bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscarinic, Ca++ antagonist and specific butyrylcholinesterase inhibitory activity of dried ginger extract might explain its use in dementia
Authors: Ghayur Muhammad N , Gilani Anwarul H , Ahmed Touqeer , Khalid Asaad , Nawaz Sarfraz A , Agbedahunsi Joseph M , Choudhary Muhammad I , Houghton Peter J
Published: October 2010

Ginger rhizome (Zingiber officinale) has been used for centuries to treat dementia in South Asia. This study was undertaken to possibly justify its use. A 70% aqueous/methanolic extract of dried ginger (Zo.Cr) was used. Zo.Cr tested positive for the presence of terpenoids, flavonoids, secondary amines, phenols, alkaloids and saponins. When tested on isolated rat stomach fundus, Zo.Cr showed a spasmogenic effect (0.03–5.00 mg mL−1); it relaxed the tissue at concentrations ≥5 mg mL−1. The stimulant effect was resistant to blockade by hexamethonium and methysergide, but sensitive to atropine, indicating activity via muscarinic receptors. In atropinized (0.1 μM) preparations, Zo.Cr (0.3–3.0 mg mL−1) relaxed high K+ (80 mm)-induced contractions, indicating Ca++ antagonism in addition to the muscarinic effect. This possible Ca++ antagonist activity was investigated in Ca++-free conditions, with the inhibitory effect of the extract tested against contractions induced by externally administered Ca++. Zo.Cr (0.1–0.3 mg mL−1), similar to verapamil (0.03–0.10 μm), shifted the contractions induced by externally administered Ca++ to the right, thus suggesting an inhibitory interaction between Zo.Cr and voltage-operated Ca++ channels. Zo.Cr (0.1–3.0 μg mL−1) also potentiated acetylcholine peak responses in stomach fundus, similar to physostigmine, a cholinesterase inhibitor. Zo.Cr, in an in-vitro assay, showed specific inhibition of butyrylcholinesterase (BuChE) rather than acetylcholinesterase enzyme. Different pure compounds of ginger also showed spasmolytic activity in stomach fundus, with 6-gingerol being the most potent. 6-Gingerol also showed a specific anti-BuChE effect. This study shows a unique combination of muscarinic, possible Ca++ antagonist and BuChE inhibitory activities of dried ginger, indicating its benefit in dementia, including Alzheimer's disease.
Reduced prehepatic extraction of nicardipine in the presence of pioglitazone in rats
Authors: Choi Jun-Shik , Koh Young-Youp , Chung Joong-Hwa , Choi Dong-Hyun , Han Hyo-Kyung
Published: October 2010

This study investigated the effect of pioglitazone on the pharmacokinetics of oral and i.v. nicardipine in rats. Pharmacokinetic parameters were determined after nicardipine was administered orally (12 mg kg−1) or i.v. (4 mg kg−1) with or without a single dose of oral pioglitazone (0.3 or 1.0 mg kg−1). Compared with the control group given nicardipine alone, coadministration of pioglitazone significantly decreased the total plasma clearance of orally administered nicardipine (by 40.4–46.3%, P < 0.05) and significantly increased the area under the plasma concentration-time curve (by 81.8–96.3%) and the peak plasma concentration, Cmax (by 56.5–66.8%). Tmax and the terminal plasma half-life of nicardipine were not affected, however. Coadministration of oral pioglitazone did not affect the pharmacokinetics of i.v. nicardipine, implying that pioglitazone may mainly decrease the prehepatic extraction of nicardipine during intestinal absorption. In conclusion, pioglitazone significantly enhanced the oral bioavailability of nicardipine in rats by reducing its presystemic clearance.
Design and synthesis of new symmetrical derivatives of dihydropyridine containing a pyridyl group on the 3, 5-positions and evaluation of their cytotoxic and multidrug resistance reversal activity
Authors: Foroughinia Farzaneh , Javidnia Katayoun , Amirghofran Zahra , Mehdipour Ahmadreza , Miri Ramin
Published: October 2010

Today, chemotherapy is an important part in the treatment of several kinds of cancer; however, the development of drug resistance remains one of the major obstacles in successful chemotherapy. Several types of agents have been recognized as multidrug resistance (MDR) inhibitors, among which the 1,4-dihydropyridines (DHPs) have been investigated the most. P-glycoprotein inhibition has been reported as the main MDR reversal mechanism of DHPs, whilst other mechanisms such as inhibition of topoisomerase II have received less attention. Therefore, in this study new derivatives of DHP have been synthesized. Their cytotoxic activity and their effects in reversing atypical MDR have been evaluated. The results confirmed the appropriate effect of these compounds on atypical MDR. Although it was observed that these compounds had a moderate cytotoxic effect, the cytotoxicity of one compound on the K562 cell line (IC50 = 6.61 μM) was comparable with that of doxorubicin (IC50 = 4.17 μM). Finally, the Ca2+-channel antagonistic activity, an undesired effect for these compounds, was evaluated.
Polysaccharopeptide mimics ciclosporin-mediated Th1/Th2 cytokine balance for suppression of activated human T cell proliferation by MAPKp38 and STAT5 pathways
Authors: Lee Cheuk-Lun , Sit Wai-Hung , Jiang Ping-Ping , So Ivy Wing-Yan , Wan Jennifer Man-Fan
Published: October 2010

The activation of T helper (Th) cell subsets plays an important role in the human immune system. Uncontrolled Th1 and Th2 responses lead to autoimmune and inflammatory diseases, respectively. The identification of agents that modulate the Th1/Th2 cytokines is therefore essential for controlling these diseases. We recently reported that polysaccharopeptide (PSP) from Coriolus versicolor exhibited ciclosporin-like activities to control aberrant T lymphocyte activation. Here, we compared the properties of PSP with ciclosporin on cell proliferation, CD25+ expression, secretion of Th1/Th2 cytokines and activation of mitogen-activated protein kinase (MAPK)p38 and signal transducers and activators of transcription 5 (STAT5) on T cells. The data show that PSP alone suppresses the proliferation of activated T cells. PSP exhibited similar and additive inhibitory effects to ciclosporin to suppress activated T cell proliferation, Th1 cytokines and reduce CD3+/CD25+ cell expression, but not Th2 cytokine expression, which helps the cytokine balance shift towards Th2 dominance. These suppressive actions of PSP involved the MAPKp38 and STAT5 pathways. These findings refine our understanding of the effects of PSP on T lymphocytes and its adjuvant properties with the immunosuppressant ciclosporin for possible control of autoimmune diseases.
β-adrenoreceptor blocking and antihypertensive activity of PP-24, a newly synthesized aryloxypropanolamine derivative
Authors: Nikam Aniket P , Bodhankar Subhash L , Piplani Poonam , Bansal Jyotika , Thakurdesai Prasad A
Published: October 2010

PP-24 is a newly synthesized putative β-adrenoceptor antagonist. The objective of the study was to the evaluate β-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg−1) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 μg kg−1) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 μg kg−1). The pA2 of PP-24 to β1-, β2- and β3-adrenoceptors was 7.72 ± 0.082, 7.40 ± 0.082 and 6.39 ± 0.16, respectively. The β1/β2 selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses β-adrenoceptor blockade activity but with non-specific affinity for β1- and β2-adrenoceptor subtypes. The rank order of potency of the antagonists for β1-adrenoceptors was atenolol > PP-24 > propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of β-adrenoceptors.
Therapeutic efficacy of Kangen-karyu against H2O2-induced premature senescence
Authors: Cho Eun Ju , Okamoto Takuya , Yokozawa Takako
Published: October 2010

The anti-aging potential of Kangen-karyu extract was investigated using the mechanisms of the cellular aging model of stress-induced premature senescence (SIPS) in TIG-1 human fibroblasts. SIPS was induced by a sublethal dose of H2O2 and chronic oxidative stress with repeat treatment of low-dose H2O2. Reactive oxygen species generation, lipid peroxidation, and senescence-associated β-galactosidase activity were elevated in TIG-1 cells under SIPS induced by H2O2. However, Kangen-karyu extract led to significant declines in these parameters, suggesting its role in ameliorating oxidative stress-related aging. It was also observed that SIPS due to H2O2 treatment led to the loss of cell viability, whereas Kangen-karyu extract improved cell viability by attenuating H2O2-induced oxidative damage. TIG-1 cells under the condition of SIPS caused by sublethal and chronic low doses of H2O2 showed nuclear factor-κB (NF-κB) translocation to the nucleus from the cytosol, while Kangen-karyu extract inhibited NF-κB nuclear translocation, implying that Kangen-karyu extract could exert an anti-aging effect through NF-κB modulation. In addition, treatment with Kangen-karyu extract under H2O2-induced chronic oxidative stress normalized the cell cycle by reducing the number of cells in the G0/G1 phase and elevating the proportion of those in the S phase, indicating the role of Kangen-karyu extract in cell cycle regulation. On the other hand, Kangen-karyu extract did not exert such an effect on cell cycle regulation under acute oxidative stress induced by sublethal H2O2. Furthermore, treatment with Kangen-karyu extract prolonged the lifespan of TIG-1 cells under SIPS. The present study suggests that Kangen-karyu might play a therapeutic role against the aging process caused by oxidative stress.
Physicochemical interactions between drugs and superdisintegrants
Authors: Fransén Nelly , Morin Malin , Björk Erik , Edsman Katarina
Published: October 2010

We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in-vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in-vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non-ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in-vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in-vivo bioavailability of any of the drug molecules.
Salbutamol relative lung and systemic bioavailability of large and small spacers
Authors: Mazhar Syed H R A , Chrystyn Henry
Published: October 2010

Differences between the size and shape of spacers may affect the emitted dose and provide different effects when interchanged during routine use. Using a urinary pharmacokinetic method we have measured the relative lung and systemic bioavailability from urinary salbutamol excretion 30 min (USAL0.5) and 24 h (USAL24), respectively, after the inhalation of two 100-μg doses from a Ventolin Evohaler when used alone (MDI) and when attached to the Volumatic (VOL) or the Aerochamber Plus (AERO) spacers. The in-vitro properties of the emitted dose were determined. The mean (s.d.) USAL0.5 values following MDI, VOL and AERO (n = 13 volunteers) were 5.7 (1.9), 16.4 (8.2) and 14.8 (7.4) μg, respectively. VOL and AERO were significantly greater (P < 0.001 and < 0.01, respectively) than MDI. Comparison of VOL and AERO was similar with a mean ratio (90% confidence interval) of 108.2 (84.5, 138.6)%. USAL24 values between the three inhalation methods were similar. The values for the mean (s.d.) fine particle dose of two 100-μg doses emitted from MDI, VOL and AERO were 83.0 (6.8), 83.6 (4.6) and 73.6 (2.9) μg and the mass median aerodynamic diameters were 2.7 (0.03), 2.8 (0.07) and 2.9 (0.10) μm, respectively. The results showed that during routine use the Volumatic and the Aerochamber Plus spacers should provide similar lung and systemic delivery when attached to a Ventolin Evohaler.
An investigation into the influence of binary drug solutions upon diffusion and partition processes in model membranes
Authors: Fiala Sarah , Brown Marc B , Jones Stuart A
Published: October 2010

Few studies have assessed the impact of binary systems on the fundamental mathematical models that describe drug permeation. The aim of this work was to determine the influence of varying the proportions of prilocaine and lidocaine in a binary saturated solution on mass transfer across synthetic membranes. Infinite-dose permeation studies were performed using Franz diffusion cells with either regenerated cellulose or silicone membranes, and partition coefficients were determined by drug loss over 24 h. There was a linear relationship between the flux of prilocaine and lidocaine through regenerated cellulose membrane (R2 ≥ 0.985, n = 5) and their normalised ratio in solution. This linear model was also applicable for the permeation of prilocaine through silicone membrane (R2 = 0.991, n = 5), as its partition coefficient was independent of the drug ratio (15.84 ± 1.41). However, the partition coefficient of lidocaine increased from 27.22 ± 1.68 to 47.03 ± 3.32 as the ratio of prilocaine increased and this resulted in a non-linear relationship between permeation and drug ratio. Irrespective of the membrane used, the permeation of one drug from a binary system was hindered by the presence of the second, which could be attributed to a reduction in available membrane diffusion volume.
Effects of intestinal constituents and lipids on intestinal formation and pharmacokinetics of desethylamiodarone formed from amiodarone
Authors: Shayeganpour Anooshirvan , Hamdy Dalia A , Brocks Dion R
Published: October 2010

To model the impact of intestinal components associated with a high fat meal on metabolism of amiodarone, rat everted intestinal sacs were evaluated for their ability to metabolize the drug to its active metabolite (desethylamiodarone) under a variety of conditions. The preparations were obtained from fasted rats or rats pretreated with 1% cholesterol in peanut oil. After isolation of the tissues, the intestinal segments were immersed in oxygenated Krebs Henseleit buffer containing varying concentrations of bile salts, cholesterol, lecithin and lipase with or without soybean oil emulsion as a source of triglycerides. Amiodarone uptake was similar between the five 10-cm segments isolated distally from the stomach. Desethylamiodarone was measurable in all segments. Based on the metabolite-to-drug concentration ratio within the tissues, there was little difference in metabolic efficiency between segments for any of the treatments. Between treatments, however, it appeared that the lowest level of metabolism was noted in rats pretreated with 1% cholesterol in peanut oil. This reduction in metabolic efficiency was not observed in gut sacs from the fasted rats to which soybean oil emulsion was directly added to the incubation media. Despite the apparent reduction in intestinal metabolism, there was no apparent change in the ratio of metabolite-to-drug area under the plasma concentration versus time ratios of fasted rats and those given 1% cholesterol in peanut oil, suggesting that the intestinal presystemic formation of desethylamiodarone is not substantial.
Repeated injection of pegylated liposomal antitumour drugs induces the disappearance of the rapid distribution phase
Authors: Cui JingXia , Li ChunLei , Wang CaiXia , Li YanHui , Zhang Lan , Zhang Li , Yang HaiYan
Published: October 2010

Upon repeated administration, empty pegylated liposomes lose their long-circulating characteristics, referred to as the accelerated blood clearance (ABC) phenomenon. To investigate whether cytotoxic drug-containing pegylated liposomes could also elicit a similar phenomenon, two pegylated liposomal antitumour drugs (doxorubicin and mitoxantrone) were prepared, and they were administrated twice in the same animals with a 10-day interval at a dose level of 8 mg kg−1 (pegylated liposomal doxorubicin) and 4 mg kg−1 (pegylated liposomal mitoxantrone). By comparing the overall pharmacokinetics after a single-dose injection with that in animals treated with two doses, it was surprising to find that repeated administration of pegylated liposomal antitumour drugs caused the disappearance of rapid distribution phase instead of the ABC phenomenon, resulting in the conversion of a two-compartment model to a one-compartment model. Further investigation revealed that repeated injection induced the decreased uptake of liposomal antitumour drugs by the spleen at the early time point of 0.5–8 h after injection. In contrast, the deposition of liposomal antitumour drugs into liver was not affected. Therefore, the disappearance of the rapid distribution phase might be related to the reduced spleen uptake at the early time point.
Elevated leptin expression in a rat model of fracture and traumatic brain injury
Authors: Wei Yongzhong , Wang Lei , Clark Jonathan C M , Dass Crispin R , Choong Peter F M
Published: October 2010

A few studies have reported a relationship between leptin induced by brain injury and healing of bone tissue. Our objective was to measure serum and callus leptin expression within the setting of fracture and traumatic brain injury (TBI). Sixty-four male Sprague-Dawley rats were randomised equally into four groups: control, TBI group, fracture group and fracture/TBI group. Rats were sacrificed at 2, 4, 8 and 12 weeks after fracture/TBI. Serum leptin was detected using radio-immunoassay, and callus formation was measured radiologically. Callus leptin was analysed with immunohistochemistry. Serum leptin was significantly increased in the fracture, TBI and combined fracture/TBI groups compared with the control group at 2 weeks (P < 0.05). Serum leptin was significantly higher in the combined fracture/TBI group than in the fracture and TBI groups at 4 and 8 weeks (P < 0.05). The percentage of leptin-positive cells in the callus and callus volume were significantly higher in the fracture/TBI group than in the fracture-only group (P < 0.001). Thus, we demonstrated elevated leptin expression within healing bone, particularly in the first 8 weeks of a rat model combining fracture and TBI. A close association exists between leptin levels and the degree of callus formation in fractures.
Total triterpene acids, active ingredients from Fructus Corni, attenuate diabetic cardiomyopathy by normalizing ET pathway and expression of FKBP12.6 and SERCA2a in streptozotocin-rats
Authors: Qi Min-You , Liu Hao-Ran , Dai De-Zai , Li Na , Dai Yin
Published: October 2010

Total triterpene acids (TTAs) isolated from Cornus officinalis Sieb., one of the herbs contained in Liuwei Dihuang decoction, were aimed at alleviating diabetic cardiomyopathy. We hypothesized that the benefits of TTAs may result from suppressing the endothelin-reactive oxidative species (ET-ROS) pathway in the myocardium. Diabetes was produced by a single injection of streptozotocin (STZ, 60 mg kg−1, i.p.) in rats. Assessment of cardiac function, calcium handling proteins, endothelin-1 (ET-1) and redox system was conducted 8 weeks after STZ injection. Medication with TTAs (50 mg kg−1, i.g.) was installed in the last 4 weeks. The compromised cardiac function was characterized by depressed contractility (LVSP and LV+dp/dtmax) and relaxation (LVEDP and -LVdp/dtmin) in association with hyperglycaemia (30.2 ± 2.6 mmol L−1) in STZ-injected rats. Down-regulated expression of FKBP12.6 (calstabin 2), sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and phospholamban (PLB) were also found. These changes occurred in connection with an increased ET-1, up-regulated mRNA of propreET-1 and endothelin converting enzyme (ECE), and a state of oxidant stress was found by increased malondialdehyde (MDA), decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity, and an enhanced activity and expression of inducible nitric oxide synthase (iNOS) in the diabetic myocardium. After 4 weeks of treatment with TTAs, these changes were alleviated dramatically despite a mild reduction in hyperglycaemia (26.9 ± 3.4 mmol L−1). In conclusion, TTAs, as active ingredients of Liuwei Dihuang decoction, alleviated diabetic cardiomyopathy by normalizing the abnormality of FKBP12.6 and SERCA2a and ET-ROS pathway in the myocardium rather than by hypoglycaemic activity.
Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism
Authors: Yang Kyung H , Choi Young H , Lee Unji , Lee Joo H , Lee Myung G
Published: October 2010

Objectives

It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats.

Method

Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers –3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats – and inhibitors – SKF-525A (a nonspecific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats.

Key findings

The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2.

Conclusions

These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug–drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).
Review: doxorubicin delivery systems based on chitosan for cancer therapy
Authors: Tan Mei Lin , Choong Peter F M , Dass Crispin R
Published: October 2010

Objectives

This review sheds insight into an increasingly popular polymer that has been widely explored as a potential drug delivery system. The abundant, biodegradable and biocompatible polysaccharide chitosan, with many other favourable properties, has been favoured as a drug delivery system for the purposes of encapsulating and delivery of doxorubicin with reduced side-effects.

Key findings

Doxorubicin is frequently used as a frontline chemotherapeutic agent against a variety of cancers. It has largely been able to demonstrate anti-tumour effects, though there are major shortfalls of doxorubicin, which include serious side-effects such as cardiomyopathy and myelosuppression, and also an ever-present danger of extravasation during drug administration. In view of this, drug delivery systems are currently being explored as alternative methods of drug delivery in a bid to more effectively direct doxorubicin to the specific lesion site and reduce its systemic side-effects. Liposomes and dendrimers have been tested as potential carriers for doxorubicin; however they are not the focus of this review.

Recent advancements in doxorubicin and chitosan technology have shown some preliminary though promising results for cancer therapy.
Novel mucoadhesive nasal inserts based on chitosan/hyaluronate polyelectrolyte complexes for peptide and protein delivery
Authors: Luppi Barbara , Bigucci Federica , Mercolini Laura , Musenga Alessandro , Sorrenti Milena , Catenacci Laura , Zecchi Vittorio
Published: October 2010

Objectives

The purpose of this study was the preparation and characterisation of mucoadhesive nasal inserts based on chitosan/hyaluronate polyelectrolyte complexes prepared at various pHs and at different molar ratios.

Methods

A suspension of chitosan/hyaluronate complexes with or without the model drugs (vancomycin or insulin) was lyophilised into small inserts. Complexation yield, FT-IR spectra and thermogravimetric analysis were used to study the degree of interactive strength between polyions. In-vitro swelling, mucoadhesion and release tests were performed in order to investigate delivery of vancomycin and insulin in the nasal cavity.

Key findings

The results indicated that the selection of complex preparative conditions allows modulation of insert swelling and mucoadhesion ability. Nasal inserts containing vancomycin or insulin had showed completely different drug release behaviour.

Conclusions

Chitosan/hyaluronate polyelectrolyte complexes can be used for the formulation of mucoadhesive nasal inserts for the delivery of peptide and protein drugs.
Anti-African trypanocidal and antimalarial activity of natural flavonoids, dibenzoylmethanes and synthetic analogues
Authors: dos Santos Djalma A P , Braga Patricia A de C , da Silva M Fátima das G F , Fernandes João B , Vieira Paulo C , Magalhães Aderbal F , Magalhães Eva G , Marsaioli Anita J , Moraes Valéria R de S , Rattray Lauren , Croft Simon L
Published: October 2010

Objectives

The known anti-protozoal activity of flavonoids has stimulated the testing of other derivatives from natural and synthetic sources.

Methods

As part of our efforts to find potential lead compounds, a number of flavonoids isolated from Neoraputia paraensis, N. magnifica, Murraya paniculata, (Rutaceae), Lonchocarpus montanus, L. latifolius, L. subglaucescens, L. atropurpureus, L. campestris, Deguelia hatschbachii (Leguminosae), dibenzoylmethanes from L. subglaucescens and synthetic analogues were tested for in-vitro activity against chloroquine-sensitive Plasmodium falciparum and Trypanosoma brucei rhodesiense bloodstream form trypomastigotes. An assay withKB cells has been developed inorder tocompare in-vitro cytotoxicityof flavonoids with a selective action on the parasites.

Key findings

Thirteen of the compounds tested had IC50 values ranging from 4.6 to 9.9 μM against T. brucei rhodesiense. In contrast, a small number of compounds showed significant activity against P. falciparum; seven of those tested had IC50 values ranging from 2.7 to 9.5 μM. Among the flavones only one had IC50 < 10 μM (7.6 μM), whereas against T. brucei rhodesiense seven had IC50 < 10 μM. Synthetic dibenzoylmethanes were the most active in terms of number (five) of compounds and the IC50 values (2.7–9.5 μM) against P. falciparum.

Conclusions

Dibenzoylmethanes represent a novel class of compounds tested for the first time as antimalarial and trypanocidal agents.
Galactose-grafted chylomicron-mimicking emulsion: evaluation of specificity against HepG-2 and MCF-7 cell lines
Authors: Jain Vikas , Nath Banashree , Gupta Girish K , Shah Parag P , Siddiqui Maqsood A , Pant Aditya B , Mishra Prabhat R
Published: October 2010

Objectives

A chylomicron-mimicking lipid emulsion was prepared and loaded with paclitaxel (paclitaxel-CM) and was further grafted with galactose (paclitaxel-GCM) using palmitoyl-galactosamine, which was synthesized by reacting galactosamine hydrochloride with N-hydroxy succinimide ester of palmitic acid. Palmitoyl-galactosamine was used as a ligand for asialoglycoprotein receptors.

Methods

The uptake characteristics of the emulsions were evaluated in HepG-2 cells (human hepatocarcinaoma), which express asialoglycoprotein receptors, and MCF-7 (breast cancer) cells, which are devoid of these receptors.

Key findings

The incorporation efficiency of paclitaxel-CM was 68.05 ± 4.80% and that of paclitaxel-GCM was 72.10 ± 3.93% when the emulsion was prepared with 7.5% (w/w) paclitaxel/lipid phase. The globule size of paclitaxel-GCM and paclitaxel-CM was 124 ± 8.67 and 96.45 ± 5.78 nm, respectively. The release of paclitaxel from both of the formulations was fairly sustained: 50 ± 3.2% of paclitaxel in 24 h. The cytotoxicity and uptake of paclitaxel-GCM were significantly higher (P < 0.05) in HepG-2 cells than MCF-7 cells, while for paclitaxel-CM cytotoxicity and uptake were similar in the two cell lines. This study clearly demonstrates that upon surface modification palmitoyl-galactosamine remains an integral part of the formulation. Paclitaxel solubility can be improved using optimum paclitaxel/lipid phase ratios. The paclitaxel-GCM formulation recognizes asialoglycoprotein receptors over-expressed on HepG-2 cells.

Conclusions

Under our experimental conditions, the proposed paclitaxel-GCM formulation is an ideal delivery vehicle for specific targeting to liver cancer cells, which is anticipated to result in improved efficacy and reduced toxicity to normal cells.
Ginsenoside Rg3 promotes beta-amyloid peptide degradation by enhancing gene expression of neprilysin
Authors: Yang Lingling , Hao Jianrong , Zhang Jing , Xia Wenjun , Dong Xifeng , Hu Xiaoyan , Kong Feng , Cui Xing
Published: October 2010

Objectives

It has been hypothesized that the accumulation of beta-amyloid peptide (Aβ) in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease. The steady-state levels of Aβ are determined by the metabolic balance between anabolic and catabolic activity and the dysregulation of this activity leads to Alzheimer's disease. Recent evidence has shown that neprilysin (NEP) is the rate-limiting enzyme in the Aβ degradation in the brain. Ginseng, the root of Panax ginseng C.A. Meyer, is widely used as a tonic for the prevention and treatment of age-related disorders in China. We aimed to investigate the basis of this use.

Methods

In this study, we investigated the effect of ginsenoside Rg3, one of the major active components of ginseng, on the metabolism of Aβ40 and Aβ42 in SK-N-SH cells transfected with Swedish mutant β-amyloid precursor protein (SweAPP).

Results

The ELISA result showed that Rg3 significantly reduced the levels of Aβ40 and Aβ42, 19.65 ± 6.05%, 23.61 ± 6.74%, respectively (P < 0.01). The Western blot analysis showed that Rg3 reduced the levels of Aβ40 and Aβ42 through enhancing NEP gene expression, and real-time PCR assay showed that 50 μM Rg3 could significantly enhance NEP gene expression (2.9 fold at 48 h).

Conclusions

Our findings suggest that the Rg3 compound of ginseng may be useful for treating patients suffering with Alzheimer's disease.
Effects of anticancer agents and scavengers on CMV-promoter-driven exogenous gene expression in genetically modified cells
Authors: Kinoshita Atsushi , Kobayashi Daisuke , Saitoh Yukiya , Komada Fusao
Published: October 2010

Objectives

This study aimed to investigate whether the levels of rsGFP mRNA and the fluorescence levels of cytomegalovirus (CMV)-promoter-driven rsGFP (red-shifted green fluorescent protein) could be changed by using anticancer agents and also to examine the effects of co-treatment with anticancer agents and scavengers.

Methods

The pQBI25 vector, which encodes the CMV promoter and the cDNA for rsGFP, was transfected into FR cells (rat skin fibroblast cell line). FR-pQBI25 cells were then exposed to doxorubicin, 5-fluorouracil, methotrexate or paraquat with or without scavengers such as N-acetyl cysteine (NAC) and edaravone for 48 h.

Key findings

The levels of rsGFP mRNA were found to be significantly higher following doxorubicin, 5-fluorouracil and paraquat treatment but were not changed by methotrexate. These levels of rsGFP mRNA were found to be significantly lower after paraquat/edaravone co-treatment compared with paraquat alone. The fluorescence levels of rsGFP were found to be significantly higher following doxorubicin and paraquat treatment but were not changed by 5-fluorouracil and methotrexate. The levels were also found to be significantly lower after paraquat/edaravone co-treatment compared with paraquat alone and also after doxorubicin/NAC co-treatment compared with doxorubicin alone.

Conclusions

These findings suggest that CMV-promoter-driven exogenous gene expression may be partly regulated by reactive oxygen species.
Metabolism of two new benzodiazepine-type anti-leishmanial agents in rat hepatocytes and hepatic microsomes and their interaction with glutathione in macrophages
Authors: Thi M Dao Duong , Grant M Helen , Mullen Alexander B , Tettey Justice N A , MacKay Simon P , Clark Rachel L
Published: October 2010

Objectives

To measure the metabolism and toxicity of 7-chloro-4-(cyclohexylmethyl)-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (BNZ-1) and 4-cyclohexylmethyl-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (BNZ-2), two new benzodiazepine analogues found to be effective against Leishmania amastigotes in vitro.

Methods

The metabolism of BNZ-1 and -2 was investigated in isolated rat hepatocytes and rat liver microsomes. The toxicity of the compounds was assessed in a murine macrophage cell line by determining cell viability and reduced glutathione (GSH) content. The metabolism and toxicity of flurazepam was assessed for comparison.

Key findings

BNZ-1 and BNZ-2 underwent similar metabolic transformations by the liver systems, forming N-demethylated and hydroxylated metabolites, with subsequent O-glucuronidation. Flurazepam and both analogue compounds depleted macrophage GSH levels without affecting cell viability at the concentrations used (up to 100 μM), but only flurazepam inhibited glutathione reductase activity, indicating that it is acting by a different mechanism.

Conclusions

The exact mechanism responsible for GSH depletion is unknown at present. Further experiments are needed to fully understand the effects of BNZs on the parasite GSH analogue, trypanothione, which may be a direct or indirect target for these agents. Pharmacokinetic evaluation of these compounds is required to further progress their development as potential new treatments for leishmaniasis.
The sacred lotus (Nelumbo nucifera)– phytochemical and therapeutic profile
Authors: Mukherjee Pulok K , Mukherjee Debajyoti , Maji Amal K , Rai S , Heinrich Michael
Published: October 2010

Objectives

Nelumbo nucifera Gaertn. (Nymphaeaceae), also known as sacred lotus, is a well known medicinal plant. This article reviews the traditional uses, phytochemistry and therapeutic reports on different parts of N. nucifera viz. the seeds, rhizomes, leaves and flowers. This review also describes various compounds isolated from different parts of this plant and the therapeutic benefits derived from those phytoconstituents.

Key findings

There are several therapeutic benefits of this plant for which different parts are used. The extracts of rhizomes, seeds, flowers and leaves have been reported to have varied therapeutic potential. Several bioactive compounds have been derived from these plant parts belonging to different chemical groups, including alkaloids, flavonoids, glycosides, triterpenoid, vitamins etc., which all have their own therapeutic impact. Thus, the pharmacological effects and various active ingredients of different parts of N. nucifera are well understood.

In this review we explore the current pharmaceutical, phytochemical and pharmacological knowledge about this well known plant species as well as several emerging aspects for research on N. nucifera.
A study on the effect of inorganic salts in transungual drug delivery of terbinafine
Authors: Nair Anroop B , Sammeta Srinivasa M , Vaka Siva Ram K , Murthy S Narasimha
Published: October 2010

Objectives

The poor success rate of topical therapy in nail disorders is mainly because of the low permeability of keratinized nail plates. This can be overcome by utilizing potent perungual drug penetration enhancers that facilitate the drug permeation across the nail plate. This study evaluated the efficacy of inorganic salts in enhancing the trans-nail permeation using a model potent antifungal agent, terbinafine hydrochloride.

Methods

Permeation studies were carried out across human cadaver nail in a Franz diffusion cell using terbinafine solution (1 mg/ml; pH 3). Preliminary studies were carried out to assess the effect of salts (0.5 m) on the terbinafine permeation into and through the nail. Further, the influence of salt concentration (0.25–3 m) on permeation, the mechanism for the enhancement and the suitability of developing a formulation were also studied.

Key findings

Terbinafine permeation (3–5 fold) through the nail and drug load (4–7 fold) in the nail were enhanced significantly when salts were used at 0.5 m concentration. Increase in salt concentration up to 1 m increased the permeation, which decreased with further increase in salt concentration (>1 m). Mechanistic studies revealed that the enhanced permeation by salts was mainly due to their ability to increase the nail hydration and also to increase the thermodynamic activity of the drug. The cumulative amount of terbinafine permeated at 24 h from the formulated gel (9.70 ± 0.93 μg/cm2) was comparable with that of a solution (11.45 ± 1.62 μg/cm2).

Conclusions

Given the promising results from the permeation and drug load studies, it was concluded that inorganic salts could be used as potent transungual permeation enhancers.
Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers
Authors: Soyinka Julius O , Onyeji Cyprian O , Omoruyi Sharon I , Owolabi Adegbenga R , Sarma Pullela V , Cook James M
Published: October 2010

Objectives

Nevirapine and quinine are likely to be administered concurrently in the treatment of patients with HIV and malaria. Both drugs are metabolised to a significant extent by cytochrome P450 (CYP)3A4 and nevirapine is also an inducer of this enzyme. This study therefore evaluated the effect of nevirapine on the pharmacokinetics of quinine.

Methods

Quinine (600 mg single dose) was administered either alone or with the 17th dose of nevirapine (200 mg every 12 h for 12 days) to 14 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analysed for quinine and its major metabolite, 3-hydroxquinine, using a validated HPLC method.

Key findings

Administration of quinine plus nevirapine resulted in significant decreases (P < 0.01) in the total area under the concentration–time curve (AUCT), maximum plasma concentration (Cmax) and terminal elimination half-life (T1/2β) of quinine compared with values with quinine dosing alone (AUC: 53.29 ± 4.01 vs 35.48 ± 2.01 h mg/l; Cmax: 2.83 ± 0.16 vs 1.81 ± 0.06 mg/l; T1/2β: 11.35 ± 0.72 vs 8.54 ± 0.76 h), while the oral plasma clearance markedly increased (11.32 ± 0.84 vs 16.97 ± 0.98 l/h). In the presence of nevirapine there was a pronounced increase in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant increases in Cmax and AUC of the metabolite (P < 0.01).

Conclusions

Nevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co-administered with nevirapine.
Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates
Authors: Sherwin Catherine M T , McCaffrey Frances , Broadbent Roland S , Reith David M , Medlicott Natalie J
Published: October 2010

Objectives

This study aimed to investigate intravenous infusions as used in the neonatal intensive care setting, to determine the effect of gentamicin dose (mg), gentamicin concentrations (mg/ml), flow rate (ml/h) and flush volume (ml) upon the length of infusion time.

Methods

Intravenous infusions were set up to simulate administration of gentamicin to neonates. Dextrose (10%, w/v) was administered as the primary intravenous fluid at 3.8 or 18.7 ml/h. Gentamicin doses (0.5 mg/0.2 ml, 2 mg/0.2 ml, 2.5 mg/1.0 ml, or 10 mg/1.0 ml) were delivered into the intravenous line at a T-connection using a Graseby pump over 35 min. This was followed by a saline flush of 1 or 2 ml over a further 35 min. At the end of each experiment a 2 ml 0.9% saline bolus was given. Analysis of gentamicin collected at 5-min intervals was by an HPLC method.

Key findings

The experiment demonstrated that under the infusion conditions neonates weighing 2.5 kg would receive only 80% of the drug at 60 min, increasing to 90–95% by 75 min. In extremely low birth weight neonates (0.5 kg), even lower percentage of gentamicin recovery occurred. At 60 min only 60% of the intended gentamicin dose had been delivered and this increased to only 70% by 75 min.

Conclusions

The delivery of gentamicin administered by intravenous infusion is substantially extended in extremely low birth weight neonates. This appeared to be primarily due to the small volumes and low infusion rates used in these patients.
Antiplatelet effects of piplartine, an alkamide isolated fromPiper tuberculatum: possible involvement of cyclooxygenase blockade and antioxidant activity
Authors: Fontenele Juvenia B , Leal L Kalyne A M , Silveira Edilberto R , Felix F Helder , Felipe Cícero F Bezerra , Viana Glauce S B
Published: October 2010

Objectives

Piplartine (piperlongumine; 5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl]-2(1H) pyridinone) is an alkaloid amide isolated from Piper species (Piperaceae). It has been reported to show multiple pharmacological activities in vitro and in vivo.

Methods

We evaluated the in-vitro antiplatelet effect of piplartine isolated from the roots of P. tuberculatum, on human platelet aggregation induced in platelet-rich plasma by the agonists collagen, adenosine 5′-diphosphate (ADP), arachidonic acid (AA) and thrombin.

Key findings

Piplartine (100μg/ml) caused a 30% inhibition in platelet aggregation when collagen was the agonist. At 200 μg/ml, piplartine significantly inhibited the aggregation induced by arachidonic acid (100%), collagen (59%) or ADP (52%) but not that induced by thrombin. The highest concentration of piplartine (300 μg/ml) inhibited thrombin- (37%), ADP- (71%) and collagen- (98%) induced aggregation. The inhibitory effect of piplartine on ADP-induced platelet aggregation was not modified by pretreatment with pentoxifylline (a phosphodiesterase inhibitor), l-arginine (a substrate for nitric oxide synthase) or ticlopidine (a P2Y12 purinoceptor antagonist). However, aspirin, a well-known inhibitor of cyclooxygenase, greatly increased the inhibitory effect of piplartine on arachidonic-acid-induced platelet aggregation.

Conclusions

The mechanism underlying the piplartine antiplatelet action is not totally clarified. It could be related to the inhibition of cyclooxgenase activity and a decrease in thromboxane A2 formation, similar to that occurring with aspirin. This and other possible mechanisms require further study.
RT-PCR analysis of ABC, SLC and SLCO drug transporters in human lung epithelial cell models
Authors: Endter Sibylle , Francombe Danielle , Ehrhardt Carsten , Gumbleton Mark
Published: October 2010

Objectives

Carrier-mediated transport mechanisms play crucial roles in drug absorption and elimination processes, as well as in the transport of endogenous molecules affecting cellular regulation and function. In this study we used RT-PCR analysis to characterise the mRNA transcript expression of a wide range of membrane carrier transporters in several in-vitro lung epithelial cell models. Transporters studied included: 11 ATP-binding cassette (ABC) transporters, 11 solute carrier (SLC) transporters and 9 solute carrier organic anion (SLCO) transporters.

Methods

The cell culture models included both established cell lines (A549, Calu-3, 16HBE14o-, BEAS-2B) and freshly isolated lung epithelial cells in primary culture (human bronchial and alveolar epithelial cells).

Key findings

The expression profiles of several clinically relevant drug transporters were characterised using RT-PCR analysis. Our results showed differential transporter expression in cell culture models from different regions of the lung and also highlighted disparities when comparing lung cell lines with primary cell culture models. Differences in transporter expression between cell models of pulmonary and gastrointestinal origin were also noted.

Conclusions

The information will guide and validate the use of in-vitro lung epithelial cell lines in the study of pulmonary administered drugs and candidate molecules.
Specific aminopeptidases of excised human nasal epithelium and primary culture: a comparison of functional characteristics and gene transcripts expression
Authors: Agu Remigius U , Obimah Dominic U , Lyzenga Wendy J , Jorissen Mark , Massoud Emad , Verbeke Norbert
Published: October 2010

Objectives

To investigate whether growing human nasal epithelium as primary cultures alters aminopeptidase B (APB), aminopeptidase N (APN) and dipeptidyldipeptidase (DPPIV) metabolic characteristics, and mRNA gene transcript expression.

Methods

The formation of 7-amino-methyl coumarin from specific substrates for APN (l-alanine-4-methyl-coumaryl-7-amide, APB (l-arginine-4-methyl-coumaryl-7-amide) and DPPIV (glycyl-l-proline-4-methyl-coumaryl-7-amide) was used to estimate the Km, Vmax and the effect of aminopeptidases inhibitors on the enzymes. Polymerase chain reaction was used to investigate gene expression.

Key findings

Results of this study showed that: (1) both the excised tissues and primary cultures of human nasal epithelium expressed APN, APB and DPPIV activity; (2) the Km of APB, APN and DPPIV was not significantly different in cell and tissue homogenates; (3) except for APN, the Vmax was not significantly different in the two metabolism models; (4) there was no statistically significant difference in the behaviours of APB, APN and DPPIV in response to inhibition by puromycin and bestatin in the two models; (5) the mRNA transcripts that encode APB, APN and DPPIV were expressed in both cell culture and tissue homogenate.

Conclusions

Based on the results of this study, it may be concluded that nasal primary culture system is suitable for investigating peptide and protein metabolism and enzymatic stability in human nasal epithelium. Except for APN, the tissue culture conditions did not significantly alter the functional and molecular expression of the aminopeptidases.