Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy

We prepared fast dissolving oral thin film that contains dexamethasone and base materials, including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40 °C and 75% in humidity for up to 24 weeks. The film was disintegrated within 15 s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min. Subsequently, pharmacokinetic properties of dexamethasone were compared in rats with oral administration of 4 mg dexamethasone suspension or topical application of the film preparation containing 4 mg dexamethasone to the oral cavity. Pharmacokinetic parameters were similar between the two groups in which C_max (h), T_max (μg/mL), AUC (μg/mL/h) and half-life (h) were 12.7 ± 6.6 (mean ± SD, N = 10), 3.4 ± 1.4, 93.6 ± 37.8 and 1.66 ± 0.07, respectively, for oral suspension and 13.3 ± 4.0, 3.2 ± 1.0, 98.0 ± 22.3 and 1.65 ± 0.06, respectively, for film preparation. These findings suggest that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.     

IVIVC for Fenofibrate Immediate Release Tablets Using Solubility and Permeability as In Vitro Predictors for Pharmacokinetics

The goal of this study was to investigate the in vitro-in vivo correlation (IVIVC) for fenofibrate immediate release (IR) tablet formulations based on MeltDose®-technique. The in vitro determined drug solubility and permeability data were related to the C_max values observed from two in vivo human studies. Solubility and permeation studies of fenofibrate were conducted in medium simulating the fasted state conditions in the upper jejunum, containing the surfactant compositions of the six formulations at different concentrations. The behavior of all surfactant compositions was characterized by surface tension, dynamic light scattering, and cryo-TEM. The obtained solubility and permeation data were combined and compared with the C_max values for the fenofibrate formulations, assuming a 50 mL in vivo dissolution volume. A good IVIVC was observed for five fenofibrate formulations (R² = 0.94). The in vitro studies revealed that the formulation compositions containing sodium lauryl sulfate (SLS) interfered with the vesicular drug solubilizing system of the biorelevant medium and antagonized its solubilization capacity. The opposing interaction of surfactants with the emulsifying physiological constituents in intestinal juice should be taken into consideration in order to prevent unsatisfactory in vivo performance of orally administered formulations with low soluble active pharmaceutical ingredients.     

Alteration of pharmacokinetics of proguanil in healthy volunteers following concurrent administration of efavirenz

Efavirenz and proguanil are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of proguanil is mediated principally by CYP2C19 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on proguanil disposition. Fifteen healthy volunteers were each given 300 mg single oral doses of proguanil alone or with the 9th dose of efavirenz (400 mg daily for 11 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for proguanil and its major metabolite, cycloguanil, using a validated HPLC method. Co-administration of proguanil and efavirenz resulted in significant increases (p < 0.05) in C_max, T_max, AUC_T and elimination half-life (T_1/2β) of proguanil compared with values for proguanil alone [C_max: 2.55 ± 0.24 mg/l vs 3.75 ± 0.48 mg/l; T_max: 2.80 ± 0.99 h vs 4.80 ± 0.99 h; AUC_T: 45.58 ± 12.75 mg h/l vs 97.00 ± 23.33 mg h/l; T_1/2β: 16.50 ± 4.55 h vs 23.24 ± 4.08 h]. Also, efavirenz caused a pronounced decrease in the AUC(metabolite)/AUC(unchanged drug) ratio of proguanil along with a significant decrease (p < 0.05) in C_max and AUC of the metabolite.These results indicate that efavirenz significantly alters the pharmacokinetics of proguanil. These suggest that the protection against malaria by proguanil may be decreased when the drug is co-administered with efavirenz and the antimalarial efficacy is dependent on cycloguanil plasma levels.     

Comparison of average,scaled average,and population bioequivalence methods for assessment of highly variable drugs: An experience with doxifluridine in beagle dogs

Several strategies for overcoming the challenge of establishing bioequivalence (BE) for highly variable drugs (HVDs; drugs having within-subject variability >0.3) have been considered in recent years. Within-subject variability of the area under the curve (AUC_4 h) and peak concentration (C_max) of doxifluridine in the minimal group (n = 24) were 0.444 and 0.491, respectively, meeting the criteria for an HVD. For the large group (n = 60), within-subject variability of the AUC_4 h and C_max were 0.431 and 0.493, respectively. The 90% confidence interval for the AUC_4 h and C_max of the ratio of the test drug to the reference drug exceeded the acceptable BE limits (0.80–1.25) of the ABE (average bioequivalence), in both the minimal and large groups. However, the 90% CI fell within the extended BE limits (0.61–1.64) of the SABE (scaled average bioequivalence), calculated using within-subject variability. The 95% CI of the AUC_4 h and C_max of the ratio of test to reference drug were within the extended BE limit (<1.73) of the PBE (population bioequivalence), calculated using total variance. Our results suggest that the SABE method may be useful for evaluating the BE of HVDs and for meeting the need for international guidelines for BE.     

Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting

The estradiol(E₂)-loaded chitosan nanoparticles (CS-NPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP). The CS-NPs had a mean size of (269.3 ± 31.6) nm, a zeta potential of +25.4 mV, and loading capacity of E₂ CS-NPs suspension was 1.9 mg ml⁻¹, entrapment efficiency was 64.7% on average. Subsequently, this paper investigated the levels of E₂ in blood and the cerebrospinal fluid (CSF) in rats following intranasal administration of E₂ CS-NPs. E₂-loaded CS-NPs were administered to male Wister rats either intranasally or intravenously at the dose of 0.48 mg kg⁻¹. The plasma levels achieved following intranasal administration (32.7 ± 10.1 ng ml⁻¹; t_max 28 ± 4.5 min) were significantly lower than those after intravenous administration (151.4 ± 28.2 ng ml⁻¹), while CSF concentrations achieved after intranasal administration (76.4 ± 14.0 ng ml⁻¹; t_max 28 ± 17.9 min) were significantly higher than those after intravenous administration (29.5 ± 7.4 ng ml⁻¹ t_max 60 min). The drug targeting index (DTI) of nasal route was 3.2, percent of drug targeting (DTP%) was 68.4%. These results showed that the E₂ must be directly transported from the nasal cavity into the CSF in rats. Finally, compared with E₂ inclusion complex, CS-NPs improved significantly E₂ being transported into central nervous system (CNS).     

Hexyl Aminolaevulinate Is a More Effective Topical Photosensitiser Precursor than Methyl Aminolaevulinate and 5-Aminolaevulinic Acids When Applied in Equimolar Doses

Aminolaevulinic acid (ALA) is known to poorly penetrate into thick lesions, such as nodular basal cell carcinomas. Short chain ALA esters, possessing increased lipophilicity relative to their hydrophilic parent, have previously been shown to be highly efficient at inducing protoporphyrin IX (PplX) production in cell culture, at equimolar concentrations. In contrast, in vitro skin permeation and in vivo animal studies, which up to now have compared prodrugs on a % w/w basis, have failed to demonstrate such benefits. For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into an o/w cream preparation. In vitro penetration studies into excised porcine skin revealed that increased levels of h-ALA, compared to ALA and m-ALA were found in the upper skin layers, at all drug loadings studied. Topical application of the formulations to nude murine skin in vivo, revealed that creams containing h-ALA induced significantly higher levels of peak PplX fluorescence (F_max = 289.0) at low concentrations compared to m-ALA (F_max = 159.2) and ALA (F_max = 191.9). Importantly, this study indicates that when compared on an equimolar basis, h-ALA has improved skin penetration, leading to enhanced PpIX production compared to the parent drug and m-ALA. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3486–3498, 2010     

Improving sublingual delivery of weak base compounds using pHmax concept: Application to propranolol

The purpose of the present work was to provide theoretical and experimental support in generating an optimal pH (pH_max) for a representative weak base compound (propranolol), that can lead to enhanced sublingual absorption. Initially equations for pH-solubility and pH-permeability profiles were derived and compared to the profiles obtained experimentally. Excellent correlation (R² = 0.999) of solubility profiles was obtained using non-linear regression, and the permeability profiles further predicted that at certain pH (pH_max), optimal mucosal permeation could be achieved. Subsequently, in a pharmacokinetics study, a buffered sublingual propranolol tablet, designed to achieve its pH_max (when dissolved in saliva), were compared to that from a marketed product (Inderal^® which could not achieve pH_max) in 8 healthy subjects. Each subject received the products sublingually for 15 min followed by swallowing the remaining drug–saliva. The plasma propranolol concentrations of AUC during first 30 min from the buffered tablet were significantly higher than that from the Inderal^® tablet (p < 0.05), and no significant differences in the remaining AUC were observed. These in vitro and in vivo results on propranolol provided experimental confirmation of the pH_max concept as well as its utility in sublingual drug delivery. Such an approach may be applicable to other similar compounds to improve sublingual drug delivery.     

Oxidative stress contributes to silica nanoparticle-induced cytotoxicity in human embryonic kidney cells

In order to elucidate the nanoparticle-induced cytotoxicity and its mechanism, the effects of 20 and 50 nm silica nanoparticles on cultured human embryonic kidney (HEK293) cells were investigated. Cell viability, mitochondrial function, cell morphology, reactive oxygen species (ROS), glutathione (GSH), thiobarbituric acid reactive substance (TBARS), cell cycle and apoptosis were assessed under control and silica exposed conditions. Exposure to 20 or 50 nm SiO₂ nanoparticles at dosage levels between 20 and 100 μg/ml decreased cell viability in a dose-dependent manner. Median lethal dose (LD₅₀) of 24 h exposure was 80.2 ± 6.4 and 140.3 ± 8.6 μg/ml for 20 and 50 nm SiO₂ nanoparticles, respectively. Morphological examination revealed cell shrinkage and nuclear condensation after SiO₂ nanoparticle exposure. Increase in intracellular ROS level and reduction in GSH content were also observed in SiO₂ nanoparticle-exposed HEK293 cells. Increase in the amount of TBARS suggested an elevated level of lipid peroxidation. Flow cytometric analysis showed that SiO₂ nanoparticles can cause G2/M phase arrest and apoptotic sub-G1 population increase in a dose-dependent manner. In summary, exposure to SiO₂ nanoparticles resulted in a dose-dependent cytotoxicity in cultured HEK293 cells that was associated with increased oxidative stress.     

Budesonide Nanoparticle Agglomerates as Dry Powder Aerosols With Rapid Dissolution

: Nanoparticle technology represents an attractive approach for formulating poorly water-soluble pulmonary medicines. Unfortunately, nanoparticle suspensions used in nebulizers or metered dose inhalers often suffer from physical instability in the form of uncontrolled agglomeration or Ostwald ripening. In addition, processing such suspensions into dry powders can yield broad particle size distributions. To address these encumbrances, a controlled nanoparticle flocculation process has been developed. Nanosuspensions of the poorly water-soluble drug budesonide were prepared by dissolving the drug in organic solvent containing surfactants followed by rapid solvent extraction in water. Different surfactants were employed to control the size and surface charge of the precipitated nanoparticles. Nanosuspensions were flocculated using leucine and lyophilized. Selected budesonide nanoparticle suspensions exhibited an average particle size ranging from ~ 160 to 230 nm, high yield and high drug content. Flocculated nanosuspensions produced micron-sized agglomerates. Freeze-drying the nanoparticle agglomerates yielded dry powders with desirable aerodynamic properties for inhalation therapy. In addition, the dissolution rates of dried nanoparticle agglomerate formulations were significantly faster than that of stock budesonide. The results of this study suggest that nanoparticle agglomerates possess the microstructure desired for lung deposition and the nanostructure to facilitate rapid dissolution of poorly water-soluble drugs.     

Bactericidal activity of daptomycin versus vancomycin in the presence of human albumin against vancomycin-susceptible but tolerant methicillin-resistant Staphylococcus aureus (MRSA) with daptomycin minimum inhibitory concentrations of 1–2 μg/mL

This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) = 0.5/16, 1/32, 2/32 and 1/32 μg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4 μg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations (C_max) (65.70/98.60 μg/mL) and trough concentrations (C_min) (7.90/9.13 μg/mL) in the presence and absence of a physiological human albumin concentration (4 g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C_max (41.45/8.18 μg/mL) and C_min (4.98/0.76 μg/mL). Vancomycin C_max and C_min concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C_max and C_min. C_max was rapidly bactericidal (≤4 h) with >5 log₁₀ reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C_max. C_min exhibited similar final colony counts at 0 h and 24 h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at ≤4 h for strains with an MIC of 1 μg/mL and ca. 2 log CFU/mL reduction at ≤6 h for strains with an MIC of 2 μg/mL. This activity was significantly higher than the activity of the free C_min fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.     

Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro–in silico–in vivo approach

Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO₄)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44 μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of C_max and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8–1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f₂ factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients, this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro–in silico–in vivo approach.     

Development of Mucoadhesive Films for Buccal Administration of Flufenamic Acid: Effect of Cyclodextrin Complexation

A new mucoadhesive film for topical administration in the oral cavity of flufenamic acid, a poorly soluble anti-inflammatory drug, has been developed, using complexation with hydroxypropyl-β-cyclodextrin (HPβCD) to improve drug dissolution and release rate. Buccal films were prepared utilising chitosan as mucoadhesive polymer, KollicoatIR® as film-forming polymer and glycerol as plasticiser. Different combinations of these components were used and the obtained films were characterised for weight, thickness, swelling, mucoadhesive and mechanical properties. The film containing chitosan 2%, glycerol 7.5% and KollicoatIR® 1% showed the best properties for the development of the film formulation. The selected film was loaded with the plain drug and its colyophilised and coground products with HPβCD, and in vitro release studies in simulated saliva were performed. The improved drug dissolution properties, obtained by complexation with HPβCD, were critical to achieve complete release from film formulation during 4–5 h. On the contrary, film loaded with the plain drug showed incomplete release, not exceeding 70% release after 5 h. The developed film formulation containing the drug as complex with HPβCD can assure a prolonged drug release directly at the inflammation site and can be proposed as a new therapeutic tool in the treatment of oral mucosa inflammations.     

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (T_g) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated.FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a T_g of 101.2 °C, whereas the T_g for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days.The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively.The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster T_max compared to the solution and amorphous and crystalline free acid. C_max for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster T_max compared to the amorphous and crystalline free acid.     

Postmarketing In Vitro/In Vivo Assessment of Fixed Dose Combination Products of First Line Antiretrovirals

The purpose of this study was to evaluate the postmarket pharmaceutical equivalence, stability and bioequivalence of generic and innovator fixed dose combination products of lamivudine (3TC) and zidovudine (AZT) 150/300 mg tablets available in Nigeria. An isocratic HPLC-UV method was developed and validated for the quantitative determination of 3TC and AZT in human plasma and pharmaceutical samples. The model independent f₂ similarity factor was used to compare the dissolution profiles of the two products stored at accelerated and longterm stability conditions for 6 months. The f₂ values for 3TC and AZT in both products were found to be greater than 51. Also, the tablets were stable according to the USP potency and drug dissolution criteria with more than 80% of drug dissolution in 30 min indicating the pharmaceutical equivalence of the two products. The 90% confidence interval for the ratios of generic/innovator pharmacokinetic parameters for 3TC/AZT were 73.5–112.6/63.4–95.8 (C_max); 68.5–105.6/68.0–114.8 (AUC_0–t); and 64.2–106.2/80.1–120.3 (AUC_0–∞) respectively. The pharmacokinetic parameters failed to fully demonstrate bioequivalence between the products. The results underscored the importance of assessing the quality of the combination drug products that would ensure the safety and efficacy of the generic drug products available in the market.     

Influence of ABCB1 gene polymorphisms on the pharmacokinetics of azithromycin among healthy Chinese Han ethnic subjects

The aim of this study was to evaluate the effects of ABCB1 gene polymorphisms on azithromycin pharmacokinetics in Chinese Han ethnic subjects. In total, 20 healthy volunteers with various ABCB1 genotypes (6 with 2677GG/3435CC, 8 with 2677GT/3435CT, 6 with 2677TT/3435TT) were enrolled. Each was given a single oral dose of 500 mg azithromycin. Plasma concentration was measured for up to 96 h by LC/MS/MS. As shown, C_max was significantly lower among individuals with 2677TT/3435TT genotype (468.0 ± 173.4 ng ? h/ml) than those with 2677GG/3435CC (911.2 ± 396.4 ng ? h/ml, p = 0.013). However, the t_max value was higher among subjects with 2677TT/3435TT (2.0 ± 0.5 h) than those with 2677GT/3435CT (1.6 ± 0.3 h) or 2677GG/3435CC (1.4 ± 0.4 h) genotypes (p = 0.068 and p = 0.026, respectively). Furthermore, the AUC _last tended to be higher among subjects with 2677GG/3435CC than those with 2677GT/3435CT or 2677TT/3435TT genotypes (5000.2 ± 1610.0 vs. 4558.0 ± 805.0 vs. 4131.0 ± 995.1 ng/ml). Our results showed for the first time that azithromycin pharmacokinetics may be influenced by particular polymorphisms of the ABCB1 gene. Individualized dosage regimen design incorporating such information may improve the efficacy of the drug while reducing adverse reactions.     

Penetration of doripenem into prostatic tissue following intravenous administration in prostatectomy patients

This study examined the prostatic penetration of doripenem in prostatectomy patients. Doripenem 500 mg was administered by a 0.5-h infusion and venous blood and prostatic tissue samples were obtained up to 5 h afterwards. Drug concentrations in plasma and prostatic tissue were measured chromatographically. The observed maximum concentration (C_max) (mean ± standard deviation; n = 9) was 27.5 ± 5.1 μg/mL in plasma and 5.09 ± 1.94 μg/g in prostate tissue and the prostate/plasma C_max ratio was 0.189 ± 0.078. The area under the drug concentration–time curve (AUC) was 49.7 ± 6.9 μg h/mL in plasma and 3.93 ± 1.89 μg h/g in prostate tissue and the prostate/plasma AUC ratio was 0.081 ± 0.047. Based on a three-compartment pharmacokinetic analysis, average drug exposure times above 0.25 μg/mL (the minimum inhibitory concentration for isolates of common pathogens) in the prostate were 23.2% for 500 mg once daily, 46.2% for 500 mg twice daily and 69.9% for 500 mg three times daily. The 500-mg regimens all achieved the drug exposure time target (bacteriostatic 20% or bactericidal 40%) in the prostate, despite the relatively low penetrability of doripenem.     

Clinical Pharmacokinetics of Paclitaxel Liposome with a New Route of Administration in Human Based on the Analysis with Ultra Performance Liquid Chromatography

We investigated the clinical pharmacokinetics of paclitaxel liposome with a new route of administration, which was intrapleural infusion, in nine advanced nonsmall-cell lung cancer (NSCLC) patients with malignant pleural effusions after a single administration. Paclitaxel concentrations were measured in pleural fluid and plasma using a simple and rapid ultra performance liquid chromatography (UPLC) method following intra-and inter-day validations. In subjects, AUC_0–96h values in pleural fluid and plasma were 17831 ± 6439 μgh/mL and 778 ± 328 μgh/mL, respectively, and T_max values were initial time and 6.67 h after administration and the corresponding C_max values were 558 ± 44 μg/mL and 12.89 ± 6.86 μg/mL, respectively. The T_{1/2 IP}, CL_IP and Vd_IP values in pleural fluid were 76 ± 48 h, 0.005 ± 0.002 L/hm² and 0.53 ± 0.23 L/m², respectively. The T_1/2,_pla, CL_pla, and Vd_pla values in plasma were 68.34 ± 56.74 h, 0.184 ± 0.080 L/hm², and 17.53 ± 16.57 L/m², respectively. However, some paclitaxel concentrations from several patients in plasma could not be detected at some designed time-points. Our results might offer new opportunities to design and determine individually appropriate therapeutic dosage regimens based on a pharmacokinetic profile.     

In vivo preliminary investigations of the effects of the benzimidazole anthelmintic drug flubendazole on rat embryos and fetuses

Flubendazole, in a new formulation with high systemic bioavailability, has been proposed as a macrofilaricide against filarial diseases.To investigate embryotoxic activity, the new flubendazole formulation was administered orally to Sprague Dawley rats at 2, 3.46, 6.32 mg/kg/day on gestation day (GD) 9.5 and 10.5. Embryos/fetuses were evaluated on GD 11.5, 12.5 or 20.At 6.32 mg/kg/day (C_max = 0.801 μg/mL after single administration), flubendazole initially induced an arrest of embryonic development followed by a generalized cell death that led to 100% embryolethality by GD 12.5.At 3.46 mg/kg/day (C_max = 0.539 μg/mL after single administration), flubendazole markedly reduced embryonic development by GD 12.5 without causing cell death. On GD 20, 80% of fetuses showed malformations.At 2 mg/kg/day (C_max = 0.389 μg/mL after single administration), it did not interfere with rat embryofetal development.     

Human urotensin II in internal mammary and radial arteries of patients undergoing coronary surgery

AimsInternal mammary (IMA) and radial artery (RA) have different incidence of vasospasm and long-term patency rates in arterial grafting. We compared the vasoreactivity of human urotensin II (hU-II) and its receptor with mechanism investigations in IMA and RA.MethodsIMA and RA taken from patients undergoing coronary bypass surgery were studied in organ baths. Urotensin receptor expression was determined by RT-PCR.ResultshU-II contracted IMA with pD₂ of 8.57 ± 0.41 and 45.4 ± 9.1% E_max of contraction to 100 mM KCl, whereas caused less contractile responses in RA (pD₂:8.30 ± 0.79, E_max:20.4 ± 4.8%, p < 0.05). Nifedipine inhibited hU-II-contraction in IMA. In U₄₆₆₁₉-precontraction, hU-II elicited comparable relaxation in IMA (pD₂:8.39 ± 0.43, E_max:56.1 ± 4.0%) and RA (pD₂:9.03 ± 0.46, E_max:65.2 ± 7.1%). The relaxation was abolished by endothelium denudation and by indomethacin, oxadiazoloquinoxalinone or N^ω-nitro-l-arginine, oxyhemoglobin, and Ca²⁺-activated K⁺ channel (K_Ca) blockers. Urotensin receptor mRNA was detected in both arteries.ConclusionshU-II is an important spasmogen in arterial grafts with receptors expressed in IMA and RA. hU-II elicits stronger contraction in IMA than in RA and a moderate endothelium-dependent relaxation attributable to nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor with involvement of K_Ca activation. The relaxant response of endothelium-intact IMA and RA to hU-II demonstrates the importance of preservation of endothelium in these grafts.     

Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery

A novel targeting drug delivery system (TDDS) has been developed. Such a TDDS was prepared by W₁/O/W₂ solvent extraction/evaporation method, adopting poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] as the drug carrier, folic acid (FA) as the targeting ligand, and doxorubicin (DOX) as the model anticancer drug. The average size, drug loading capacity and encapsulation efficiency of the prepared DOX-loaded, folate-mediated P(HB-HO) nanoparticles (DOX/FA–PEG–P(HB-HO) NPs) were found to be around 240 nm, 29.6% and 83.5%. The in vitro release profile displayed that nearly 50% DOX was released in the first 5 days. The intracellular uptake tests of the nanoparticles (NPs) in vitro showed that the DOX/FA–PEG–P(HB-HO) NPs were more efficiently taken up by HeLa cells compared to non-folate-mediated P(HB-HO) NPs. In addition, DOX/FA–PEG–P(HB-HO) NPs (IC₅₀ = 0.87 μM) showed greater cytotoxicity to HeLa cells than other treated groups. In vivo anti-tumor activity of the DOX/FA–PEG–P(HB-HO) NPs showed a much better therapeutic efficacy in inhibiting tumor growth, and the final mean tumor volume was 178.91 ± 17.43 mm³, significantly smaller than normal saline control group (542.58 ± 45.19 mm³). All these results have illustrated that our techniques for the preparing of DOX/FA–PEG–P(HB-HO) NPs developed in present work are feasible and these NPs are effective in selective delivery of anticancer drug to the folate receptor-overexpressed cancer cells. The new TDDS may be a competent candidate in application in targeting treatment of cancers.