Search

Response surface methodology (RSM) was used to develop and optimize the mesomorphic phase formulation for a meloxicam transdermal dosage form. A mixture design was applied to prepare formulations which consisted of three independent variables including oleic acid (X(1)), distilled water (X(2)) and ethanol (X(3)). The flux and lag time (LT) were selected as dependent variables. The result showed that using mesomorphic phases as vehicles can significantly increase flux and shorten LT of drug. The analysis of variance showed that the permeation parameters of meloxicam from formulations were significantly influenced by the independent variables and their interactions. The X(3) (ethanol) had the greatest potential influence on the flux and LT, followed by X(1) and X(2). A new formulation was prepared according to the independent levels provided by RSM. The observed responses were in close agreement with the predicted values, demonstrating that RSM could be successfully used to optimize mesomorphic phase formulations.

The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of (+)-catechin could be improved by utilizing elastic liposomes. Liposomes containing soy phosphatidylcholine, cholesterol, and Tween 80 in the presence of 15% ethanol were prepared by a thin-film method and subsequent sonication and extrusion. The size, zeta potential, and stability of the liposomes in simulated gastrointestinal (GI) media were characterized. The mean size of liposomes was 35-70 nm, which decreased with an increase in the Tween 80 concentration. The zeta potential of the system was about-15 mV. More than 80% of the (+)-catechin was entrapped in the aqueous core of liposomes produced with 1% Tween 80. Liposomes entrapping (+)-catechin remained stable in the presence of GI fluids, especially in simulated intestinal fluid. The liposomes showed suppressed and sustained release of (+)-catechin compared with that from an aqueous solution. The aqueous control and liposomes were orally administered to rats. The blood level of liposomal (+)-catechin was enhanced at a later stage after administration compared with the free control. In the experiment on the brain distribution, liposomes with elastic properties showed 2.9- and 2.7-fold higher (+)-catechin accumulations compared with the aqueous solution in the cerebral cortex and hippocampus, respectively. Greater compound accumulations with liposomes were also detected in the striatum and thalamus. The experimental results suggest that elastic liposomes may offer a promising strategy for improving (+)-catechin delivery via oral ingestion.

The objective of this work was to develop a safe and effective delivery vehicle for topical treatment of gemcitabine. The physicochemical properties, drug release rate, drug level in plasma and bladder, and histological changes of tissue after drug administration were investigated. The electrical conductivity, mean size, and viscosity of drug-loaded microemulsions were 0.8—102.0 μS/cm, 116.8—322.5 nm, and 42.9—105.0 cps×103, respectively. Gemcitabine loaded microemulsions showed a slower and sustained release. After intravesical administration of aqueous control and microemulsions treated, the drug concentrations in plasma were 15.11 μg/ml and 2.81—12.82 μg/ml, respectively, and the accumulation in bladder were 18.27 μg and 9.12—64.16 μg, respectively. Microemulsions slightly decreased the systemic absorption and significantly enhanced the accumulation in bladder tissue. Moreover, the preliminary toxicity studies revealed no overt adverse histological changes or tissue irritation by the microemulsion application. Therefore, the microemulsions were suggested to be a promising drug carrier for intravesical chemotherapy.

Nicardipine hydrochloride has been used widely for the treatment of angina pectoris and hypertension. Because of its extensive first pass metabolism after oral administration, the transdermal administration of nicardipine microemulsions was developed in this study.Microemulsions consisted of isopropyl myristate (IPM), surfactant mixture of Tween 80/Span 80 and/or Tween 80/Span 20, co-surfactant (ethanol) and aqueous phase. Pseudo-ternary phase diagrams were constructed using water titration method. The effect of component of microemulsion on the percutaneous absorption of drug was evaluated by in vitro permeation study.The area of microemulsion isotropic region in the presence of ethanol was comparably larger in the absence of ethanol. The mean droplet size of nicardipine microemulsions ranged from 70 to 123 nm. With addition of ethanol, the droplet size became smaller. The permeation rate and extent of nicardipine microemulsion transport across rat skin was affected by the components of microemulsion. Nicardipine microemulsion had higher flux at surfactant mixture with lower hyrophile-lipophile balance (HLB) value and Tween content.The microemulsion consisted of 52% IPM, 35% surfactant mixture and 13% water had higher permeation rate through rat skin above 122.53 ± 1.87 μg/cm2/h and was expected to develop a transdermal delivery system.

Hesperetin is one of the flavonoids and possess anti-inflammatory, UV-protecting and antioxidant effects. Permeation issues for topical delivery systems of such effects are occasionally problematic, and in view of the fact that microemulsions are potential carriers for transdermal delivery system, the objective of this study was to design an optimal microemulsion formulation by in vitro permeation study for hesperetin topical dosage form and determine its topical photoprotective effect and skin irritation by in vivo study. The hesperetin-loaded microemulsion showed an enhanced in vitro permeation compared to the aqueous and isopropyl myristate (IPM) suspension dosage form of hesperetin. In comparison, the effect of co-surfactant on the drug permeation capacity, propylene glycol showed highest permeation rate, followed by ethanol, glycerol and polyethylene glycol (PEG 400). Sunscreen agent padimate O, as a transdermal enhancer could increase the permeation rate of hesperetin. In case of in vivo study, the hesperetin-loaded microemulsion showed significant topical whitening effect and diminished skin irritation when compared with the non-treatment group, indicating that the hesperetin microemulsion could be used as an effective whitening agent.

Topical photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an alternative therapy for many non-melanoma skin cancers. The major limitation of this therapy, however, is the low permeability of ALA through the stratum corneum (SC) of the skin. The objective of the present work was to characterize ethosomes containing ALA and to enhance the skin production of protoporphyrin IX (PpIX), compared to traditional liposomes. Results showed that the average particle sizes of the ethosomes were less than those of liposomes. Moreover, the entrapment efficiency of ALA in the ethosome formulations was 8-66% depending on the surfactant added. The particle size of the ethosomes was still approximately

The objective of this study was to prepare sodium nonivamide acetate (SNA) microemulsion for topical administration. Microemulsions consisted of a mixed surfactant of Tween 80 and Span 20 as surfactant, ethanol as cosurfactant, isopropyl myristate (IPM) as an oil phase and water as an external phase. The effect of composition of microemulsion including the ratio of oil phase/surfactant/aqueous phase, various cosurfactant and polymer on the character and permeability of microemulsion were evaluated. The mean droplet size of SNA microemulsions ranged from 64 to 208 nm. Microemulsions showed potent enhancement effect for SNA transdermal delivery by a 3.7-7.1-fold increase when compared with the control group. Microemulsion containing ethanol as cosurfactant had the highest enhancement effect. With incorporated polymer, the viscosity of microemulsions increased resulting in the decrease in penetration rate of SNA. However, the permeability of SNA delivered from microemulsion was higher than SNA from volatile vehicles (pH 4.2 buffer containing 25% ethanol) reported in an earlier study, therefore microemulsions could be an effective vehicle for topical delivery of SNA.

In this study, we compared the irritation inhibition of various types of anti-irritants such as antihistamines (cyprohetadine, diphenhydramine, and promethazine), alpha-hydroxy acids (gluconolactone and gluco-delta-lactone), corticosteroids (betamethasone and clobetasol), and ion channel modulating agents (amiloride, ethacrynic acid, nifedipine, and verapamil) on the adverse dermatological reaction caused by captopril gel using noninvasive bioengineering methods including measuring the transepidermal water loss (TEWL) and the color change of skin surface [such as change chroma (delta C) and difference in color (delta E) between the gel-treated site and the untreated site]. In addition, the influence of these anti-irritants on the penetration capacity of captopril through the rabbit skin was also investigated. The results showed that the TEWL, change chroma (delta C), and difference in color (delta E) of skin were significantly reduced via incorporating diphenhydramine and clobetasol, indicating that both substances had potent irritation inhibition activity. Moreover, these substances had no effect on the percutaneous absorption of captopril gel. However, flux of the captopril with anti-irritants was about 480 microg/cm2/h and the required minimum administration area to obtain the minimum effective concentration was about 15 cm2, indicating that this formulation could possibly be developed for a transdermal drug delivery system.

The purpose of this study was to develop and optimize the propranolol once-daily extended release formulations containing HPMC, Microcrystalline cellulose (MCC) and lactose. In vitro studies, the response surface methodology and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals. The constrained mixture experimental design was used to prepare systematic model formulations, which were composed of three formulation variables: the content of HPMC ( X 1 ), MCC ( X 2 ), and lactose ( X 3 ). The drug release percent at 1.5, 4, 8, 14 and 24 h were the target responses and were restricted to 15–30, 35–55, 55–75, 75–90 and 90–110%, respectively. The results showed that the optimized formulation provided a dissolution pattern equivalent to the predicted curve, which indicated that the optimal formulation could be obtained using response surface methodology. The mechanism of drug release from HMPC matrix tablets followed non-Fickian diffusion. In the vivo study, the MRT was prolonged for matrix tablets when compared with commercial immediate release tablets. Furthermore, a linear relationship between in vitro dissolution and in vivo absorption was observed in the beagle dogs.

Sodium nonivamide acetate (SNA) is a newly synthetic analogue of capsaicin which produces no overt pungent sensation or irritation. In this present study, the effects and roles of penetration enhancers for SNA through rat skin were investigated by in vitro skin penetration experiment and differential scanning calorimeter (DSC) determination. The penetration fluxes of SNA after the incorporation of enhancers increased in the order of Polysorbate 20sodium laurylsulfateor = benzalkonium chloride. This result was consistent with that of DSC profiles which indicated the disruptive effects of surfactants on the rat stratum corneum increased in the order of Polysorbate 20sodium laurylsulfatebenzalkonium chloride. The information gained is particularly helpful in the development of SNA transdermal drug delivery system.

Background: Zolpidem is a new hypnotic that is supposed to have fewer side effects than traditional benzodiazepines. Some psychotic reactions, such as visual or hypnagogic hallucinations, have been reported to be associated with zolpidem use. Case Report: A young female experienced three episodes of hallucination associated with the use of zolpidem. The visual or hypnagogic hallucination happened after she had stopped zolpidem and then restarted it 2 days later. Conclusion: We postulate that hypnagogic or visual hallucinations associated with zolpidem use may be related to rapid withdrawal and restarting of zolpidem. The possible mechanism may be associated with the changes in the GABAA receptor. Avoiding “as needed” use of zolpidem and using the lowest effective dose may prevent these adverse effects.

The water-insoluble polymer ethylcellulose is used as a retardant to prepare the sustained release of potassium chloride microspheres by drying in a liquid process. The effect of sustained release of potassium from ethylcellulose microspheres was evaluated by the in vitro dissolution test, and was compared to a commercial product (Slow-K). The results showed that ethylcellulose microspheres loaded with potassium chloride could be easily prepared and satisfactory results could be obtained considering size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-93 and 36%, respectively. However, the potassium/ethylcellulose 2/2 (30-45 mesh) microspheres showed the similar sustained release effect of commercial product.

The aim of the present work was to evaluate the effect of sustained release of potassium chloride semi-solid matrices prepared with different kinds and added amounts of Gelucires by the in vitro dissolution test and in vivo oral absorption study, and compared with a commercial product (slow-K). The results indicating that the release rates of potassium from experimental formulations were dependent on the type of semi-solid matrices (Gelucires). The higher the melting point of the Gelucires was incorporated, the slower release rate of the active substance was observed. Moreover, the values of similarity factor of Formulae F05 and F09 versus the reference in three kinds of dissolution medium ( f 2 ) were higher than 50, indicating that these experimental formulations had similar sustained release effects to the reference (slow-K) in dissolution test. In vivo study, the cumulative amount (mEq) of potassium excreted curve and the excretion rate curve of F05 and F09 were found to be similar to that of slow-K, and there were no significant differences ( P >0.05) in the maximum excretion rate and the mean time to reach the maximum rate between formulations and slow-K, indicating that the potassium chloride sustained release dosage form could be prepared using the Gelucires as lipid excipients.

The effects of antioxidants and chelating agent on the stability of captopril in aqueous and semisolid were determined in this study. Then the influence of the combination of additives including antioxidants, anti-irritants and penetration enhancer on stability, skin irritation and penetration capacity of captopril in semisolid dosage form was investigated. In the stability study, the degradation of captopril followed the first-order kinetic. The chelating agent EDTA showed a potent stability effect and obviously increased the shelf-life up to 14-fold that of control gel. The anti-irritants such as clobetasol and diphenhydramine had potent inhibition irritation activity and the effect was not retarded by the addition of EDTA. Moreover, the captopril gel containing penetration enhancer, anti-irritants and chelating agent had a higher penetration capacity and the minimum therapeutic concentration could be obtained by applying about 13.24 cm 2 of administered area, indicating that the formulation can possibly be developed for a transdermal drug delivery system.

A novel bilayer chitosan membrane was prepared by a combined wet/dry phase inversion method and evaluated as a wound dressing. This new type of bilayer chitosan wound dressing, consisting of a dense upper layer (skin layer) and a sponge-like lower layer (sublayer), is very suitable for use as a topical delivery of silver sulfadiazine (AgSD) for the control of wound infections. Physical characterization of the bilayer wound dressing showed that it has excellent oxygen permeability, that it controls the water vapor transmission rate, and that it promotes water uptake capability. AgSD dissolved from bilayer chitosan dressings to release silver and sulfadiazine. The release of sulfadiazine from the bilayer chitosan dressing displayed a burst release on the first day and then tapered off to a much slower release. However, the release of silver from the bilayer chitosan dressing displayed a slow release profile with a sustained increase of silver concentration. The cultures of Pseudomonas aeruginosa and Staphylococcus aureus in agar plates showed effective antimicrobial activity for 1 week. In vivo antibacterial tests confirmed that this wound dressing is effective for long-term inhibition of the growth of Pseudomonas aeruginosa and Staphylococcus aureus at an infected wound site. The results in this study indicate that the AgSD-incorporated bilayer chitosan wound dressing may be a material with potential antibacterial capability for the treatment of infected wounds.

The aim of this present study was to investigate the in vitro transdermal iontophoretic delivery of three diclofenac salts-diclofenac sodium (DFS), diclofenac potassium (DFP), and diclofenac diethylammonium (DFD). A series of physicochemical and electrical variables which might affect iontophoretic permeation of diclofenac salts was studied. Application of 0.3 mA/cm 2 current density significantly increased the transdermal flux of diclofenac salts as compared to passive transport. The iontophoretic enhancement increased in the order of DFS>DFP>DFD. The permeability coefficient of diclofenac salts all decreased with increasing donor concentration during iontophoresis. The addition of buffer ions and salt ions such as NaCI, KCI, and C 4 H 12 CIN reduced the permeation of diclofenac salts due to competition. However, this effect was lesser for DFD than for DFS and DFP. Comparing the various application modes of iontophoresis, the discontinuous on/off mode showed lower but more constant flux than the continuous mode.

The skin permeation of estradiol from various proniosome gel formulations across excised rat skin was investigated in vitro. The encapsulation efficiency and size of niosomal vesicles formed from proniosomes upon hydration were also characterized. The encapsulation (%) of proniosomes with Span surfactants showed a very high value of about 100%. Proniosomes with Span 40 and Span 60 increased the permeation of estradiol across skin. Both penetration enhancer effect of non-ionic surfactant and vesicle-skin interaction may contribute to the mechanisms for proniosomes to enhance estradiol permeation. Niosome suspension (diluted proniosomal formulations) and proniosome gel showed different behavior in modulating transdermal delivery of estradiol across skin. Presence or absence of cholesterol in the lipid bilayers of vesicles did not reveal difference in encapsulation and permeation of the associated estradiol. The types and contents of non-ionic surfactant in proniosomes are important factors affecting the efficiency of transdermal estradiol delivery.

The purpose of this investigation was to assess the pharmacokinetics (plasma concentration) and pharmacodynamics (heart rate, blood pressure (BP), and plasma renin activity (PRA)) of captopril experimental gel in normotensive rabbits and spontaneously hypertensive rats (SHRs) by reference to a short duration intravenous administration of the drug. In normotensive rabbits, the blood concentration versus time course of captopril after transdermal administration could be described well by a two-compartment model, and the maximum plasma concentration (5.68±2.05 μg ml −1 ) was achieved in about 7 h. The increase in plasma captopril concentration led to increases in PRA and reductions in BP. A simple E max model adequately described the relationship between the percentage change of mean blood pressure (MBP) and the blood concentration of the captopril. The maximum reduction in MBP ( E max ) was 36.23% and the concentration at half maximum effect (EC 50 ) was 0.24 μg ml −1 . The captopril was continuously released from the gel formulation and protected the SHRs in lower BP throughout the period of transdermal therapy. These results indicated that the development of captopril transdermal drug delivery system was possible. Further research was warranted on a modified formulation of captopril, which was optimized for transdermal delivery of the drug.

The objective of this study was to evaluate the influence of a rate-controlling membrane and adhesive on the in vitro permeation of nicotine. The physicochemical properties of the adhesive, including adhesion and rheology (viscosity), were also detected. Higher permeability of nicotine was observed through a hydrophilic membrane than through a hydrophobic membrane. Natural rubber and silicone were used as the adhesive bases, respectively. The silicone adhesive showed the highest adhesion among all adhesive formulations. To increase the adhesion of natural rubber, a tackifier (polyisoprene) and a secondary tackifier (terpene polymer; Px 1150) were incorporated into the formulations to achieve acceptable adhesion. The nicotine permeation through silicone adhesive and three natural rubber adhesives with the secondary tackifier (2%, 4%, and 6% Px 1150) was close to that from a commercially available patch (Habitrol), although the loading amount of nicotine was not the same. A longer lag time during the in vitro permeation study of nicotine was required for the adhesives prepared in our laboratory than for the commercially available patch.

The effect of clobetasol 17-propionate (CP), a potent corticosteroid, in various cream bases on the permeation through artificial membrane was sought. Four formulations were then chosen for a further in vivo skin blanching assay. After calculation of the relationship between in vivo flux0-8 hr determined from a surface recovery technique and in vitro release rate0-8 hr of CP from various formulations, a high correlation coefficient of 0.9996 was achieved. Therefore, the in vitro release study could be used as an index to predict and evaluate the in vivo penetration capacity of CP cream to screen the effective formulation preclinically. After a series of in vivo investigations in this study, it was concluded that myristic acid-added formulations may show a bioequivalence with commercial Dermovate. Furthermore, the flux calculated from the surface recovery technique and delta E detected from the skin blanching assay may be useful as parameters evaluating the quality and effectiveness of CP cream.

Chi-Te Huang,1 Ming-Jun Tsai,2,3 Yu-Hsuan Lin,1 Yaw-Sya Fu,4 Yaw-Bin Huang,5 Yi-Hung Tsai,5 Pao-Chu Wu11School of Pharmacy, Kaohsiung Medical University, Kaohsiung City, 2Department of Neurology, China Medical University Hospital, Taichung, 3School of Medicine, Medical College, China Medical University, Taichung, 4Faculty of Biomedical Science and Environmental Biology, 5Graduate Institute of Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung City, Taiwan, Republic of ChinaAbstract: The aim of this study was to evaluate the potential of microemulsions as a drug vehicle for transdermal delivery of citalopram. A computerized statistical technique of response surface methodology with mixture design was used to investigate and optimize the influence of the formulation compositions including a mixture of Brij 30/Brij 35 surfactants (at a ratio of 4:1, 20%–30%), isopropyl alcohol (20%–30%), and distilled water (40%–50%) on the properties of the drug-loaded microemulsions, including permeation rate (flux) and lag time. When microemulsions were used as a vehicle, the drug permeation rate increased significantly and the lag time shortened significantly when compared with the aqueous control of 40% isopropyl alcohol solution containing 3% citalopram, demonstrating that microemulsions are a promising vehicle for transdermal application. With regard to the pharmacokinetic parameters of citalopram, the flux required for the transdermal delivery system was about 1280 µg per hour. The microemulsions loaded with citalopram 3% and 10% showed respective flux rates of 179.6 µg/cm2 and 513.8 µg/cm2 per hour, indicating that the study formulation could provide effective therapeutic concentrations over a practical application area. The animal study showed that the optimized formulation (F15) containing 3% citalopram with an application area of 3.46 cm2 is able to reach a minimum effective therapeutic concentration with no erythematous reaction.Keywords: citalopram, microemulsion, transdermal delivery systems

A new, simple and precise method using ion-pair high-performance liquid chromatography was developed for the determination of piroxicam in ointment and plasma. A reversed-phase system was used, consisting of a 5-μm NOVA-PAK C18 column with acetunitrile-water (42:58 v/v) containing 0.01M tetrabutylammoniium phosphate and adjusted to pH 7.5 by phosphoric acid as the mobile phase. The flow rate was 0.8 ml/min and the effluent was monitored at 355 nm. The sensitivities of this method were 2 ng/ml levels of piroxicam in ointment and plasma samples using indomethacin as internal standard.

Background The launch of imatinib has turned chronic myeloid leukaemia (CML) into a chronic illness due to the dramatic improvement in survival. Several recent studies have demonstrated that poor adherence to imatinib may hamper the therapeutic outcomes and result in increased medical expenditures, whilst research on exploring the reasons for non-adherence to imatinib is still limited. Objective This study aimed to explore the experience of patients as they journey through their CML treatments and associated imatinib utilisation in order to understand the perceptions, attitudes and concerns that may influence adherence to imatinib treatment. Setting This study was conducted at oncology outpatient clinics in a medical centre in southern Taiwan. Methods CML patients who regularly attended the oncology outpatient clinics to receive imatinib treatment from October 2011 to March 2012 were invited to participate in the study. Semi-structured face-to-face interviews were used to explore patients’ experiences and views of their treatment, their current CML status and CML-related health conditions, their concerns about imatinib treatment and imatinib-taking behaviours. Patient interviews were recorded, transcribed verbatim and thematically analysed using the constant comparison approach. Main outcome measure Themes related to patients’ views of the disease and health conditions, worries and concerns influencing imatinib utilisation behaviours are reported. Results Forty-two CML patients participated in the interviews. The emerging themes included: acceptance of current disease and health status, misconceptions about disease progression, factors associated with adherence to imatinib, concerns and management of adverse drug effects. Participants regarded CML as a chronic disease but had misconceptions about disease progression, therapeutic monitoring, resistance to imatinib and symptoms of side effects. Participants were generally adherent to imatinib and favoured long-term prescriptions to avoid regular outpatient visits for medication refills. Experiencing adverse effect was the main reason influencing adherence and led to polypharmacy. Most participants altered medicine-taking behaviours to maintain long-term use of imatinib. Conclusion Taiwanese CML patients are adherent to imatinib but report changing their medication-taking behaviour due to adverse drug effects and associated polypharmacy. Patients’ misconceptions of the disease and medication suggests that it is necessary to improve communication between patients and healthcare professionals. Routinely providing updated information as part of the patient counselling process should be considered as a means of improving this communication.

Dipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for

Background Since the launch of imatinib, chronic myeloid leukaemia has become a chronic condition requiring costly long-term treatment. Emerging evidence from several short-term studies has raised concerns on the detrimental clinical outcomes and waste of resources associated with poor adherence to imatinib. Objective This study aims to evaluate the effects of long-term imatinib adherence on clinical treatment responses and mortality. Setting This retrospective cohort study was conducted in a medical centre in southern Taiwan. Method Chronic myeloid leukaemia patients who were prescribed for more than 1 month of imatinib were identified and their medical charts were reviewed from the first date of imatinib prescription to the last date of medical record or upon patients’ death. Patients’ basic characteristics, imatinib prescriptions, results of laboratory tests, episodes of imatinib-related side effects and mortality rate were recorded. Main outcome measure Participants’ basic characteristics, medication possession ratio and their mortality rate; the association between the medication possession ratio and treatment responses. Results Of the 119 included patients, the mean follow-up time was 3.9 ± 2.9 patient-years and the mean medication possession ratio was 89.7 %. At the 18th month of imatinib treatment, 67.2, 54.3 and 34.5 % patients achieved complete cytogenetic, major molecular and complete molecular responses, respectively. There was a significant difference in the 4-year survival rate between the adherence (n = 87) and non-adherence (n = 32) groups (91 vs. 72 %; p = 0.0076). Logistic regression analysis revealed that imatinib adherence was the only factor that significantly influenced the 18th month complete cytogenetic response [odds ratio (OR) 11.6; 95 % confidence interval (CI) 1.7, 114.7; p = 0.0131] and major molecular response (OR 5.1; 95 % CI 1.1, 26.8; p = 0.0351). Cox regression analysis demonstrated that a medication possession ratio greater than 90 % significantly reduced the mortality risk (hazard ratio 0.1; 95 % CI 0.01, 0.60; p = 0.0118). Conclusion Chronic myeloid leukaemia patients’ long-term adherence to imatinib is significantly associated with the 18th month treatment responses including the cytogenetic response, molecular response and the long-term survival rate in clinical practice.

Background The acid-suppressive agents have been linked with an increased risk of infectious disease. The relationship between these drugs and Mycobacterium Tuberculosis (TB) was not been reported. Methods We conducted a case–control study using data from National Health Insurance research database of Taiwan. From 1996 till 2008, and 6541 cases were defined as TB infection/activation (ICD-9 coding plus prescription two of four first-line anti-TB regimen for at least one month). Control subjects who were matched to the TB cases by age and sex were selected with 10:1 ratio. Medical records including acid-suppressive agent prescription and comorbidity, and socioeconomic status were analyzed. Results TB infection/activation was more frequent to comorbidity with chronic diseases, alcohol abuse, malignancy, immune deficient/suppression status and acid-related disease (peptic ulcer, reflux esophagitis). Among the TB cases, there was higher exposure record to acid-suppressive agents within 3 months before TB index date (OR 2.43(2.06-2.88) and 1.90 (1.68-2.14) for proton pump inhibitor (PPI) and histamine 2 receptor antagonist (H2RA) respectively). After adjusting confounding factors, PPIs prescription 3 months before TB index date had an association of TB infection/activation (adjusted OR 1.63(1.61-1.63)). Similar result was found in H2RA user (adjusted OR 1.51(1.50-1.52)). The association of acid-suppressive agents in TB infection/activation was fade gradually when the drug prescription period extended. Conclusions Recent prescription of acid-suppressive agent seems to associate the TB infection/activation. In the society where TB was prevalent, evaluation of pulmonary TB before prescription of PPI or H2RA is warranted.

Background TGF-β is a key modulator in the regulation of cell proliferation and migration, and is also involved in the process of cancer development and progression. Previous studies have indicated that TGF-β responsiveness is determined by TGF-β receptor partitioning between lipid raft/caveolae-mediated and clathrin-mediated endocytosis. Lipid raft/caveolae-mediated endocytosis facilitates TGF-β degradation and thus suppressing TGF-β responsiveness. By contrast, clathrin-mediated endocytosis results in Smad2/3-dependent endosomal signaling, thereby promoting TGF-β responsiveness. Because betulinic acid shares a similar chemical structure with cholesterol and has been reported to insert into the plasma membrane, we speculate that betulinic acid changes the fluidity of the plasma membrane and modulates the signaling pathway associated with membrane microdomains. We propose that betulinic acid modulates TGF-β responsiveness by changing the partitioning of TGF-β receptor between lipid-raft/caveolae and non-caveolae microdomain on plasma membrane. Methods We employed sucrose-density gradient ultracentrifugation and confocal microscopy to determine membrane localization of TGF-β receptors and used a luciferase assay to examine the effects of betulinic acid in TGF-β-stimulated promoter activation. In addition, we perform western blotting to test TGF-β-induced Smad2 phosphorylation and fibronectin production. Results and conclusions Betulinic acid induces translocation of TGF-β receptors from lipid raft/caveolae to non-caveolae microdomains without changing total level of TGF-β receptors. The betulinic acid-induced TGF-β receptors translocation is rapid and correlate with the TGF-β-induced PAI-1 reporter gene activation and growth inhibition in Mv1Lu cells. Electronic supplementary material The online version of this article (doi:10.1186/s12929-016-0229-4) contains supplementary material, which is available to authorized users.

Furo(3,2-C)quinolin-4-ylamino)phenyl)ethanoe-O-methyl-oxime (CCK3) is an antitumor agent, particularly active against the growth of the renal cancer cell, UO-31, and two melanoma cancer cells, UACC-257 and UACC-62, as indicated in the NCI's full panel of 60 human cancer cell lines cytotoxicity evaluation. From the structure-activity relationships between amsacrine and CCK3, C CK3 was expected to have longer half-life than amsacrine in plasma. Therefore, a reversed-phase high performance liquid chromatogr aphy method was developed and validated for the determination of pharmacokinetics of CCK3 in rats. The plasma samples were spiked w ith the internal standard 2-naphthol and extracted using dichloromethane. A C18 column (55 × 4 mm) was used for the separation of analytes with a mobile phase consisted of 30% acetonitrile, 5% tetrahydrofuran and 65% pH 3.0 of McIlvaine buffer at a flow rat e of 1.0 mL/min. CCK3 was detected and utilized by electrochemical detector at 1.0 voltage and 10 nA. Intra- and inter-day precisi on and accuracy were acceptable down to the limit of quantitation of 10 ng/mL. The lower limit of detection was 5 ng/mL. As for the in vivo study, the pharmacokinetic parameters of CCK3 in rats after intravenous administration of 3.97 and 7.94 mg/kg were determined. The apparent volume of distribution, half-life and clearance showed no significant difference between these two dosages. The area under the plasma concentration time curve increased proportionally with increase in dose. The half-life of CCK3 was prolonged 3 fold s, compared to amsacrine. Therefore, CCK3 might have the potential to be tested clinically.