pH 8. Duodenum and ileum contained the highest esterase activities. Pure hog pancreas cholesterol-esterase broke down oleoyl-DHEA at rates similar to those of oleoyl-cholesterol. The intestinal and liver esterases were differently activated by taurocholate and showed different pH-activity patterns than cholesterol esterase, suggesting that oleoyl-DHEA can be hydrolysed by a number of esterases in the lumen (e.g. cholesterol-esterase), in the intestinal wall and the liver. CONCLUSION: The esterase activities found may condition the pharmacological availability (and depot effect) of orally administered steroid hormone fatty acid esters such as oleoyl-DHEA. The oral administration of oleoyl-DHEA in order to extend DHEA plasma availability has not been proved effective, since the ester is rapidly hydrolysed, probably in the intestine itself, and mainly converted to DHEA-sulfate at least in females.
Estradiol valerate and alcohol intake: dose-response assessments.
Quirarte GL, Reid LD, de la Teja IS … +5 more , Reid ML, Sánchez MA, Díaz-Trujillo A, Aguilar-Vazquez A, Prado-Alcalá RA
BMC Pharmacol · 2007 Mar · PMID 17335585 · Full text
BACKGROUND: An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This...
BACKGROUND: An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies. RESULTS: With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake. CONCLUSION: The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries.
Mapping the contribution of beta3-containing GABAA receptors to volatile and intravenous general anesthetic actions.
Zeller A, Arras M, Jurd R … +1 more , Rudolph U
BMC Pharmacol · 2007 Feb · PMID 17319964 · Full text
BACKGROUND: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substa...
BACKGROUND: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by beta3-containing GABAA receptors. This was determined by using the beta3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In this communication, we analyzed the contribution of beta3-containing GABAA receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of beta3(N265M) mice. RESULTS: Isoflurane decreased core body temperature and heart rate to a smaller degree in beta3(N265M) mice than in wild type mice, indicating a minor but significant role of beta3-containing GABAA receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of beta3-containing GABAA receptors. The anterograde amnesic action of propofol was indistinguishable in beta3(N265M) and wild type mice, suggesting that it is independent of beta3-containing GABAA receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in beta3(N265M) mice than in wild type mice, pointing to a limited involvement of beta3-containing GABAA receptors in these actions. The lack of etomidate- and propofol-induced immobilization in beta3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds. CONCLUSION: Our results provide evidence for a defined role of beta3-containing GABAA receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed.
A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones.
Koss DJ, Hindley KP, David KC … +8 more , Mancini I, Guella G, Sepcić K, Turk T, Rebolj K, Riedel G, Platt B, Scott RH
BMC Pharmacol · 2007 Feb · PMID 17274812 · Full text
BACKGROUND: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The...
BACKGROUND: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism. Recently, water soluble compounds have been synthesised that are structurally related to the natural polymers but bear a different number of pyridinium units. These compounds may share a number of bio-activities with poly-APS. Using electrophysiology, calcium imaging and 1,6-diphenyl-1,3,5-hexatriene imaging, the pore forming properties of poly-APS and four related synthetic oligomers have been tested on primary cultured rat hippocampal neurones. RESULTS: Acute application of poly-APS (0.5 microg/ml), reduced membrane potential, input resistance and suppressed action potential firing. Poly-APS evoked inward cation currents with linear current-voltage relationships similar to actions of pore formers on other cell types. Poly-APS (0.005-5 microg/ml) also produced Ca2+ transients in approximately 41% of neurones. The dose-dependence of poly-APS actions were complex, such that at 0.05 microg/ml and 5 microg/ml poly-APS produced varying magnitudes of membrane permeability depending on the order of application. Data from surface plasmon resonance analysis suggested accumulation of poly-APS in membranes and subsequent enhanced poly-APS binding. Even at 10-100 fold higher concentrations, none of the synthetic compounds produced changes in electrophysiological characteristics of the same magnitude as poly-APS. Of the synthetic oligomers tested compounds 1 (monomeric) and tetrameric 4 (5-50 microg/ml) induced small transient currents and 3 (trimeric) and 4 (tetrameric) produced significant Ca2+ transients in hippocampal neurones. CONCLUSION: Poly-APS induced pore formation in hippocampal neurones and such pores were transient, with neurones recovering from exposure to these polymers. Synthetic structurally related oligomers were not potent pore formers when compared to poly-APS and affected a smaller percentage of the hippocampal neurone population. Poly-APS may have potential as agents for macromolecular delivery into CNS neurones however; the smaller synthetic oligomers tested in this study show little potential for such use. This comparative analysis indicated that the level of polymerisation giving rise to the supermolecular structure in the natural compounds, is likely to be responsible for the activity here reported.
Inhibition of PKC activity blocks the increase of ETB receptor expression in cerebral arteries.
Henriksson M, Vikman P, Stenman E … +2 more , Beg S, Edvinsson L
BMC Pharmacol · 2006 Nov · PMID 17129394 · Full text
BACKGROUND: Previous studies have shown that there is a time-dependent upregulation of contractile endothelin B (ETB) receptors in middle cerebral arteries (MCA) after organ culture. This upregulation is dependent on mit...
BACKGROUND: Previous studies have shown that there is a time-dependent upregulation of contractile endothelin B (ETB) receptors in middle cerebral arteries (MCA) after organ culture. This upregulation is dependent on mitogen-activated protein kinases and possibly protein kinase C (PKC). The aim of this study was to examine the effect of PKC inhibitors with different profiles on the upregulation of contractile ETB receptors in rat MCA. Artery segments were incubated for 24 hours at 37 degrees C. To investigate involvement of PKC, inhibitors were added to the medium before incubation. The contractile endothelin-mediated responses were measured and real-time PCR was used to detect endothelin receptor mRNA levels. Furthermore, immunohistochemistry was used to demonstrate the ETB receptor protein distribution in the MCA and Western blot to measure which of the PKC subtypes that were affected by the inhibitors. RESULTS: The PKC inhibitors bisindolylmaleimide I, Ro-32-0432 and PKC inhibitor 20-28 attenuated the ETB receptor mediated contractions. Furthermore, Ro-32-0432 and bisindolylmaleimide I decreased ETB receptor mRNA levels while PKC inhibitor 20-28 reduced the amount of receptor protein on smooth muscle cells. PKC inhibitor 20-28 also decreased the protein levels of the five PKC subtypes studied (alpha, betaI, gamma, delta and epsilon). CONCLUSION: The results show that PKC inhibitors are able to decrease the ETB receptor contraction and expression in MCA smooth muscle cells following organ culture. The PKC inhibitor 20-28 affects the protein levels, while Ro-32-0432 and bisindolylmaleimide I affect the mRNA levels, suggesting differences in activity profile. Since ETB receptor upregulation is seen in cerebral ischemia, the results of the present study provide a way to interfere with the vascular involvement in cerebral ischemia.
6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant.
Levy AS, Simon O, Shelly J … +1 more , Gardener M
BMC Pharmacol · 2006 Oct · PMID 17010215 · Full text
BACKGROUND: 6-Shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. Confirmation of this contribution was sought in this study in Sprague- Dawley rats (200-2...
BACKGROUND: 6-Shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. Confirmation of this contribution was sought in this study in Sprague- Dawley rats (200-250 g) treated with a single injection (0.5 ml of 1 mg/ml) of a commercial preparation of complete Freund's Adjuvant (CFA) to induce monoarthritis in the right knee over a period of 28 days. During this development of arthritis, each rat received a daily oral dose of either peanut oil (0.2 ml-control) or 6-shogaol (6.2 mg/Kg in 0.2 ml peanut oil). RESULTS: Within 2 days of CFA injection, the control group produced maximum edematous swelling of the knee that was sustained up to the end of the investigation period. But, in the 6-shogaol treated group, significantly lower magnitudes of unsustained swelling of the knees (from 5.1 +/- 0.2 mm to 1.0 +/- 0.2 mm, p < 0.002, n = 6) were produced during the investigation period. Unsustained swelling of the knees (from 3.2 +/- 0.6 mm to 0.8 +/- 1.1 mm, p < 0.00008, n = 6) was also produced after 3 days of treatment with indomethacin (2 mg/Kg/day) as a standard anti-inflammatory drug, but during the first 2 days of drug treatment swelling of the knees was significantly larger (11.6 +/- 2.0 mm, p < 0.0002, n = 6) than either the controls or the 6-shogaol treated group of rats. This exaggerated effect in the early stage of indomethacin treatment was inhibited by montelukast, a cysteinyl leukotriene receptor antagonist. Also, 6-shogaol and indomethacin were most effective in reducing swelling of the knees on day 28 when the controls still had maximum swelling. The effect of 6-shogaol compared to the controls was associated with significantly lower concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) in the blood and infiltration of leukocytes, including lymphocytes and monocytes/macrophages, into the synovial cavity of the knee. There was also preservation of the morphological integrity of the cartilage lining the femur compared to damage to this tissue in the peanut oil treated control group of rats. CONCLUSION: From these results, it is concluded that 6-shogaol reduced the inflammatory response and protected the femoral cartilage from damage produced in a CFA monoarthritic model of the knee joint of rats.
Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis.
Hamacher A, Weigt M, Wiese M … +3 more , Hoefgen B, Lehmann J, Kassack MU
BMC Pharmacol · 2006 Sep · PMID 16978403 · Full text
BACKGROUND: Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at h...
BACKGROUND: Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D1-D5 and 5HT2A receptors and to assign them to different classes according to their dopamine/5HT2A receptor profile. RESULTS: Regardless of using affinity data (pKi values at D1-D5 and 5HT2A) or selectivity data (15 log (Ki ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT2A ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of Ki ratios used for principal component analysis from 15 to two (the D1/D2 and D2/5HT2A Ki ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D2-like receptor profile (D2L > D3 > D4.4) than clozapine (D4.4 > D2L > D3). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D1 selectivity. CONCLUSION: In conclusion, two compounds with a novel dopamine/5HT2A receptor profile, LE404 and LE410, with some differences in their respective D1/D2 receptor affinities including a validated pharmacophore-based 3D-QSAR model for D1 antagonists are presented.
A pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat cultured sensory neurones.
Temraz TA, Houssen WE, Jaspars M … +4 more , Woolley DR, Wease KN, Davies SN, Scott RH
BMC Pharmacol · 2006 Jul · PMID 16824204 · Full text
BACKGROUND: Whole cell patch clamp recording and intracellular Ca2+ imaging were carried out on rat cultured dorsal root ganglion (DRG) neurones to characterize the actions of crude extracts and purified samples from Red...
BACKGROUND: Whole cell patch clamp recording and intracellular Ca2+ imaging were carried out on rat cultured dorsal root ganglion (DRG) neurones to characterize the actions of crude extracts and purified samples from Red Sea soft corals. The aim of the project was to identify compounds that would alter the excitability of DRG neurones. RESULTS: Crude extracts of Sarcophyton glaucum and Lobophyton crassum attenuated spike frequency adaptation causing DRG neurones to switch from firing single action potentials to multiple firing. The increase in excitability was associated with enhanced KCl-evoked Ca2+ influx. The mechanism of action of the natural products in the samples from the soft corals involved inhibition of voltage-activated K+ currents. An active component of the crude marine samples was identified as 3-carboxy-1-methyl pyridinium (trigonelline). Application of synthetic 3-carboxy-1-methyl pyridinium at high concentration (0.1 mM) also induced multiple firing and reduced voltage-activated K+ current. The changes in excitability of DRG neurones induced by 3-carboxy-1-methyl pyridinium suggest that this compound contributes to the bioactivity produced by the crude extracts from two soft corals. CONCLUSION: Sarcophyton glaucum and Lobophyton crassum contain natural products including 3-carboxy-1-methyl pyridinium that increase the excitability of DRG neurones. We speculate that in addition to developmental control and osmoregulation these compounds may contribute to chemical defenses.
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