BMC Pharmacology - Most accessed articles

Effect of green tea on blood glucose levels and serum proteomic patterns in diabetic (db/db) mice and on glucose metabolism in healthy humans

Hiroshi Tsuneki — 2004-08-26T00:00:00Z

Background: Green tea is widely consumed in Asian countries and is becoming increasingly popular in Western countries. Epidemiologically, it has been suggested that green tea consumption prevents type 2 diabetes. The present study was aimed at providing evidence of improvement in glucose metabolism in diabetic mice and healthy humans upon green tea consumption. Results: Green tea promoted glucose metabolism in healthy human volunteers at 1.5 g/body in oral glucose tolerance tests. Green tea also lowered blood glucose levels in diabetic db+/db+ mice and streptozotocin-diabetic mice 2–6 h after administration at 300 mg/kg without affecting serum insulin level, whereas no effect was observed in control mice (+m/+m and normal ddY mice). The serum protein profiles of db+/db+ and +m/+m mice were analyzed for the first time by SELDI (surface-enhanced laser desorption/ionization)-TOF (time-of-flight)-MS (mass spectrometry), and then compared to investigate any effects of oral green tea administration on serum proteins. The protein profiles in db+/db+ mice showed that the spectral peak intensities at the mass/charge ratios (m/z) of 4119, 4203, 4206, 4211, 4579, 9311 and 18691 were >3 times lower, and those of 13075, 17406, 17407, 17418, 17622, 18431 and 26100 were >3 times higher than respective peak intensities in +m/+m mice. When green tea was administered to db+/db+ mice, the peak intensities were markedly decreased at m/z 11651 and 11863, and slightly decreased at m/z 4212. The peak intensities at 7495, 7595, 7808, 14983, 15614, 31204 were markedly increased after the administration. Conclusion: The present study provides evidence that green tea has an antidiabetic effect. Although we could not find simple reversed effect of green tea on the diabetes-induced modifications of the levels of several serum proteins, we found that the 4211 (4212) Da protein level that was decreased in the diabetic state was further decreased after green tea administration. This is the first report demonstrating that a certain serum protein may be involved in the antihyperglycemic effect of green tea. The contribution of this protein should be further studied.

An efficient drug delivery vehicle for botulism countermeasure

Peng Zhang — 2009-10-27T00:00:00Z

Background: Botulinum neurotoxin (BoNT) is the most potent poison known to mankind. Currently no antidote is available to rescue poisoned synapses. An effective medical countermeasure strategy would require developing a drug that could rescue poisoned neuromuscular synapses and include its efficient delivery specifically to poisoned presynaptic nerve terminals. Here we report a drug delivery strategy that could directly deliver toxin inhibitors into the intoxicated nerve terminal cytosol. Results: A targeted delivery vehicle was developed for intracellular transport of emerging botulinum neurotoxin antagonists. The drug delivery vehicle consisted of the non-toxic recombinant heavy chain of botulinum neurotoxin-A coupled to a 10-kDa amino dextran via the heterobifunctional linker 3-(2-pyridylthio)-propionyl hydrazide. The heavy chain served to target botulinum neurotoxin-sensitive cells and promote internalization of the complex, while the dextran served as a platform to deliver model therapeutic molecules to the targeted neurons. Our results indicated that the drug delivery vehicle entry into neurons was via BoNT-A receptor mediated endocytosis. Once internalized into neurons, the drug carrier component separated from the drug delivery vehicle in a fashion similar to the separation of the BoNT-A light chain from the holotoxin. This drug delivery vehicle could be used to deliver BoNT-A antidotes into BoNT-A intoxicated cultured mouse spinal cord cells. Conclusion: An effective BoNT-based drug delivery vehicle can be used to directly deliver toxin inhibitors into intoxicated nerve terminal cytosol. This approach can potentially be utilized for targeted drug delivery to treat other neuronal and neuromuscular disorders. This report also provides new knowledge of endocytosis and exocytosis as well as of BoNT trafficking.

Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells

Audun Vik-Mo — 2009-08-29T00:00:00Z

Background: Disturbances in lipid homeostasis and myelination have been proposed in the pathophysiology of schizophrenia and bipolar disorder. We have previously shown that several antipsychotic and antidepressant drugs increase lipid biosynthesis through activation of the Sterol Regulatory Element-Binding Protein (SREBP) transcription factors, which control the expression of numerous genes involved in fatty acid and cholesterol biosynthesis. The aim of the present proof-of-principle study was to investigate whether such drugs also affect lipid transport and export pathways in cultured human CNS and liver cells. Results: Quantitative PCR and immunoblotting were used to determine the level of lipid transport genes in human glioblastoma (GaMg) exposed to clozapine, olanzapine, haloperidol or imipramine. The effect of some of these drugs was also investigated in human astrocytoma (CCF-STTG1), neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cells. We found significant transcriptional changes of cholesterol transport genes (ApoE, ABCA1, NPC1, NPC2, NPC1L1), which are predominantly controlled by the Liver X receptor (LXR) transcription factor. The up-regulation was observed after 24 to 48 hours of drug exposure, which is markedly delayed as compared to the drug-induced SREBP-controlled stimulation of lipid biosynthesis seen after 6 hours. Conclusion: Our data show that stimulation of cellular lipid biosynthesis by amphiphilic psychotropic drugs is followed by a transcriptional activation of cholesterol transport and efflux pathways. Such effects may be relevant for both therapeutic effects and metabolic adverse effects of psychotropic drugs.

The mode of action of dimeticone 4% lotion against head lice, Pediculus capitis.

Ian Burgess — 2009-02-20T00:00:00Z

Background: Treatment of head lice using physically acting preparations based on silicones is currently replacing insecticide use due to widespread resistance to neurotoxic agents. It has been postulated that some products act by asphyxiation, although the limited experimental evidence and the anatomy of the louse respiratory system suggest this is unlikely. Results: Observation over several hours of lice treated using 4% high molecular weight dimeticone in a volatile silicone base showed that, although rapidly immobilised initially, the insects still exhibited small movements of extremities and death was delayed. One common effect of treatment is inhibition of the louse's ability to excrete water by transpiration through the spiracles. Inability to excrete water that is ingested as part of the louse blood meal appears to subject the louse gut to osmotic stress resulting in rupture. Scanning electron microscopy coupled with X-ray microanalysis to detect silicon showed dimeticone lotion is deposited in the spiracles and distal region of the tracheae of lice and in some cases blocks the lumen or opening entirely. Conclusion: This work raises doubts that lice treated using dimeticone preparations die from anoxia despite blockage of the outer respiratory tract because movements can be observed for hours after exposure. However, the blockage inhibits water excretion, which causes physiological stress that leads to death either through prolonged immobilisation or, in some cases, disruption of internal organs such as the gut.

N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes

Rong Shi — 2009-04-15T00:00:00Z

Background: While doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use. This is the first report of the chemoprotective efficacy of a relatively new thiol antioxidant, N-acetylcysteine amide (NACA), on DOX-induced cell death in cardiomyocytes. We hypothesized that NACA would protect H9c2 cardiomyocytes from DOX-induced toxicity by reducing oxidative stress. Accordingly, we determined the ability of NACA to mitigate the cytotoxicity of DOX in H9c2 cells and correlated these effects with the production of indicators of oxidative stress. Results: DOX at 5 μM induced cardiotoxicity while 1) increasing the generation of reactive oxygen species (ROS), 2) decreasing levels and activities of antioxidants and antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase) and 3) increasing lipid peroxidation. NACA at 750 μM substantially reduced the levels of ROS and lipid peroxidation, as well as increased both GSH level and GSH/GSSG ratio. However, treating H9c2 cells with NACA did little to protect H9c2 cells from DOX-induced cell death. Conclusion: Although NACA effectively reduced oxidative stress in DOX-treated H9c2 cells, it had minimal effects on DOX-induced cell death. NACA prevented oxidative stress by elevation of GSH and CYS, reduction of ROS and lipid peroxidation, and restoration of antioxidant enzyme activities. Further studies to identify oxidative stress-independent pathways that lead to DOX-induced cell death in H9c2 are warranted.

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

Jose Portugal — 2009-09-16T00:00:00Z

Background: Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity. Results: Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute's drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures. Conclusion: For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute's 60-cell line data set tend to have common structural features.

Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway

Desheng Lu — 2009-11-30T00:00:00Z

Background: Wnt signaling affects fundamental development pathways by regulating cell proliferation and differentiation. Aberrant activation of Wnt/β-catenin signaling promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. Results: In order to identify the novel antagonists for the Wnt/β-catenin pathway, we employed a cell-based Wnt reporter system (TOPflash) to screen a library of 960 known drugs. We identified spiperone, a psychotropic drug, as a novel Wnt inhibitor, which specifically blocks canonical Wnt signaling prior to the activation of β-catenin. The Wnt inhibitory function of spiperone is not associated with its dopamine-, serotonin- and sigma-receptor antagonist properties. Instead, spiperone increases intracellular calcium levels in a similar manner to thapsigargin, that also impedes Wnt signal transduction. Inhibition of protein kinase C had no effect on spiperone-mediated antagonism of Wnt signaling. Conclusion: Spiperone is a calcium regulator. It inhibits Wnt signaling by enhancing intracellular calcium levels.

Bioequivalence study of three ibuprofen formulations after single dose administration in healthy volunteers

Peter Bramlage — 2008-10-29T00:00:00Z

Background: This phase I study was designed to determine the bioavailability and bioequivalence of 400 mg Eudorlin® extra* (Ibuprofen) in comparison to two reference formulations (400 mg Nurofen® forte and 400 mg Migränin® after single dose administration under fasting conditions in healthy subjects. Therefore the design of a randomized, open label, multiple sequence cross-over study with a wash-out period of 7–10 days was used. Results: AUC0-t(last) and AUC0-∞ (90%CI) were within the 80 to 125% interval required for bioequivalence as stipulated in the current regulations of the EMEA. Cmax (90%CI) was within the EMEA acceptance range of 75 to 133%. Detailed analyses showed that Cmax of Eudorlin® extra was higher than that of Nurofen® forte (36.62 vs. 32.92 μg/ml; p = 0.0014) and that of Migränin® (35.94 vs. 30.87 μg/ml; p < 0.0001). The time to maximum plasma concentration (tmax) was shorter with Eudorlin® extra than with Nurofen forte (1.14 vs. 1.82 h; p < 0.0001) and Migränin (1.13 vs. 1.78 h; p = 0.0031). Only 1 patient experienced an adverse with possible relation to the study drug taking Migränin®. Conclusion: It is concluded that Eudorlin® extra is bioequivalent to the two reference preparations Nurofen® forte and Migränin® for both, the extent and the rate of absorption, after single dose administration in healthy volunteers according to the guidance of the EMEA. Within this frame, peak plasma concentrations are however reached earlier and peaks are higher compared to the reference products.* Eudorlin® extra may have different brand names in different countries

Preferential uptake of the non steroid anti-inflammatory drug diclofenac into inflamed tissues after a single oral dose in rats

A. Schweitzer — 2009-03-16T00:00:00Z

Background: Diclofenac is a nonsteroidal anti-inflammatory drug which is available as prescription (RX) and over-the-counter (OTC) medication for the systemic and topical treatment of painful and inflammatory conditions such as arthritis and back pain. This study was undertaken to investigate the distribution and retention of diclofenac and/or its metabolites in inflamed tissues, using the carrageenan-induced inflammation model and quantitative whole body autoradiography in rats. Methods: [14C]diclofenac sodium was administrated as a single 2 mg/kg oral dose 1 h after injection of carrageenan into one front and one hind footpads and subcutaneously into the dorsum of the neck of rats. A control animal received saline injections. Three carrageenan-treated rats and one control rat were sacrificed at 1, 4, 8, and 24 h after [14C]diclofenac sodium administration (total of 4 rats/time point). The carcasses were immediately snap-frozen and prepared for cryosectioning. Lengthwise whole-body sections (40 μm thick), including all major tissues, were obtained from different levels across the body. The tissue concentrations of total radiolabeled components were determined using quantitative autoradioluminography. Results: The radioactivity patterns demonstrated that diclofenac and/or its metabolites preferentially distributed into the inflamed tissues. In unharmed tissues the distribution was similar in control and treated animals. The exposure, based on the areas under the tissue concentration versus time (AUC0-tlast), was 26 and 53 fold higher in the inflamed neck and inflamed footpads of treated animals than in control rats; the exposures in unharmed tissues were similar in the treated and control rats, and the AUC0-tlast was 17 fold higher in the inflamed paws than in the non inflamed footpads of the carrageenan-treated rats. The higher exposure in the inflamed tissues may be explained partly to the fact that the elimination of total radiolabeled components from inflamed tissues (t1/2 = 6 h) appeared lower than from the corresponding unharmed tissues (t1/2 = 2 h). Conclusion: This animal study demonstrated that diclofenac and/or its metabolites were rapidly and preferentially taken up and retained in inflamed tissues. Although there were theoretical considerations that mildly acidic NSAID may show some preferential distribution in inflamed tissues there was no clear experimental proof for diclofenac until the present study.

Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models

Nancy Lee — 2009-04-15T00:00:00Z

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in the TSC1 or TSC2 genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes. Results: Here, we examine the efficacy of a prolonged maintenance dose of rapamycin in Tsc2+/- mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden in Tsc2+/- mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months ≤ age < 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months ≤ age < 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age < 13 months; but we did not observe any improvement with combination IFN-g plus rapamycin in this study. We also used a Tsc2-/- subcutaneous tumor model to evaluate other classes of drugs including sorafenib, atorvastatin, and doxycycline. These drugs were tested as single agents and in combination with rapamycin. Our results demonstrate that the combination of rapamycin and sorafenib increased survival and may decrease tumor volume as compared to rapamycin treatment alone while sorafenib as a single agent was no different than control. Atorvastatin and doxycycline, either as single agents or in combination with rapamycin, did not improve outcomes as compared with controls. Conclusion: Our results indicate that prolonged treatment with low doses of mTOR inhibitors may result in more complete and durable TSC-related tumor responses, and it would be reasonable to evaluate this strategy in a clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in combination with inhibiting the mTOR pathway may be another useful strategy for the treatment of TSC-related tumors.