Intraoperative corneal thickness measurements during corneal collagen cross-linking with isotonic riboflavin solution without dextran in corneal ectasia

Objective: To monitor the changes in corneal thickness during the corneal collagen cross-linking procedure by using isotonic riboflavin solution without dextran in ectatic corneal diseases.

Materials and Methods: The corneal thickness measurements were obtained before epithelial removal, after epithelial removal, following the instillation of isotonic riboflavin solution without dextran for 30?min, and after 10?min of ultraviolet A irradiation.

Results: Eleven eyes of eleven patients with progressive keratoconus (n?=?10) and iatrogenic corneal ectasia (n?=?1) were included in this study. The mean thinnest pachymetric measurements were 391.82?±?30.34?µm (320–434?µm) after de-epithelialization of the cornea, 435?±?21.17?µm (402–472?µm) following 30?min instillation of isotonic riboflavin solution without dextran and 431.73?±?20.64?µm (387–461?µm) following 10?min of ultraviolet A irradiation to the cornea.

Conclusion: Performing corneal cross-linking procedure with isotonic riboflavin solution without dextran might not induce corneal thinning but a little swelling throughout the procedure.     

Effect of chronic smoking on lens nucleus as assessed by Pentacam HR lens densitometry in young adults

Objective: To evaluate the effects of chronic tobacco smoking on lens nucleus by Pentacam HR lens densitometry (LD) in young adults.

Design: Prospective cross-sectional case series.

Methods: Thirty subjects (23?M, 7 F) who were chronic cigarette smokers (≥10 cigarettes/day for at least 2 years) (group 1) and another 30 subjects (23?M, 7 F) who did not smoke (group 2), were included in this study. The patients were matched for age and sex between the groups. The exclusion criteria were any history of ocular surgery, any systemic disorders and any ocular diseases except for mild refractive disorders. Lens densitometry measurements were done with the Pentacam HR (Oculus, Wetzlar, Germany). The Schirmer test and pachymetry measurements were also performed.

Results: Mean age of the patients for both groups was 28.90?±?8.20 years (range: 18–40 years). Mean lens densitometry (LD) measurements of Group 1 (chronic cigarette smoking group) were higher than those of Group 2 (control group) in all LD techniques; however only mean “peak” LD measurements showed a statistically significant difference between these two groups (Group 1: 8.67?±?0.61, Group 2: 8.44?±?0.70, p?=?0.04). The mean Schirmer test value was 12.43?±?5.60?mm in Group 1 and 13.00?±?4.26?mm in Group 2 (p?=?0.55). The mean central corneal thickness (CCT) value was 564.23?±?34.61?µm in Group 1 and 550.47?±?32.94?µm in Group 2 (p?=?0.03).

Discussion: The Pentacam HR LD seems to be an important option for the evaluation of lens nucleus in young adults, because it gives objective and quantitative data.

Conclusion: Although chronic smoking increases lens nucleus density in young adults, the effect is not statistically significant when compared with the control group.     

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characterization and drug release

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47?±?11 and 67?±?12?µg 5-FU?mg^?1 microspheres and the percentage of entrapment efficiency was between 52?±?12 and 74?±?13. Microspheres were of small size (average diameter: 0.9?±?0.4–1.4?±?0.8?µm microspheres without drug; 1.1?±?0.5–1.7?±?0.9?µm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger T_g. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of T_g of the polymer of the microspheres. The presence of 5-FU did not modify the T_g values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28–129?h) was in the order PLA?>?PLGA 75/25?>?PLGA 50/50. A burst effect (17–20%) was observed during the first hour and then a period of constant release rate (3.52?±?0.82–1.46?±?0.26?µg 5-FU?h^?1 per milligram of microspheres) up to 8 or 13?h, depending on the polymer, was obtained.     

Evaluation of the anti-inflammatory activity of N,N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride

This study investigated the anti-inflammatory effect of N, N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride, D1, on carrageenan-induced edema. In addition, its effect on hyaluronidase-induced vascular permeability was also tested. D1 was synthesized, and anti-inflammatory activity was determined by carrageenan-induced hind paw edema in rats (n?=?30) at 50, 100, and 200?mg kg^?1 doses of D1 and also a 25?mg kg^?1 dose of indomethacin. The effects of D1 and indomethacin on hyaluronidase-induced capillary permeability were investigated in rabbits (n?=?18) at a 100?mg kg^?1 dose of D1 and 25?mg kg^?1 dose of indomethacin. D1 inhibited carrageenan-induced inflammation by 40, 20, and 10% at 50, 100, and 200?mg kg^?1 doses after 1?h. The inhibitions were 22.5, 32.7, 28.6% and 15.6, 33.4, 8.9% at 2?h and 3?h, respectively. The inhibitions due to indomethacin (25?mg kg^?1 dose) were 67.5, 87.8, and 91.1%, at 1?h, 2?h, and 3?h, respectively. The subcutaneous spreading areas of Trypan blue at 1, 5, 30, and 60?min after subcutaneous injection of hyaluronidase were 172.6?±?41.6, 210.2?±?39.7, 363?±?50, and 400.2?±?46.7?mm² in the D1 (100?mg kg^?1) treated group. The spreading areas at these time periods were 38.8?±?3.7, 48.2?±?4.5, 100.6?±?6.9, and 119.8?±?22.5?mm² in the indomethacin treated group. Our results showed that D1 inhibits carrageenan-induced inflammation in rats. A tendency to decrease the capillary permeability suggested that the mechanism of action of the anti-inflammatory effect of D1 may partly depend on inhibition of the hyaluronidase enzyme.     

Corneal endothelial changes in long-term cannabinoid users

Purpose: The aim of this study was at evaluating the effects of long-term cannabis use on the corneal endothelial cells with the specular microscopy.

Methods: The study enrolled 28 eyes of 28 patients diagnosed with cannabinoid use disorder. The cannabinoid group was selected among patients who had been using the substance for three days or more per week over the past one year. Thirty-two eyes of 32 age- and sex-matched healthy individuals enrolled as control group in the study. Corneal endothelial cell density (CD), coefficient of variation (CV) and hexagonal cell ratio (HEX) values were analyzed by specular microscopy.

Results: The mean CD was 2900?±?211 cells/mm² in the cannabinoid group and 3097?±?214 cells/mm² in the control group (p?p?>?0.05). No significant difference was present between the cannabinoid and the control groups in terms of mean CV value. The mean HEX was 52?±?5% in the cannabinoid group and 53?±?10% in the control group (p?>?0.05). There was not a significant difference between the cannabinoid and the control groups in terms of mean HEX value.

Conclusion: A significant decrease in CD was found in cannabinoid users compared the control group.     

Ocular surface findings in patients with rheumatoid arthritis under methotrexate or biological agent therapy

Purpose: To evaluate the ocular findings in patients with rheumatoid arthritis (RA) treated with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) or MTX with biological agents.

Methods: One hundred and twelve eyes of 56 patients with RA and treated with MTX or MTX with biological agents were included in the study. Patients were divided into two groups using DMARDs only (group 1) and patients using DMARDs and biologic agents together (group 2). In both groups; Schirmer’s II test, tear film break-up time (tBUT), central corneal thickness (CCT), corneal volume (CV), intraocular pressure (IOP) measurement, and anterior segment and fundus examinations of the eye with slit lamp were carried out. Ocular surface disease index (OSDI) score questionnaire were performed.

Results: Thirty-eight patients with a mean age of 53.00?±?8.19 years were in group 1 and 18 patients with a mean age of 51.00?±?9.54 years were in group 2. The mean duration of RA was 6.89?±?7.96 years in group 1 and 5.70?±?9.00 years in group 2. There was a statistically significant difference between two groups with tBUT, CCT, CV, IOP (p < 0.05) and there was no significant difference with age, sex, disease duration, disease activity, and Schirmer’s II test (p > 0.05). The disease duration showed a significant moderate negative correlation with CCT and CV in group 2 (p < 0.05).

Conclusions: Although tBUT values were significantly higher in the combination treatment group, CCT and CV values were significantly lower. Due to the decrease in corneal thickness, IOP was determined to be significantly lower.     

Clinical trial evaluating Viscoat and Visthesia ophthalmic viscosurgical devices in corneal endothelial loss after cataract extraction and intraocular lens implantation

Purpose: To assess and compare the safety and the efficacy of VisThesia? and Viscoat® in cataract surgery.

Methods: This prospective randomized clinical trial included 44 eyes of 44 patients that were assigned randomly to undergo phacoemulsification either with VisThesia? or with Viscoat®. Preoperative data included age, gender, visual acuity, IOP and mean endothelial cell density. Postoperative, best corrected visual acuity (BCVA), IOP, mean endothelial cell density and painful sensation during surgery were recorded.

Results: BCVA, evaluated with Snellen chart in decimal fraction, was statistically improved in both groups. Specifically, mean BCVA in VisThesia group was increased from 0.28?±?1.8 SD preoperatively to 0.83?±?1.4 SD postoperatively, whereas, in the Viscoat group, BCVA was increased from 0.31?±?2.1 SD preoperatively, to 0.85?±?1.2 SD after surgery (p?>?0.1). The mean postoperative IOP was lower in the VisThesia group, but the difference was not statistically significant (p?>?0.1). Preoperatively, the mean endothelial cell count was 2322.3?±?161.1 SD cells/mm² in Viscoat group and 2304.8?±?142.8 SD cells/mm² in the VisThesia group, similar between groups (p?>?0.1). At day 15 after cataract surgery the postoperative endothelial cell count was 2102.9?±?182.8 SD cells/mm² in Viscoat group and 2032.6?±?160.4 SD cells/mm² in the VisThesia group (p?>?0.1). The mean endothelial cell decrease was 212?cells/mm² (9.1%) in the Viscoat group and 272?cells/mm² (11.8%) in the VisThesia group. The difference was not statistically significant between the two groups (t-test?=?0.18, p?>?0.1). This value is within standard normal endothelial cell decrease after a cataract surgery. Painful sensation was not reported during any stage of the procedure.

Conclusions: Topical-intracameral anesthesia with VisThesia? allows cataract surgery without any painful sensation in the majority of patients. Both Viscoat® and VisThesia? have similar safety profile during intra- and post-operative period and identical endothelial protection, as endothelial cell loss is within normal limits.     

Potent enhancement of transdermal absorption and stability of human tyrosinase plasmid (pAH7/Tyr) by Tat peptide and an entrapment in elastic cationic niosomes

Abstract

Enhancement of transdermal absorption through rat skin and stability of the human tyrosinase plasmid (P) using Tat (T) and an entrapment in elastic cationic niosomes (E) were described. E (Tween61:cholesterol:DDAB at 1:1:0.5 molar ratio) were prepared by the freeze-dried empty liposomes (FDELs) method using 25% ethanol. TP was prepared by a simple mixing method. TPE was prepared by loading T and P in E at the T:P:E ratio of 0.5:1:160 w/w/w. For gel formulations, P, TP, PE and TPE were incorporated into Carbopol 980 gel (30?µg of plasmid per 1?g of gel). For the transdermal absorption studies, the highest cumulative amounts and fluxes of the plasmid in viable epidermis and dermis (VED) were observed from the TPE of 0.31?±?0.04?µg/cm² and 1.86?±?0.24?µg/cm²/h (TPE solution); and 4.29?±?0.40?µg/cm² and 25.73?±?2.40?µg/cm²/h (TPE gel), respectively. Only plasmid from the PE and TPE could be found in the receiving solution with the cumulative amounts and fluxes at 6?h of 0.07?±?0.01?µg/cm² and 0.40?±?0.08?µg/cm²/h (PE solution); 0.10?±?0.01?µg/cm² and 0.60?±?0.06?µg/cm²/h (TPE solution); 0.88?±?0.03?µg/cm² and 5.30?±?0.15?µg/cm²/h (PE gel); and 1.02?±?0.05?µg/cm² and 6.13?±?0.28?µg/cm²/h (TPE gel), respectively. In stability studies, the plasmid still remained at 4?±?2?°C and 25?±?2?°C of about 48.00–65.20% and 27.40–51.10% (solution); and 12.34–38.31% and 8.63–36.10% (gel), respectively, whereas at 45?±?2?°C, almost all the plasmid was degraded. These studies indicated the high potential application of Tat and an entrapment in elastic cationic niosomes for the development of transdermal gene delivery system.     

Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

Cyclodextrin-based nanosponges: effective nanocarrier for Tamoxifen delivery

The purpose of the present study was to develop Tamoxifen loaded β-cyclodextrin nanosponges for oral drug delivery. The three types of Tamoxifen loaded β-cyclodextrin nanosponges were synthesized by varying the molar ratios of β-cyclodextrin to carbonyldiimidazole as a crosslinker viz. 1:2, 1:4 and 1:8. The Tamoxifen nanosponge complex (TNC) with particle size of 400–600?nm was obtained by freeze drying method. Differential scanning calorimetry, Fourier transformed infra-red spectroscopy and X-ray powder diffraction studies confirmed the complexation of Tamoxifen with cyclodextrin nanosponge. AUC and C_max of TNC formulation (1236.4?±?16.12 µg·mL^?1 h, 421.156?±?0.91 µg/mL) after gastric intubation were 1.44 fold and 1.38 fold higher than plain drug (856.079?±?15.18 µg·mL^?1 h, 298.532?±?1.15 µg/mL). Cytotoxic studies on MCF-7 cells showed that TNC formulation was more cytotoxic than plain Tamoxifen after 24 and 48?h of incubation.     

Swept-source optical coherence tomography analysis in asthmatic children under inhaled corticosteroid therapy

Purpose: To evaluate retinal nerve fiber layer thickness (RNFLT), ganglion cell layer thickness (GCLT), subfoveal choroidal thickness (SFCT), and central retinal thickness (CRT) in asthmatic children who were under inhaled corticosteroid treatment by using Swept-Source Optical Coherence Tomography (SS-OCT).

Material and methods: Fifty-three children were prospectively analyzed in the study. Group 1 included 31 asthmatic children and group 2 included 22 healthy children. Asthmatic children received a dose 250?μg daily of inhaled fluticasone propionate (Flexotide, GlaxoSmithKline, Middlesex, UK). Allergy parameters including, exposure to smoke, eosinophil count, percentage of eosinophils, immunoglobuline (Ig) E levels, number of asthma attacks, number of sensitivity to allergens and follow-up time were recorded. The RNFLT, GCLT, SFCT, and CRT were analyzed with SS-OCT and the data were compared between the groups.

Results: There were 13 girls (41.9%) and 18 boys (58.1%) in group 1 and 13 girls (59.1%) and 9 boys (40.9%) in group 2 (p?=?0.22). The mean age was 9.3?±?2.2 years in group 1 and 9.9?±?1.5 years in group 2 (p?=?0.08). The mean CRT (239.26?±?34.56 µm versus 226.82?±?26.23 µm, p?=?0.22) and mean SFCT (273.97?±?40.95 µm versus 280.41?±?32.78 µm, p?=?0.54) did not significantly differ between the groups. The superior, inferior, and average RNFLT were significantly lower in group 1 than group 2 (p?p?p?Conclusions: The SS-OCT revealed that asthmatic children under inhaled corticosteroid treatment have lower RNFLT than healthy subjects.     

Identification of cytochrome P450 enzymes involved in the metabolism of 3′,4′-methylenedioxy-α-pyrrolidinopropiophenone (MDPPP), a designer drug,in human liver microsomes

The metabolism of 3′,4′-methylenedioxy-α-pyrrolidinopropiophenone (MDPPP), a novel designer drug, to its demethylenated major metabolite 3′,4′-dihydroxy-pyrrolidinopropiophenone (di-HO-PPP) was studied in pooled human liver microsomes (HLM) and in cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes. CYP2C19 catalysed the demethylenation with apparent K_m and V_max values of 120.0?±?13.4?µM and 3.2?±?0.1?pmol/min/pmol?CYP, respectively (mean?±?standard deviation). CYP2D6 catalysed the demethylenation with apparent K_m and V_max values of 13.5?±?1.5?µM and 1.3?±?0.1 pmol/min/pmol?CYP, respectively. HLM exhibited a clear biphasic profile with an apparent K_m,1 value of 7.6?±?9.0 and a V_max,1 value of 11.1?±?3.6?pmol/min/mg?protein, respectively. Percentages of intrinsic clearances of MDPPP by specific CYPs were calculated using the relative activity factor (RAF) approach with (S)-mephenytoin-4′-hydroxylation or bufuralol-1′-hydroxylation as index reactions for CYP2C19 or CYP2D6, respectively. MDPPP, di-HO-PPP and the standard 4′-methyl-pyrrolidinohexanophenone (MPHP) were separated and analysed by liquid chromatography-mass spectrometry in the selected-ion monitoring (SIM) mode. The CYP2D6-specific chemical inhibitor quinidine (3?µM) significantly (p?相似文献   

Simultaneous quantification by HPLC of the phenolic compounds for the crude drug of Prunus serotina subsp. capuli

Context: Prunus serotina Ehrenb. subsp. capuli (Cav.) McVaugh (Rosaceae), commonly known as “capulin”, is a native North American tree, commercialized and used in folk medicine for the treatment of the hypertension, gastrointestinal illnesses, and cough.

Objective: This work developed a suitable HPLC method for quantifying the major active constituents of the infusion of P. serotina, the most important preparation consumed by populations around the world.

Materials and methods: The analytical method was performed using a Fortis-RP column (150?mm?×?4.6?mm; film thickness 5?µm). The mobile phase consisted of an isocratic acetate buffer solution (pH 2.7; A) and methanol (B) (65:35 v/v) at a flow rate of 1.0?mL?min^?1.

Results: The proposed method was applied to the quantification of 1–3 in several samples of the leaves of P. serotina. The results indicated that amounts of 1–3 in the samples analyzed are uniform, and greater amounts of chlorogenic acid (2; 479.9?±?33.6?µg?g^?1, dry matter) along with hyperoside (1; 185.7?±?55.3?µg?g^?1, dry matter) were present. On the other hand, benzaldehyde (3; 118.2?±?12.1?µg?g^?1 dry matter) was found to be in lower concentration.

Conclusions: A simple, sensitive, precise, and reproducible HPLC method for the simultaneous quantification of 1–3 in P. serotina was developed and validated. This is the first report on the quantification of 1–3 as active principles, and compound 1 was selected as a marker of P. serotina, which could be useful to guarantee the quality of the crude drug and herbal products.     

Cardiovascular effects induced by N-(4'-dihydro)-piperoylthiomorpholine in normotensive rats

Objectives We have tested the cardiovascular effects of N‐(4′‐dihydro)‐piperoylthiomorpholine (LASSBio 365) on rats using an in‐vivo and in‐vitro approach. Methods LASSBio 365 (0.025, 0.05, 0.1, 0.25, 0.5 or 1 mg/kg, randomly injected) was administered to conscious unrestrained rats and the mean arterial pressure and heart rate were measured. The effects of LASSBio 365 (3 × 10^?6–3 × 10^?4m ) on rat isolated aortic rings with and without endothelium were investigated. Key findings LASSBio 365 induced a dose‐dependent decrease in mean arterial pressure and heart rate (ED50 = 158 ± 53 µg/kg). The effects evoked by LASSBio 365 (0.5 mg/kg) were inhibited by pretreatment with atropine. In anaesthetized rats, electrocardiogram recordings revealed second/third degree sinoatrial and atrioventricular blockade induced by the compound, which were completely inhibited after cardiac muscarinic blockade or cervical bilateral vagotomy. In rat isolated aortic rings, LASSBio 365 (3 × 10^?6–3 × 10^?4m ) was capable of antagonizing the contractile effects induced by phenylephrine (1 µm ) or KCl (80 mm ) (IC50 = 107 ± 6; 92 ± 6 µm , respectively). This effect was not inhibited after removal of the vascular endothelium (IC50 = 84 ± 4; 92 ± 10 µm , respectively). LASSBio 365 (10^?6–10^?4m ) antagonized CaCl₂‐induced contractions in a concentration‐dependent manner. Furthermore, LASSBio 365 (98 µm ) inhibited contractions produced by noradrenaline (1 µm ), but not those induced by caffeine (20 mm ). Conclusions These results suggested that LASSBio 365 produced negative chronotropism and reduced peripheral resistance that were probably due to the stimulation of cardiac muscarinic pathways. Peripheral vasodilation was probably linked to voltage‐dependent Ca²⁺‐channel blockade and/or specific inhibition of Ca²⁺ release from noradrenaline‐sensitive intracellular stores.     

Sulfation of resveratrol in human liver: Evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1

Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3′-phosphoadenosine-5′-phosphosulfate, three metabolites (M1–3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4′-O-sulfate, and trans-resveratrol-3-O-4′-O-disulfate, respectively. The kinetics of M1 formation in human liver cytosol exhibited an pattern of substrate inhibition with a K_i of 21.3?±?8.73?µM and a V_max/K_m of 1.63?±?0.41?µL?min^?1mg^?1 protein. Formation of M2 and M3 showed sigmoidal kinetics with about 56-fold higher V_max/K_m values for M3 than for M2 (2.23?±?0.14 and 0.04?±?0.01?µL?min^?1?mg^?1). Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. In conclusion, the results elucidate the enzymatic pathways of resveratrol in human liver, which must be considered in humans following oral uptake of dietary resveratrol.     

Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro

1.?The aim of this work was to examine the differences in the inhibitory potency of individual enantiomers and racemic mixtures of selected chiral drugs on human liver microsomal cytochromes P450.

2.?The interaction of enantiomeric forms of six drugs (tamsulosin, tolterodine, citalopram, modafinil, zopiclone, ketoconazole) with nine cytochromes P450 (CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1A2) was examined. HPLC methods were used to estimate the extent of the inhibition of specific activity in vitro.

3.?Tamsulosin (TAM) and tolterodine (TOL) inhibited CYP3A4 activity with an enantiospecific pattern. The inhibition of CYP3A4 activity differed for R-TAM (K_i 2.88?±?0.12?µM) and S-TAM (K_i 14.22?±?0.53?µM) as well as for S-TOL (K_i 1.71?±?0.03?µM) and R-TOL (K_i 4.78?±?0.17?µM). Also, the inhibition of CYP2C19 by ketoconazole (KET) cis-enantiomers exhibited enantioselective behavior: the (+)-KET (IC₅₀ 23.64?±?6.25?µM) was more potent than (?)-KET (IC₅₀ 66.12?±?12.6?µM). The inhibition of CYP2C19 by modafinil (MOD) enantiomers (R-MOD IC₅₀?=?51.79?±?8.58?µM, S-MOD IC₅₀?=?48.62?±?9.74?µM) and the inhibition of CYP2D6 by citalopram (CIT) enantiomers (R-CIT IC₅₀?=?68.17?±?5.70?µM, S-CIT IC₅₀?=?62.63?±?7.89?µM) was not enantiospecific.

4.?Although enantiospecific interactions were found (TAM, TOL, KET), they are probably not clinically relevant as the plasma levels are generally lower than the drug concentration needed for prominent inhibition (at least 50% of CYP activity).     

Identification of cytochrome P450 enzymes involved in the metabolism of 4′-methoxy-α-pyrrolidinopropiophenone (MOPPP), a designer drug,in human liver microsomes

1. The metabolism of 4′-methoxy-α-pyrrolidinopropiophenone (MOPPP), a novel designer drug, to its demethylated major metabolite 4′-hydroxy-pyrrolidinopropio-phenone (HO-PPP) was studied in pooled human liver microsomes (HLM) and in cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes.

2. CYP2C19 catalysed the demethylation with apparent K_m and V_max values of 373.4 ± 45.1?μM and 6.0 ± 0.3?pmol?min^?1?pmol^?1 CYP, respectively (mean ± SD). Both CYP2D6 and HLM exhibited clear biphasic profiles with apparent K_m,1 values of 1.3 ± 0.4 and 22.0 ± 6.5?μM, respectively, and V_max,1 values of 1.1 ± 0.1 pmol?min^?1?pmol^?1 CYP and 169.1 ± 20.5?pmol?min^?1?mg^?1 protein, respectively.

3. Percentages of intrinsic clearances of MOPPP by particular CYPs were calculated using the relative activity factor (RAF) approach with (S)-mephenytoin-4′-hydroxylation or bufuralol-1′-hydroxylation as index reactions for CYP2C19 or CYP2D6, respectively.

4. MOPPP, HO-PPP and the standard 3′,4′-methylenedioxy-pyrrolidinopropio-phenone (MDPPP) were separated and analysed by liquid chromatography–mass spectrometry in the selected-ion monitoring (SIM) mode.

5. The CYP2D6 specific chemical inhibitor quinidine (3?μM) significantly (?p<0.0001) inhibited HO-PPP formation by 91.8 ± 0.5% (mean ± SEM) in incubation mixtures with HLM and 2?μM MOPPP.

6. It can be concluded from the data obtained from kinetic and inhibition studies that polymorphically expressed CYP2D6 is the enzyme mainly responsible for MOPPP demethylation.     

Reduced central corneal thickness in patients with isotretinoin treatment

Context: It is well known that oral isotretinoin treatment causes numerous ocular side-effects.

Objective: To investigate the effect of systemic isotretinoin treatment on central corneal thickness (CCT) values due to meibomian gland disease (MGD).

Participants: In this prospective study, 47 patients (27 men, 20 women) with nodulocystic acne vulgaris treated with oral isotretinoin (0.8?mg/kg daily) were included.

Methods: All patients were analyzed with the Pentacam Scheimpflug topography at baseline, on the 3rd and 6th month of treatment. Main outcome measures were MGD scores and CCT.

Results: The mean age of patients was 25.1?±?4.4 years. The mean MGD scores were significantly higher at 3rd month (1.3?±?0.9) and 6th month (1.5?±?1.0) of treatment compared with baseline (1.1?±?0.9) (p?p?p?=?0.038, r?=??0.221).

Conclusion: Isotretinoin treatment causes higher MGD scores. A statistically significant decrease in CCT due to MGD was detected at 6th month of treatment.     

The anti-tumor effect of folate-targeted liposome microbubbles loaded with oridonin as ultrasound-triggered tumor-targeted therapeutic carrier system

In this study, folate receptor (FR) targeted liposome microbubbles loaded with oridonin (ORI) (F-LMB-ORI), liposome loaded with ORI (L-ORI) and liposome microbubbles loaded with ORI (LMB-ORI) were prepared. In vitro release properties, cellular uptake and cytotoxicity in HepG-2 cells as well as in vivo antitumor effects in HepG-2 cells tumor-bearing mice of F-LMB-ORI, L-ORI and LMB-ORI were evaluated upon ultrasound exposure. Results showed cytotoxicity assay on F-LMB-ORI gave IC₅₀ of 0.508?±?0.018?µmol/mL on HepG-2 cells and LMB-ORI; L-ORI gave IC₅₀ of 2.424?±?0.116?µmol/mL, 3.031?±?0.122?µmol/mL in vitro, respectively. These drug delivery carriers were able to control the release of ORI. F-LMB-ORI exhibited higher binding to HepG-2 cells in comparison to LMB-ORI and L-ORI. F-LMB-ORI improved antitumor activity of ORI obviously in comparison to L-ORI, LMB-ORI under in vivo ultrasound. After the treatment for 14 d, the tumor inhibition ratio for F-LMB-ORI (the dose of ORI: 1.5?×?10^?2?g·kg^?1, once a day) was 87.6%, obviously higher than that of LMB-ORI group, L-ORI group and free ORI (the dose of ORI: 1.5?×?10^?2?g·kg^?1, once a day) which were 71.5%, 64.3% and 43.4%, respectively.     

The promising effect of barberry (Zereshk) extract against experimental pulmonary microvascular remodeling and hypertension: A comparison with sildenafil

Context: Despite the beneficial effects of barberry (Berberis integerrima Berberidaceae) on decreasing systemic hypertension, its influence has not been investigated on pulmonary hypertension.

Objective: The objective of this study is to examine the effect of barberry fruit, on monocrotaline-induced pulmonary hypertension.

Materials and methods: Nine groups were arranged as follows: the control group, the monocrotaline (M) group, the barberry groups with doses of 50, 100, and 200 (mg/kg), the M plus barberry groups, and the M plus sildenafil group. Two weeks after a single injection of monocrotaline (60?mg/kg, s.c.), barberry water extracts or sildenafil (30?mg/kg/d) were gavaged daily for 2 weeks. At the end of the 4th week, hemodynamic, biochemical, and histopathological parameters were assessed.

Results: In comparison with the M group, barberry (200?mg/kg) or sildenafil significantly reduced the right ventricular systolic pressure (RVSP) (22.95?±?1.78?mm Hg and 30.71?±?1.64?mm Hg, versus 41.28?±?1.5?mm Hg), right ventricular hypertrophy (RVH) (0.39?±?0.03 and 0.42?±?0.02, versus 0.57?±?0.02), and the medial wall thickness (MWT) (4.56?±?0.15?µm and 5.97?±?0.19?µm, versus 7.02?±?0.43?µm). Barberry or sildenafil had no significant effect on the plasma level of endothelin-1, glutathione peroxidase, and the malondialdehide of lung.

Conclusion: 200?mg/kg of barberry has an improving effect on the monocrotaline-induced pulmonary hypertension. This effect was stronger than that of the sildenafil's and may have been mediated through mechanisms other than the modulation of the endothelin-1 or redox system.