BMC Pharmacology[JOURNAL]
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200 papers
Alpha-2 adrenergic-induced changes in rectal temperature in adult and 13-day old rats following acute and repeated desipramine administration.
Deupree JD, Burke WJ, Bylund DB
BMC Pharmacol · 2008 Oct · PMID 18831759 · Full text
BACKGROUND: The effects of acute and repeated treatment with desipramine on the functional response of alpha2-adrenoceptors were tested in adult and 13-day old rats. The functional response measured was hypothermia that...
BACKGROUND: The effects of acute and repeated treatment with desipramine on the functional response of alpha2-adrenoceptors were tested in adult and 13-day old rats. The functional response measured was hypothermia that was induced by brimonidine, an alpha2-adrenoceptor agonist. The change in the extent of the brimonidine-induced hypothermia following pretreatment with either single or 4 twice-daily injections of desipramine was compared in 13-day old and adult (65-75 days old) male rats. RESULTS: Brimonidine, alone, lowered rectal temperature to a greater extent in juvenile than in adult rats, and this response was dose-dependently blocked by the selective alpha2-adrenoceptor antagonist, RX821002, in both groups of rats. Single desipramine administration lowered rectal temperature in the absence of brimonidine in adult but not in juvenile rats. The adult rats developed tolerance to this hypothermic effect after 4 days of desipramine treatment (10 mg/kg twice daily). Repeated desipramine treatment of adult rats also resulted in an enhancement in the brimonidine-induced hypothermic effect 24 h after the last dose, a time when above 90% of desipramine and its metabolite, desmethyldesipramine, had cleared the brain, but not at 14, 48 or 96 h after the last dose. In juvenile rats repeated injections of desipramine (3 mg/kg twice daily for 4 days) had no effect on the alpha2-agonist-induced hypothermia when brimonidine was given 14, 24, 63 and 96 h after the last dose of desipramine. CONCLUSION: The results suggest that juvenile rats response differently than adult rats to agonist stimulation of alpha2-adrenoceptors with and without pretreatment with the antidepressant desipramine. In the absence of desipramine pretreatment, the alpha2-adrenoceptor-induced hypothermic effect in juvenile rats is greater than in adult rats. Acute injections of desipramine, in the absence of agonist produced a hypothermic effect in adult but not juvenile rats. In addition, the increased alpha2-agonist-induced hypothermic effect following repeated injections of desipramine that is seen in adult rats is not seen in juvenile rats.
Pharmacokinetics and transcriptional effects of the anti-salmon lice drug emamectin benzoate in Atlantic salmon (Salmo salar L.).
Olsvik PA, Lie KK, Mykkeltvedt E … +4 more , Samuelsen OB, Petersen K, Stavrum AK, Lunestad BT
BMC Pharmacol · 2008 Sep · PMID 18786259 · Full text
BACKGROUND: Emamectin benzoate (EB) is a dominating pharmaceutical drug used for the treatment and control of infections by sea lice (Lepeophtheirus salmonis) on Atlantic salmon (Salmo salar L). Fish with an initial mean...
BACKGROUND: Emamectin benzoate (EB) is a dominating pharmaceutical drug used for the treatment and control of infections by sea lice (Lepeophtheirus salmonis) on Atlantic salmon (Salmo salar L). Fish with an initial mean weight of 132 g were experimentally medicated by a standard seven-day EB treatment, and the concentrations of drug in liver, muscle and skin were examined. To investigate how EB affects Atlantic salmon transcription in liver, tissues were assessed by microarray and qPCR at 7, 14 and 35 days after the initiation of medication. RESULTS: The pharmacokinetic examination revealed highest EB concentrations in all three tissues at day 14, seven days after the end of the medication period. Only modest effects were seen on the transcriptional levels in liver, with small fold-change alterations in transcription throughout the experimental period. Gene set enrichment analysis (GSEA) indicated that EB treatment induced oxidative stress at day 7 and inflammation at day 14. The qPCR examinations showed that medication by EB significantly increased the transcription of both HSP70 and glutathione-S-transferase (GST) in liver during a period of 35 days, compared to un-treated fish, possibly via activation of enzymes involved in phase II conjugation of metabolism in the liver. CONCLUSION: This study has shown that a standard seven-day EB treatment has only a modest effect on the transcription of genes in liver of Atlantic salmon. Based on GSEA, the medication seems to have produced a temporary oxidative stress response that might have affected protein stability and folding, followed by a secondary inflammatory response.
Methoxylation enhances stilbene bioactivity in Caenorhabditis elegans.
Wilson MA, Rimando AM, Wolkow CA
BMC Pharmacol · 2008 Aug · PMID 18700960 · Full text
BACKGROUND: Stilbenes are 1,2-diphenylethylene congeners produced by plants in response to stress. Many stilbenes also exhibit xenobiotic activities in animal cells, such as inhibition of cancer cell growth, neuroprotect...
BACKGROUND: Stilbenes are 1,2-diphenylethylene congeners produced by plants in response to stress. Many stilbenes also exhibit xenobiotic activities in animal cells, such as inhibition of cancer cell growth, neuroprotection, and immune modulation. In vivo, hydroxylated stilbenes are metabolized by glucuronidation to facilitate excretion. Methoxylated stilbenes are metabolized more slowly, which may have a positive effect on in vivo bioactivity. Here, we have directly compared in vivo bioactivities of methoxylated and hydroxylated stilbenes in a whole organism using the roundworm Caenorhabditis elegans, an advantageous experimental system for such studies due to its rapid lifecycle, genetic amenability and relatively low-cost. RESULTS: Toxicity towards C. elegans adults was observed for trimethoxylated and dimethoxylated stilbenes, as well as the monomethoxylated stilbene desoxyrhapontigenin. Toxicity was not observed for the monomethoxylated stilbene, pinostilbene, nor for hydroxylated stilbenes. The methoxylated stilbenes that exhibited toxicity also showed stronger inhibitory effects than the hydroxylated stilbenes on germline tumor growth in gld-1(q485) adults. However, steady-state levels of three inhibitory methoxylated stilbenes did not directly correlate to their relative bioactivities. CONCLUSION: These findings demonstrate that, for the group of stilbenes investigated, methoxylation generally increased bioactivity in vivo in a whole organism, with the exception of pinostilbene. Differences in bioactivity in C. elegans adults did not appear to correlate with differential uptake. Rather, we speculate that methoxylated stilbenes may have increased interactions with biological targets in vivo or may interact with specific targets unaffected by hydroxylated stilbenes. The potent activities of methoxylated stilbenes provide a basis for further investigations to identify in vivo targets for these compounds.
Ameliorative role of Atorvastatin and Pitavastatin in L-Methionine induced vascular dementia in rats.
Koladiya RU, Jaggi AS, Singh N … +1 more , Sharma BK
BMC Pharmacol · 2008 Aug · PMID 18691432 · Full text
BACKGROUND: Statins, HMG-CoA reductase inhibitors, are widely prescribed drugs for dyslipidemias. Recent studies have indicated number of cholesterol independent actions of statins including their beneficial effects on v...
BACKGROUND: Statins, HMG-CoA reductase inhibitors, are widely prescribed drugs for dyslipidemias. Recent studies have indicated number of cholesterol independent actions of statins including their beneficial effects on vascular endothelial dysfunction and memory deficits associated with dementia of Alzheimer's type. However the potential of statins in dementia of vascular origin still remains to be explored. Therefore, the present study has been designed to investigate the effect of Atorvastatin & Pitavastatin on vascular endothelial dysfunction associated memory deficits in rats. In this study L-Methionine induced vascular dementia was assessed by Morris water-maze (MWM) test. Biochemical analysis was also performed to unfold possible mechanism of statins mediated modulation of vascular dementia. RESULTS: L-Methionine produced endothelial dysfunction as reflected by significant decrease in serum nitrite concentration. L-Methionine treated rats performed poorly on MWM indicating impairment of memory as well. These rats also showed a significant rise in brain oxidative stress, acetylcholinesterase (AChE) activity and serum total cholesterol levels. Both Atorvastatin as well as Pitavastatin attenuated L-Methionine induced endothelial dysfunction associated memory deficits. Statins also reversed L-Methionine induced rise in brain oxidative stress, AChE activity and serum cholesterol. CONCLUSION: The beneficial effects of statins may be attributed to their multiple effects and the study highlights the potential of these drugs in vascular dementia.
A classification model to predict synergism/antagonism of cytotoxic mixtures using protein-drug docking scores.
Boik JC, Newman RA
BMC Pharmacol · 2008 Jul · PMID 18664274 · Full text
BACKGROUND: Safer and more effective mixtures of anticancer drugs are needed, and modeling can assist in this endeavor. This paper describes classification models that were constructed to predict which fixed-ratio mixtur...
BACKGROUND: Safer and more effective mixtures of anticancer drugs are needed, and modeling can assist in this endeavor. This paper describes classification models that were constructed to predict which fixed-ratio mixtures created from a pool of 10 drugs would show a high degree of in-vitro synergism against H460 human lung cancer cells. One of the tested drugs was doxorubicin and the others were natural compounds including quercetin, curcumin, and EGCG. Explanatory variables were based on virtual docking profiles. Docking profiles for the 10 drugs were obtained for 1087 proteins using commercial docking software. The cytotoxicity of all 10 drugs and of 45 of the 1,013 possible mixtures was tested in the laboratory and synergism indices were generated using the MixLow method. Model accuracy was assessed using cross validation, as well as using predictions on a new set of 10 tested mixtures. Results were compared to models where explanatory variables were constructed using the pseudomolecule approach of Sheridan. RESULTS: On this data set, the pseudomolecule and docking data approach produce models of similar accuracy. Leave-one-out precision for the negative (highly synergistic) class and the positive (low- or non-synergistic) class was 0.73 and 0.80, respectively. Precision for a nonstandard leave-many-out cross validation procedure was 0.60 and 0.77 for the negative and positive classes, respectively. CONCLUSION: Useful classification models can be constructed to predict drug synergism, even in those situations where a limited subset of component drugs can be tested. Compared to the pseudomolecule approach, the virtual docking approach has the advantage of greater potential for biologic interpretation. This distinction may become important as virtual docking software becomes more accurate and docking results more closely resemble actual binding affinities. This is the first published report of a model designed to predict the degree of in-vitro synergism based on the pseudomolecule or docking data approach.
Structure-activity models of oral clearance, cytotoxicity, and LD50: a screen for promising anticancer compounds.
Boik JC, Newman RA
BMC Pharmacol · 2008 Jun · PMID 18554402 · Full text
BACKGROUND: Quantitative structure-activity relationship (QSAR) models have become popular tools to help identify promising lead compounds in anticancer drug development. Few QSAR studies have investigated multitask lear...
BACKGROUND: Quantitative structure-activity relationship (QSAR) models have become popular tools to help identify promising lead compounds in anticancer drug development. Few QSAR studies have investigated multitask learning, however. Multitask learning is an approach that allows distinct but related data sets to be used in training. In this paper, a suite of three QSAR models is developed to identify compounds that are likely to (a) exhibit cytotoxic behavior against cancer cells, (b) exhibit high rat LD50 values (low systemic toxicity), and (c) exhibit low to modest human oral clearance (favorable pharmacokinetic characteristics). Models were constructed using Kernel Multitask Latent Analysis (KMLA), an approach that can effectively handle a large number of correlated data features, nonlinear relationships between features and responses, and multitask learning. Multitask learning is particularly useful when the number of available training records is small relative to the number of features, as was the case with the oral clearance data. RESULTS: Multitask learning modestly but significantly improved the classification precision for the oral clearance model. For the cytotoxicity model, which was constructed using a large number of records, multitask learning did not affect precision but did reduce computation time. The models developed here were used to predict activities for 115,000 natural compounds. Hundreds of natural compounds, particularly in the anthraquinone and flavonoids groups, were predicted to be cytotoxic, have high LD50 values, and have low to moderate oral clearance. CONCLUSION: Multitask learning can be useful in some QSAR models. A suite of QSAR models was constructed and used to screen a large drug library for compounds likely to be cytotoxic to multiple cancer cell lines in vitro, have low systemic toxicity in rats, and have favorable pharmacokinetic properties in humans.
Pharmacological Properties of DOV 315,090, an ocinaplon metabolite.
Berezhnoy D, Gravielle MC, Downing S … +5 more , Kostakis E, Basile AS, Skolnick P, Gibbs TT, Farb DH
BMC Pharmacol · 2008 Jun · PMID 18554397 · Full text
BACKGROUND: Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre-anesthetic sedation and muscle relaxa...
BACKGROUND: Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre-anesthetic sedation and muscle relaxation. It has been hypothesized that these various pharmacological effects are mediated by different GABAA-R subtypes. If this hypothesis is correct, then it may be possible to develop compounds targeting particular GABAA-R subtypes as, for example, selective anxiolytics with a diminished side effect profile. The pyrazolo[1,5-a]-pyrimidine ocinaplon is anxioselective in both preclinical studies and in patients with generalized anxiety disorder, but does not exhibit the selectivity between alpha1/alpha2-containing receptors for an anxioselective that is predicted by studies using transgenic mice. RESULTS: We hypothesized that the pharmacological properties of ocinaplon in vivo might be influenced by an active biotransformation product with greater selectivity for the alpha2 subunit relative to alpha1. One hour after administration of ocinaplon, the plasma concentration of its primary biotransformation product, DOV 315,090, is 38% of the parent compound. The pharmacological properties of DOV 315,090 were assessed using radioligand binding studies and two-electrode voltage clamp electrophysiology. We report that DOV 315,090 possesses modulatory activity at GABAA-Rs, but that its selectivity profile is similar to that of ocinaplon. CONCLUSION: These findings imply that DOV 315,090 could contribute to the action of ocinaplon in vivo, but that the anxioselective properties of ocinaplon cannot be readily explained by a subtype selective effect/action of DOV 315,090. Further inquiry is required to identify the extent to which different subtypes are involved in the anxiolytic and other pharmacological effects of GABAA-R modulators.
Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives.
Volvert ML, Seyen S, Piette M … +4 more , Evrard B, Gangolf M, Plumier JC, Bettendorff L
BMC Pharmacol · 2008 Jun · PMID 18549472 · Full text
BACKGROUND: Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphip...
BACKGROUND: Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphiphilic S-acyl thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and so enhancing transketolase activity. As the brain is particularly sensitive to thiamine deficiency, we wanted to test whether intracellular thiamine and thiamine phosphate levels are increased in the brain after oral benfotiamine administration. RESULTS: Benfotiamine that is practically insoluble in water, organic solvents or oil was solubilized in 200 mM hydroxypropyl-beta-cyclodextrin and the mice received a single oral administration of 100 mg/kg. Though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours, no significant increase was observed in the brain. When mice received a daily oral administration of benfotiamine for 14 days, thiamine derivatives were increased significantly in the liver but not in the brain, compared to control mice. In addition, incubation of cultured neuroblastoma cells with 10 muM benfotiamine did not lead to increased intracellular thiamine levels. Moreover, in thiamine-depleted neuroblastoma cells, intracellular thiamine contents increased more rapidly after addition of thiamine to the culture medium than after addition of benfotiamine for which a lag period was observed. CONCLUSION: Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Benfotiamine, an S-acyl derivative practically insoluble in organic solvents, should therefore be differentiated from truly lipid-soluble thiamine disulfide derivatives (allithiamine and the synthetic sulbutiamine and fursultiamine) with a different mechanism of absorption and different pharmacological properties.
Antagonist affinity measurements at the Gi-coupled human histamine H3 receptor expressed in CHO cells.
Baker JG
BMC Pharmacol · 2008 Jun · PMID 18538007 · Full text
BACKGROUND: The H3 histamine receptor is a Gi-coupled GPCR that has been proven to exist in different agonist-induced states, including that defined by the protean agonist proxyfan. Several GPCRs are now known to exist i...
BACKGROUND: The H3 histamine receptor is a Gi-coupled GPCR that has been proven to exist in different agonist-induced states, including that defined by the protean agonist proxyfan. Several GPCRs are now known to exist in different states. For some of these, antagonist affinity measurement remain constant regardless of the state of the receptor, for others e.g. the beta-adrenoceptors, the antagonist affinity measurements vary considerably depending on which agonist-dependent state is being identified. The purpose of this study was to examine the antagonist affinity measurements at the Gi-coupling human H3 receptor, paying particular attention to measurements made in the presence of full agonists, partial agonists and the proxyfan protean agonist-induced state of the receptor. RESULTS: CHO cells stably expressing the human histamine H3 receptor and a CRE-SPAP reporter were used. Measurements of CRE-gene transcription and 3H-cAMP accumulation were made. A range of ligands of different agonist efficacies were determined, including some partial agonists e.g. VUF 5681. Unlike other Gi-coupled receptors, no Gs-coupled state of the receptor was detected with these ligands. Antagonist affinity measurements were constant, whether the measurements were made in the presence of a full agonist, a partial agonist or the protean agonist proxyfan. CONCLUSION: In contrast to all three subtypes of the beta-adrenoceptors, but in keeping with the traditional pharmacological dogma, antagonist affinity measurements remained constant at the human H3 receptor, including the medium-efficacy proxyfan-induced state of the receptor and the VUF5681-induced state of the receptor.
Comparison of four different colorimetric and fluorometric cytotoxicity assays in a zebrafish liver cell line.
Bopp SK, Lettieri T
BMC Pharmacol · 2008 May · PMID 18513395 · Full text
BACKGROUND: A broad spectrum of cytotoxicity assays is currently used in the fields of (eco)toxicology and pharmacology. To choose an appropriate assay, different parameters like test compounds, detection mechanism, spec...
BACKGROUND: A broad spectrum of cytotoxicity assays is currently used in the fields of (eco)toxicology and pharmacology. To choose an appropriate assay, different parameters like test compounds, detection mechanism, specificity, and sensitivity have to be considered. Furthermore, tissue or cell line can influence test performance. For zebrafish (Danio rerio), as emerging model organism, cell lines are now increasingly used, but few studies examined cytotoxicity in these cell systems. Therefore, we compared four cytotoxicity assays in the zebrafish liver cell line, ZFL, to test four differently acting model compounds. The tests comprised two colorimetric assays (MTT assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and the LDH assay detecting lactate dehydrogenase activity) and two fluorometric assays (alamarBlue(R) using resazurin, and CFDA-AM based on 5-carboxyfluorescein diacetate acetoxymethyl ester). Model compounds were the pharmaceutical Tamoxifen, its metabolite 4-Hydroxy-Tamoxifen, the fungicide Flusilazole and the polycyclic aromatic hydrocarbon Benzo[a]pyrene. RESULTS: All four assays performed well in the ZFL cells and led to reproducible dose-response curves for all test compounds. Effective concentrations causing 10% or 50% loss of cell viability (EC10 and EC50 values) varied by a maximum factor of 7.0 for the EC10 values and a maximum factor of 1.8 for the EC50 values. The EC values were not statistically different between the four assays, which is due to the assessed unspecific effects of the compounds. However, most often, the MTT assay and LDH assay showed the highest and lowest EC values, respectively. Nevertheless, the LDH assay showed the highest intra- and inter-assay variabilities and the lowest signal-to-noise ratios. In contrast to MTT, the other three assays have the advantage of being non-destructive, easy to handle, and less time consuming. Furthermore, AB and CFDA-AM can be combined on the same set of cells without damaging the cells, allowing later on their use for the investigation of other endpoints. CONCLUSION: We recommend the alamarBlue and CFDA-AM assays for cytotoxicity assessment in ZFL cells, which can be applied either singly or combined.
RU486 did not exacerbate cytokine release in mice challenged with LPS nor in db/db mice.
Yang B, Trump RP, Shen Y … +5 more , McNulty JA, Clifton LG, Stimpson SA, Lin P, Pahel GL
BMC Pharmacol · 2008 May · PMID 18474108 · Full text
BACKGROUND: Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerb...
BACKGROUND: Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFalpha levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice. RESULTS: Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFalpha in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFalpha and further increased serum corticosterone. CONCLUSION: RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFalpha release, possibly due to the increased release of glucocorticoids.
Antidepressant drugs modulate growth factors in cultured cells.
Henkel AW, Sperling W, Rotter A … +6 more , Reulbach U, Reichardt C, Bönsch D, Maler JM, Kornhuber J, Wiltfang J
BMC Pharmacol · 2008 Mar · PMID 18318898 · Full text
BACKGROUND: Different classes of antidepressant drugs are used as a treatment for depression by activating the catecholinergic system. In addition, depression has been associated with decrease of growth factors, which ca...
BACKGROUND: Different classes of antidepressant drugs are used as a treatment for depression by activating the catecholinergic system. In addition, depression has been associated with decrease of growth factors, which causes insufficient axonal sprouting and reduced neuronal damage repair. In this study, antidepressant treatments are analyzed in a cell culture system, to study the modulation of growth factors. RESULTS: We quantified the transcription of several growth factors in three cell lines after application of antidepressant drugs by real time polymerase chain reaction. Antidepressant drugs counteracted against phorbolester-induced deregulation of growth factors in PMA-differentiated neuronal SY5Y cells. We also found indications in a pilot experiment that magnetic stimulation could possibly modify BDNF in the cell culture system. CONCLUSION: The antidepressant effects antidepressant drugs might be explained by selective modulation of growth factors, which subsequently affects neuronal plasticity.
A global view of drug-therapy interactions.
Nacher JC, Schwartz JM
BMC Pharmacol · 2008 Mar · PMID 18318892 · Full text
BACKGROUND: Network science is already making an impact on the study of complex systems and offers a promising variety of tools to understand their formation and evolution in many disparate fields from technological netw...
BACKGROUND: Network science is already making an impact on the study of complex systems and offers a promising variety of tools to understand their formation and evolution in many disparate fields from technological networks to biological systems. Even though new high-throughput technologies have rapidly been generating large amounts of genomic data, drug design has not followed the same development, and it is still complicated and expensive to develop new single-target drugs. Nevertheless, recent approaches suggest that multi-target drug design combined with a network-dependent approach and large-scale systems-oriented strategies create a promising framework to combat complex multi-genetic disorders like cancer or diabetes. RESULTS: We here investigate the human network corresponding to the interactions between all US approved drugs and human therapies, defined by known relationships between drugs and their therapeutic applications. Our results show that the average paths in this drug-therapy network are shorter than three steps, indicating that distant therapies are separated by a surprisingly low number of chemical compounds. We also identify a sub-network composed by drugs with high centrality measures in the drug-therapy network, which represent the structural backbone of this system and act as hubs routing information between distant parts of the network. CONCLUSION: These findings provide for the first time a global map of the large-scale organization of all known drugs and associated therapies, bringing new insights on possible strategies for future drug development. Special attention should be given to drugs which combine the two properties of (a) having a high centrality value in the drug-therapy network and (b) acting on multiple molecular targets in the human system.
Role of sulphated polysaccharides from Sargassum Wightii in Cyclosporine A-induced oxidative liver injury in rats.
Josephine A, Nithya K, Amudha G … +3 more , Veena CK, Preetha SP, Varalakshmi P
BMC Pharmacol · 2008 Feb · PMID 18289374 · Full text
BACKGROUND: Seaweeds or marine algae have long been made up a key part of the Asian diet, and as an antioxidant, sulphated polysaccharides have piqued the interest of many researchers as one of the ocean's greatest treas...
BACKGROUND: Seaweeds or marine algae have long been made up a key part of the Asian diet, and as an antioxidant, sulphated polysaccharides have piqued the interest of many researchers as one of the ocean's greatest treasures. The present investigation suggests the therapeutic potential of sulphated polysaccharides from marine brown algae "Sargassum wightii" in Cyclosporine A (CsA)- induced liver injury. CsA is a potent immunosuppressive agent used in the field of organ transplantations and various autoimmune disorders. However, hepatotoxicity due to CsA remains to be one of the major clinical challenges. METHODS: The effect of sulphated polysaccharides on CsA-induced hepatotoxicity was studied in adult male albino rats of Wistar strain, and the animals were randomized into four groups with six rats in each. Group I served as vehicle control. Group II rats were given CsA at a dosage of 25 mg/kg body weight, orally for 21 days. Group III rats were given sulphated polysaccharides at a dosage of 5 mg/kg body weight, subcutaneously for 21 days. Group IV rats were given sulphated polysaccharides simultaneously along with CsA, as mentioned in Group II for 21 days. RESULTS: CsA provoked hepatotoxicity was evident from the decreased activities of hepatic marker enzymes. A significant rise in the level of oxidants, along with a striking decline in both the enzymic and non-enzymic antioxidants, marks the severity of oxidative stress in CsA-induced rats. This in turn led to enhanced levels of lipid peroxidation, 8-hydroxy-2-deoxy guanosine and protein carbonyls, along with a decrease in ATPase activities and alterations in lipid profile. Histopathological changes also strongly support the above aberrations. However, concomitant treatment with sulphated polysaccharides restored the above deformities to near control and prevented the morphological alterations significantly. CONCLUSION: Thus, the present study highlights that sulphated polysaccharides can act therapeutically against CsA-induced hepatotoxicity.
Inhibition of 11betaHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice.
Sundbom M, Kaiser C, Björkstrand E … +5 more , Castro VM, Larsson C, Selén G, Nyhem CS, James SR
BMC Pharmacol · 2008 Feb · PMID 18269730 · Full text
BACKGROUND: A substantial body of evidence indicates that reduced plasma adiponectin levels may be key in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. Glucocorticoids decrease the le...
BACKGROUND: A substantial body of evidence indicates that reduced plasma adiponectin levels may be key in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. Glucocorticoids decrease the levels of adiponectin in animals and humans. Cortisone is transformed to its active form cortisol, via 11beta-hydroxysteroid dehydrogenase (HSD) type 1. This study sought to ascertain if inhibition of 11beta HSD1 with a new selective inhibitor, BVT116429, affects the concentrations of circulating adiponectin with concomitant effects on glucose homeostasis in diabetic mice. RESULTS: KKAy mice were treated with BVT116429 (3, 10, 30 mg/kg), rosiglitazone (5 mg/kg) or vehicle once daily for ten days. Plasma adiponectin levels rose in mice treated with BVT116429 and this was found to be both the hexameric and the high molecular weight multimeric forms of adiponectin. Seven days of treatment with the 11beta HSD1-inhibitor BVT116429 decreased basal insulin levels but no changes in glucose tolerance were seen. After ten days of treatment, fasting blood glucose level was decreased by BVT116429 comparable to the effects of rosiglitazone. Another 11beta HSD1 inhibitor, BVT2733, improved HbA1c but had no effect on adiponectin. CONCLUSION: Inhibition of 11beta HSD1 can be expected to be beneficial for treating the pathology of type 2 diabetes mellitus. The differences seen in adiponectin between BVT116429 and BVT2733 could be explained by different pharmacodynamics exerted by the compounds in different tissues in the body. Increases in adiponectin concentrations may be an integral component in the mechanism of action of this new11beta HSD1 inhibitor and may be a useful marker of efficacy during the clinical development of 11beta HSD1 inhibitor compounds.
Comparative study of the antimutagenic properties of vitamins C and E against mutation induced by norfloxacin.
Alba MA, Sánchez RR, Pérez NJ … +4 more , Navarrete JS, Paz RF, Montoya-Estrada A, Gómez JJ
BMC Pharmacol · 2008 Feb · PMID 18267022 · Full text
BACKGROUND: Norfloxacin like other fluoroquinolones, is known to mbe mutagenic for Salmonella typhimurium TA102 strain. This mutagenic effect is due to free oxygen radicals (ROS), because it is inhibited by antioxidants...
BACKGROUND: Norfloxacin like other fluoroquinolones, is known to mbe mutagenic for Salmonella typhimurium TA102 strain. This mutagenic effect is due to free oxygen radicals (ROS), because it is inhibited by antioxidants such as beta-carotene and naturally occurring antioxidants of Roheo discolor and other plants. The aim of this work was to evaluate combination therapy with norfloxacin and vitamins C and E, to reduce the possible genotoxic risk associated with fluoroquinolones. METHOD: The antimutagenicity of alpha-tocoferol (Vitamin E) and ascorbic acid (Vitamin C) against norfloxacin-induced mutation was evaluated on S. typhimurium TA102, using the aroclor-1254-induced S9 rat liver homogenate. The minimum inhibitory concentration (MIC) a measure of the bactericidal effect of norfloxacin, was obtained in vitro by the plate dilution method. RESULTS: Vitamin E (0.5 mg per Petri dish) induced a statistically significant reduction (P < 0.001) in the mutagenicity of norfloxacin, whereas Vitamin C (1 mg per Petri dish) had no such effect. Neither of these vitamins altered the MIC for norfloxacin against 25 uropathogenic strains of Escherichia coli. CONCLUSION: These results suggest that Vitamin E is a potent antimutagen that would be worthwhile being used in conjunction with fluoroquinolone treatment. The minimal antimutagenic effect of Vitamin C observed under these experimental conditions may have been because Vitamin C in the Ames test induces a Fenton reaction, and if divalent cations are present, it can act as a pro-oxidant rather than an antioxidant. Ascorbic acid should be further evaluated in the presence of different divalent cations concentrations.
Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25-35)-induced amnesia.
Storozheva ZI, Proshin AT, Sherstnev VV … +7 more , Storozhevykh TP, Senilova YE, Persiyantseva NA, Pinelis VG, Semenova NA, Zakharova EI, Pomytkin IA
BMC Pharmacol · 2008 Jan · PMID 18215309 · Full text
BACKGROUND: Accumulated evidence suggests that insulin resistance and impairments in cerebral insulin receptor signaling may contribute to age-related cognitive deficits and Alzheimer's disease. The enhancement of insuli...
BACKGROUND: Accumulated evidence suggests that insulin resistance and impairments in cerebral insulin receptor signaling may contribute to age-related cognitive deficits and Alzheimer's disease. The enhancement of insulin receptor signaling is, therefore, a promising strategy for the treatment of age-related cognitive disorders. The mitochondrial respiratory chain, being involved in insulin-stimulated H2O2 production, has been identified recently as a potential target for the enhancement of insulin signaling. The aim of the present study is to examine: (1) whether a specific respiratory substrate, dicholine salt of succinic acid (CS), can enhance insulin-stimulated insulin receptor autophosphorylation in neurons, and (2) whether CS can ameliorate cognitive deficits of various origins in animal models. RESULTS: In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation. In animal models, CS significantly ameliorated cognitive deficits, when administered intraperitoneally for 7 days. In 16-month-old middle-aged C57Bl/6 mice (a model of normal aging), CS enhanced spatial learning in the Morris water maze, spontaneous locomotor activity, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to the age-matched control (saline). In rats with chronic cerebral hypoperfusion, CS enhanced spatial learning, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to control rats (saline). In rats with beta-amyloid peptide-(25-35)-induced amnesia, CS enhanced passive avoidance performance and increased activity of brain choline acetyltransferase, as compared to control rats (saline). In all used models, CS effects lasted beyond the seven-day treatment period and were found to be significant about two weeks following the treatment. CONCLUSION: The results of the present study suggest that dicholine salt of succinic acid, a novel neuronal insulin sensitizer, ameliorates cognitive deficits and neuronal dysfunctions in animal models relevant to age-related cognitive impairments, vascular dementia, and Alzheimer's disease.
The presence of beta2-adrenoceptors sensitizes alpha2A-adrenoceptors to desensitization after chronic epinephrine treatment.
Bawa-Khalfe T, Altememi GF, Mandyam CD … +3 more , Schwarz LA, Eikenburg DC, Standifer KM
BMC Pharmacol · 2007 Dec · PMID 18096057 · Full text
BACKGROUND: In addition to the regulation of blood pressure, alpha2- and beta-adrenoceptor (AR) subtypes play an important role in the modulation of noradrenergic neurotransmission in the human CNS and PNS. Several studi...
BACKGROUND: In addition to the regulation of blood pressure, alpha2- and beta-adrenoceptor (AR) subtypes play an important role in the modulation of noradrenergic neurotransmission in the human CNS and PNS. Several studies suggest that the alpha2-AR responsiveness in cells and tissues after chronic epinephrine (EPI) or norepinephrine (NE) exposure may vary, depending on the beta-AR activity present there. Recently, we reported that in BE(2)-C human neuroblastoma cells (endogenously expressing alpha2A- and beta2-AR), chronic EPI treatment (300 nM) produced a dramatic beta-adrenoceptor-dependent desensitization of the alpha2A-AR response. The aim of this study is to determine if stable addition of a beta2-AR to a second neuroblastoma cell line (SH-SY5Y), that normally expresses only alpha2A-ARs that are not sensitive to 300 nM EPI exposure, would suddenly render alpha2A-ARs in that cell line sensitive to treatment with the same EPI concentration. METHODS: These studies employed RT-PCR, receptor binding and inhibition of cAMP accumulation to confirm alpha2-AR subtype expression. Stable clones of SH-SY5Y cells transfected to stably express functional beta2-ARs (SHbeta2AR4) were selected to compare sensitivity of alpha2-AR to EPI in the presence or absence of beta2-ARs. RESULTS: A series of molecular, biochemical and pharmacological studies indicated that the difference between the cell lines could not be attributed to alpha2-AR heterogeneity. We now report that after transfection of functional beta2-AR into SH-SY5Y cells (SHbeta2AR4), chronic treatment with modest levels of EPI desensitizes the alpha2A-AR. This effect results from a beta2-AR dependent down-regulation of native alpha2A-ARs by EPI accompanied by enhanced translocation of GRK2 and GRK3 to the membrane (required for GRK-mediated phosphorylation of agonist-occupied receptors). CONCLUSION: This study further supports the hypothesis that the presence of the beta-AR renders the alpha2A-AR more susceptible to desensitization with physiological levels of EPI.
Chlorin e6 - polyvinylpyrrolidone mediated photosensitization is effective against human non-small cell lung carcinoma compared to small cell lung carcinoma xenografts.
Chin WW, Heng PW, Olivo M
BMC Pharmacol · 2007 Dec · PMID 18053148 · Full text
BACKGROUND: Photodynamic therapy (PDT) is an effective local cancer treatment that involves light activation of a photosensitizer, resulting in oxygen-dependent, free radical-mediated cell death. Little is known about th...
BACKGROUND: Photodynamic therapy (PDT) is an effective local cancer treatment that involves light activation of a photosensitizer, resulting in oxygen-dependent, free radical-mediated cell death. Little is known about the comparative efficacy of PDT in treating non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), despite ongoing clinical trials treating lung cancers. The present study evaluated the potential use of chlorin e6 - polyvinylpyrrolidone (Ce6-PVP) as a multimodality photosensitizer for fluorescence detection and photodynamic therapy (PDT) on NSCLC and SCLC xenografts. RESULTS: Human NSCLC (NCI-H460) and SCLC (NCI-H526) tumor cell lines were used to establish tumor xenografts in the chick chorioallantoic membrane (CAM) model as well as in the Balb/c nude mice. In the CAM model, Ce6-PVP was applied topically (1.0 mg/kg) and fluorescence intensity was charted at various time points. Tumor-bearing mice were given intravenous administration of Ce6-PVP (2.0 mg/kg) and laser irradiation at 665 nm (fluence of 150 J/cm2 and fluence rate of 125 mW/cm2). Tumor response was evaluated at 48 h post PDT. Studies of temporal fluorescence pharmacokinetics in CAM tumor xenografts showed that Ce6-PVP has a selective localization and a good accuracy in demarcating NSCLC compared to SCLC from normal surrounding CAM after 3 h post drug administration. Irradiation at 3 h drug-light interval showed greater tumor necrosis against human NSCLC xenografts in nude mice. SCLC xenografts were observed to express resistance to photosensitization with Ce6-PVP. CONCLUSION: The formulation of Ce6-PVP is distinctly advantageous as a diagnostic and therapeutic agent for fluorescence diagnosis and PDT of NSCLC.
Abstracts of the 13th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint Meeting with the Austrian Society of Toxicology (ASTOX) and the Hungarian Society for Experimental and Clinical Pharmacology (MFT), Vienna, Austria, 22-24 November 2007.
Singewald GM, Ebner K, Whittle N … +2 more , Ferraguti F, Singewald N
BMC Pharmacol · 2007 · PMID 18053119 · Full text
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