In vitro skin penetration of bronidox, bronopol and formaldehyde from cosmetics.

The objective was to evaluate the influence of the formulation in the in vitro transdermal absorption through pig ear skin of three preservatives, bronopol, bronidox and formaldehyde as well as the absorption of formaldehyde from bronopol and dimethyloldimethyl hydantoin (DMDM hydantoin). An aqueous solution, an O/W emulsion and a hydrogel were assayed. Bronidox and bronopol absorption depends on the formulation. The O/W emulsion was the system that least promoted absorption of bronidox while the absorption of bronopol was lower from the hydrogel. The aqueous solution provided maximal transdermal absorption of both preservatives. Moreover, the transdermal absorption of formaldehyde released from bronopol also depends on the formulation, being the aqueous solution the system that allowed greater absorption. Transdermal absorption of formaldehyde, applied directly or released from DMDM hydantoin, is not conditioned by the excipients. The degree of transdermal absorption of all the preservatives tested is low and therefore the concentrations allowed by regulations are safely used. Nonetheless, since formaldehyde was detected in the receptor compartment after a long time exposure to bronopol and DMDM hydantoin it would be important to consider the possibility of limiting the use of these two preservatives to rinse off products as is the case of bronidox.

Pharmacokinetics and Pharmacodynamics of Cenerimod, A Selective S1P1 R Modulator, Are Not Affected by Ethnicity in Healthy Asian and White Subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor (S1P1 R) modulator in phase II development for treatment of systemic lupus erythematosus. Its pharmacokinetics (PKs), pharmacodynamics (PDs), as well as safety and tolerability were investigated in white and Asian subjects to allow for recruitment of Asian patients in future studies. A randomized, double-blind, placebo-controlled parallel-group study was performed in 20 healthy male subjects (n = 10 per ethnicity). A single, oral dose of 4 mg cenerimod or placebo (ratio 8:2) was administered under fasted conditions. The PKs of cenerimod were similar in white and Asian subjects indicated by geometric mean ratios (90% confidence interval) of 0.99 (0.80-1.21) for maximum plasma concentration, 0.96 (0.75-1.24) for area under the plasma concentration-time curve from 0 to infinity, and 1.04 (0.86-1.25) for terminal half-life. Accordingly, the extent and time course of reduction in lymphocyte count (as PD biomarker) were also similar in white and Asian subjects as compared with placebo. As observed for other S1PR modulators, a transient mean (SD) heart rate reduction in white (15.1 (14.8) bpm) and Asian (11.8 (6.16) bpm) subjects was observed following administration of cenerimod. The drug was safe and well-tolerated indicated by occurrence of a single adverse event of chemical conjunctivitis in a white subject that was not suspected as study drug related. In conclusion, the determined absence of any relevant PK or PD differences supports using the same doses of cenerimod in white and Asian patients in upcoming late-phase studies.

Characteristics, Properties and Analytical Methods for Determination of Dropropizine and Levodropropizine: A Review.

Dropropizine is a peripheral antitussive drug that acts by inhibiting cough reflex through its action on the peripheral receptors and their afferent conductors. It is marketed in a racemic form or its pure enantiomer called levodropropizine and both are available worldwide in various drug dosage formulations such as tablets, sirup and oral solution. Due to the widespread use of antitussives in the clinic it is necessary to develop efficient analytical methodologies for quality control and also for pharmacokinetic, bioavailability and bioequivalence studies. This review presents a survey of the characteristics, properties and analytical methods used for drug determination, being carried out through scientific articles as well as in official compendia. From the analyzed studies, the majority reports the use of HPLC/UV techniques for drug determination, but also spectrophotometric UV/Vis methods as well as gas chromatography, and voltammetric, potentiometric and conductometric titration methods. In addition, the methodologies addressed the determination of dropropizine or levodropropizine in different types of matrices such as raw material, pharmaceutical formulations, plasma and urine. Despite the extensive clinical use of dropropizine, data from this review evidenced a still limited number of studies dealing with analytical methods for its determination in different matrices, which may be of concern since the applicability of these methods is important for quality assurance, efficacy and safety of the medicine.

Estimation of Attainment of Steady-State Conditions for Compounds With a Long Half-Life.

Half-life is a standard result reported with analysis of pharmacokinetic data. Different definitions such as noncompartmental half-life, terminal half-life, effective half-life, and context-sensitive half-life can yield substantially different estimates of the quantity "half-life." Time to attainment of steady-state conditions is generally derived from (terminal) half-life and therefore sensitive toward the definition of half-life. Thus, estimates of the time to attain steady state must be provided with a precise definition of steady state and the method used for estimation, particularly for drugs with long (terminal) half-life. For clinical purposes, terminal half-life can have limited relevance if drug concentrations in the terminal elimination phase are low. A general rule for which half-life to use is infeasible. While limited accumulation can be negligible if a plateau in pharmacokinetics/pharmacodynamics is reached or with a wide therapeutic window (ie, exposure range), small additional drug accumulation can be highly relevant for drugs with a narrow therapeutic window. Beyond the average, estimation of individual time to attainment of steady state can add highly relevant information about the variability between subjects. Simulations from population models and the use of different definitions of steady state provide an assessment of robustness of the results. The relevance of accurate estimation of time to attainment of steady state is illustrated with cenerimod, an sphingosine-1-phosphate 1 receptor modulator with long half-life currently in clinical development for which estimates of time to steady state ranged from 35 to 110 days with different calculations.

Human skin permeation rates ex vivo following exposures to mixtures of glycol ethers.

Skin exposure to cleaning products in the general and occupational population are a public health concern. Among the most frequently identified amphiphilic organic solvents in cleaning products are propylene glycol monomethyl ether (PGME) and propylene glycol n-butyl ether (PGBE). Internal dose from skin exposure may be efficiently evaluated using in vitro flow-through diffusion cells with excised human skin. Our aim in this study was two-fold; 1) characterize the permeation rates (J), time lag (Tlag), and permeation coefficients (Kp) of PGME and PGBE in human ex-vivo skin permeation assays, and 2) determine a possible mixture effect on skin permeation characteristics when applied together. Our results showed a short Tlag for PGME and was reduced further depending on the amount of PGBE in the mixture (Tlag was reduced from 2 h to 1-1.7 h) for fresh skin. PGBE Tlag slightly increased when mixed with 50 % or more PGME. Permeation rate decreased to half for both PGME and PGBE in mixture at any concentration. This substantial permeation was greater with previously frozen skin. This mixture effect could favor permeation of other compounds through human skin.

Pharmacokinetics and Tolerability of the Novel Non-immunosuppressive Fingolimod Derivative, OSU-2S, in Dogs and Comparisons with Data in Mice and Rats.

In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range. OSU-2S did not significantly modulate CYP enzyme activity up until 50 µM, and Caco-2 data suggested low permeability with active efflux at 2 µM. Apparent oral bioavailability in mice was 16% and 69% at 10 and 50 mg/kg, respectively. In rats, bioavailability was 24%, 35%, and 28% at 10, 30, and 100 mg/kg, respectively, while brain/plasma ratio was 36 at 6-h post-dose at 30 mg/kg. In dogs, OSU-2S was well tolerated with oral capsule bioavailability of 27.5%. Plasma OSU-2S exposures increased proportionally over a 2.5-20 mg/kg dose range. After 4 weeks of 3 times weekly, oral administration (20 mg/kg), plasma AUClast (26.1 µM*h), and Cmax (0.899 µM) were nearly 2-fold greater than those after 1 week of dosing, and no food effects were observed. The elimination half-life (29.7 h), clearance (22.9 mL/min/kg), and plasma concentrations of repeated oral doses support a 3-times weekly dosing schedule in dogs. No significant CBC, serum biochemical, or histopathological changes were observed. OSU-2S has favorable oral PK properties similar to fingolimod in rodents and dogs and is well tolerated in healthy animals. This work supports establishing trials of OSU-2S efficacy in dogs with spontaneous tumors to guide its clinical development as a cancer therapeutic for human patients.

Absorption, distribution, metabolism, and excretion of cenerimod, a selective S1P1 receptor modulator in healthy subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor modulator under development for treatment of systemic lupus erythematosus.This single-centre, open-label, single-dose study investigated the mass balance and excretion routes and aimed at identifying and quantifying cenerimod metabolites in plasma, urine, and faeces after oral administration of 2 mg/100 µCi (3.7 MBq) of 14C-cenerimod.Total mean cumulative recovery was 84% of the administered dose (58-100% in faeces and 4.6-12% in urine). In a 0-504 h cross-subject area under the curve plasma pool, cenerimod and two metabolites were detected accounting for 78, 6.0, and 4.9% of total radioactivity, respectively, i.e. no major metabolite was identified in plasma. Cenerimod was only detected in faeces and accounted for 17% of the radioactivity excreted in this matrix. The metabolite M32 was detected in both urine and faeces and represented 23% and 66% of radioactivity excreted in these matrices, respectively. Other metabolites of unknown structure were detected in small amounts. Overall, M32 and cenerimod accounted for 52% and 13%, respectively, of the total radioactivity recovered.Among the excreted metabolites, only the non-enzymatically formed M32 represented more than 25% of total drug-related material. Therefore, no pharmacokinetic drug-drug interaction studies are foreseen.

Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the rac-dropropizine to Sprague-Dawley rats.

Levodropropizine (LDP) is a non-opioid anti-tussive. The stereoselective pharmacokinetics and tissue distribution (TD) of LDP vs. dextrodropropizine (DDP) have been characterized after oral and intravenous (IV) administration of LDP and rac-dropropozine in rats.Oral/IV doses of 50/5.0 mg/kg and 25/2.5 rac-dropropizine and LDP were employed. TD study focused on tissues such as liver, lung and kidney. Blood samples were collected for pharmacokinetic and TD evaluation. Validated methods were used to quantitate LDP, DDP and rac-dropropizine.No stereoselectivity in pharmacokinetics was observed between LDP vs. DDP following rac-dropropizine. However, LDP pharmacokinetics after LDP administration (oral/IV) appeared to be different compared to LDP derived from rac-dropropizine.TD data were similar between the two enantiomers regardless of oral/IV rac-dropropizine administration. When LDP alone was administered, levels were comparable to those derived for LDP from rac-dropropizine after oral/IV. However, in the lung and kidney tissues, the exposure after oral dosing was higher for LDP alone as compared to LDP from rac-dropropizine.In summary, complete characterization of stereoselective pharmacokinetics and TD of rac-dropropizine has been reported after oral/IV routes. It was evident that the presence of DDP, increased the plasma/tissue exposure of LDP which was evident after oral rac-dropropizine dosing.

Quality-by-Design Approach for Biological API Encapsulation into Polymersomes Using "Off-the-Shelf" Materials: a Study on L-Asparaginase.

Polymersomes are versatile nanostructures for protein delivery with hydrophilic core suitable for large biomolecule encapsulation and protective stable corona. Nonetheless, pharmaceutical products based on polymersomes are not available in the market, yet. Here, using commercially available copolymers, we investigated the encapsulation of the active pharmaceutical ingredient (API) L-asparaginase, an enzyme used to treat acute lymphoblastic leukemia, in polymersomes through a quality-by-design (QbD) approach. This allows for streamlining of processes required for improved bioavailability and pharmaceutical activity. Polymersomes were prepared by bottom-up (temperature switch) and top-down (film hydration) methods employing the diblock copolymers poly(ethylene oxide)-poly(lactic acid) (PEG45-PLA69, PEG114-PLA153, and PEG114-PLA180) and the triblock Pluronic® L-121 (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEG5-PPO68-PEG5). Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and the risk assessment were discussed for the early phase of polymersome development. An Ishikawa diagram was elaborated focusing on analytical methods, raw materials, and processes for polymersome preparation and L-asparaginase encapsulation. PEG-PLA resulted in diluted polymersomes systems. Nonetheless, a much higher yield of Pluronic® L-121 polymersomes of 200 nm were produced by temperature switch, reaching 5% encapsulation efficiency. Based on these results, a risk estimation matrix was created for an initial risk assessment, which can help in the future development of other polymersome systems with biological APIs nanoencapsulated.

Percutaneous permeability of 1-phenoxy-2-propanol, a preservative in cosmetics.

1-Phenoxy-2-propanol (PP) is used as a preservative in cosmetics. PP is currently permitted to be used to up to 1% in cosmetic formulations in Korea and Europe. For risk assessment, percutaneous absorption is a crucial factor, but dermal absorption of PP has not yet been reported. In this study, Franz diffusion method was used to determine the percutaneous penetration of PP using the dorsal skin of rats. Each formulation of shampoo or cream, 113.6 mg/cm2, was applied to a donor compartment of Franz diffusion cell for 24 h. Receptor fluid was collected at 0, 1, 2, 4, 8, 12, and 24 h following dermal application. Remaining formulation was removed with a cotton swab after last sampling. Using tape stripping method, stratum corneum was removed. PP in epidermis and dermis was extracted in PBS for 24 h. The concentration of PP from the swab, stratum corneum, and epidermis and dermis samples was determined using high performance liquid chromatography. Total percutaneous absorption rates of PP for shampoo and cream were 50.0 ±â€¯6.0% and 33.0 ±â€¯3.2%, respectively. In vitro skin permeability was calculated as 1,377.2 ±â€¯240.1 mg/cm2 for shampoo and 1,038.0 ±â€¯72.2 mg/cm2 for cream for 24 h.

Enantioselective LC-ESI-MS/MS determination of dropropizine enantiomers in rat plasma and application to a pharmacokinetic study.

We developed and validated a simple, sensitive, selective and reliable LC-ESI-MS/MS method for direct quantitation of dropropizine enantiomers namely levodropropizine (LDP) and dextrodropropizine (DDP) in rat plasma without the need for derivatization as per regulatory guidelines. Dropropizine enantiomers and carbamazepine (internal standard) were extracted from 50 µL rat plasma using ethyl acetate. LDP and DDP resolved with good baseline separation (Rs = 4.45) on a Chiralpak IG-3 column. The mobile phase consisted of methanol with 0.05% diethylamine pumped at a flow rate of 0.5 mL/min. Detection and quantitation were done in multiple reaction monitoring mode following the transitions m/z 237 → 160 and 237 → 194 for dropropizine enantiomers and the internal standard, respectively, in the positive ionization mode. The proposed method provided accurate and reproducible results over the linearity range of 3.23-2022 ng/mL for each enantiomer. The intra- and inter-day precisions were in the ranges of 3.38-13.6 and 5.11-13.8 for LDP and 4.19-11.8 and 8.89-10.1 for DDP. Both LDP and DDP were found to be stable under different stability conditions. The method was successfully used in a stereoselective pharmacokinetic study of dropropizine enantiomers in rats following oral administration of racemate dropropizine at 100 mg/kg. The pharmacokinetic results indicate that the disposition of dropropizine enantiomers is not stereoselective and chiral inversion does not occur in rats.

Evaluation of the effects of food on levodropropizine controlled-release tablet and its pharmacokinetic profile in comparison to that of immediate-release tablet.

BACKGROUND: Levodropropizine is a non-opioid antitussive agent that inhibits cough reflex by reducing the release of sensory peptide in the peripheral region. To improve patients' compliance, a controlled-release (CR) tablet is under development. The aim of this study was to compare the pharmacokinetic (PK) profiles of the CR and immediate-release (IR) tablets of levodropropizine. In addition, the effect of food on the PK properties of levodropropizine CR tablet in healthy subjects was evaluated. SUBJECTS AND METHODS: A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence, crossover study was conducted on 47 healthy subjects. All subjects were randomly assigned to one of the six sequences, which involve combinations of the following three treatments: levodropropizine IR 60 mg three times in the fasted state (R), levodropropizine CR 90 mg two times in the fasted state (T), and levodropropizine CR 90 mg two times in the fed state (TF). Serial blood samples were collected up to 24 h after the first dose. Tolerability was assessed based on the vital signs, adverse events (AEs), and clinical laboratory tests. RESULTS: Levodropropizine CR showed lower maximum drug concentration (Cmax) and similar total exposure compared to levodropropizine IR. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) of T to R for the Cmax and area under the concentration-time curve from the 0 to 24 h time points (AUC0-24h) were 0.80 (0.75-0.85) and 0.89 (0.86-0.93), respectively. In the fed group, levodropropizine CR showed exposure similar to that in the fasted group. The GMRs (90% CIs) of TF to T for the Cmax and AUC0-24h were 0.90 (0.85-0.97) and 1.10 (1.05-1.14), respectively. No serious AEs occurred with both levodropropizine CR and IR tablets. CONCLUSION: Total systemic exposure for levodropropizine was similar in subjects receiving the CR and IR formulations in terms of the AUC. Although food delayed the absorption of levodropropizine CR, systemic exposure was not affected.

Safety Assessment of Tromethamine, Aminomethyl Propanediol, and Aminoethyl Propanediol as Used in Cosmetics.

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of tromethamine, aminomethyl propanediol, and aminoethyl propanediolas used in cosmetics. All 3 ingredients are reported to function in cosmetics as pH adjusters, and tromethamine and aminomethyl propanediol are also reported to function as fragrance ingredients. The Panel reviewed relevant animal and human data related to these ingredients, along with a previous safety assessment of aminomethyl propanediol. The Panel concluded that tromethamine, aminomethyl propanediol, and aminoethyl propanediol are safe in cosmetics in the practices of use and concentration as given in this safety assessment.

Novel cationic supersaturable nanomicellar systems of raloxifene hydrochloride with enhanced biopharmaceutical attributes.

The work describes systematic development of nanomicellar cationic supersaturable self-nanoemulsifying drug delivery systems (CS-SNEDDS) for augmenting oral biopharmaceutical performance of raloxifene hydrochloride. Plain SNEDDS formulation containing Capryol 90, Cremophor RH 40, and Transcutol HP was optimized using D-optimal mixture design. SNEDDS were characterized for emulsification time, globule size, in vitro drug release, and ex vivo permeation. The CS-SNEDDS formulation was prepared from the optimized SNEDDS by adding oleylamine as the cationic charge inducer and HPMC as the polymeric precipitation inhibitor. Evaluation of CS-SNEDDS was carried out through in vitro cell line studies on Caco-2 and MCF-7 cells, in situ perfusion, and in vivo pharmacokinetic studies, which indicated significant improvement in biopharmaceutical attributes of the drug from CS-SNEDDS over plain drug.

Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance.

New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics.

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety.

Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity.

OBJECTIVE: To determine the feasibility of using quantitative changes in vaginal permeability to small molecules as a measure of candidate microbicide toxicity. STUDY DESIGN: Controlled, open-labeled, prospective study. Seven healthy women received a single vaginal dose of hydroxyethylcellulose gel (HEC), nonoxynol-9 (N-9) or K-Y Jelly. Each gel was radiolabeled with a small molecule ((99m)Tc-DTPA) followed by 12-h blood and urine collection. Pharmacokinetic (PK) parameters of (99m)Tc-DTPA were calculated to compare the impact of each gel on vaginal permeability. Each woman served as her own control. The Friedman test with post hoc Wilcoxon test was used to detect differences among the gels. RESULTS: Vaginal permeability of (99m)Tc-DTPA was highest for the N-9 radiolabel. N-9 plasma area under the concentration curve was 2.7-fold higher (p=.04), and peak concentration was threefold higher (p=.04) compared to HEC. There were no significant PK parameter differences between HEC and K-Y Jelly or between N-9 and K-Y Jelly. Cumulative dose-adjusted median (interquartile range) 12-h timed urine gamma activity was 66.70 × 10(-4)µCi (27.90-152.00) following HEC dosing, 103.00 × 10(-4)µCi (98.20-684.00) following N-9 gel dosing and 20.30 × 10(-4)µCi (11.10-55.90) following K-Y gel dosing. The differences between urine HEC and K-Y Jelly (p=.047) and between N-9 and K-Y Jelly (p=.016) were statistically significant. CONCLUSIONS: It is feasible to measure differences in vaginal permeability among vaginal gels using a radiolabeled small molecule, though there are permeability differences that require a nuanced understanding of gel composition to interpret the results. IMPLICATIONS: Establishing the safety of both vehicle and active pharmaceutical ingredient is an essential task in microbicide development, to be determined as soon as possible. This study suggests that a combination of microbicide toxicity assessments, that is, cervicovaginal permeability, inspection and histopathology, may need to be studied simultaneously.

Localized delivery of a lipophilic proteasome inhibitor into human skin for treatment of psoriasis.

PURPOSE: Pentaerythritol tetrakis (3,5-di-tert-butyl-4-hydroxyhydrocinnamate) (PTTC) is a cinnamate tetraester with proteasome inhibitor activity, which may be used as a topical treatment in psoriasis, but has a computed log P of 23. The objective of this in vitro study was to determine the intradermal delivery, skin irritation and potential efficacy of PTTC in treating psoriasis. METHODS: Solubility studies were performed to find a suitable vehicle for PTTC. Permeation studies were performed with microneedle-treated skin. A cell culture irritation test was dosed with a positive control, negative control and PTTC. An MTT assay was performed to evaluate cell viability and irritancy. Psoriatic cell culture was also dosed with PTTC and IL-6 levels were determined by ELISA. RESULTS: Solubility was greatest in dimethyl sulfoxide and ethyl pyruvate, with dimethyl sulfoxide delivering a greater amount (2343.41 ± 384.26 µg) into stratum corneum. PTTC alone as well as topical PTTC emulsion formulation were found to be non-irritant with cell viability of 69.0 ± 5.64% and 74.6 ± 5.03%, respectively. Treatment with neat PTTC slightly reduced IL-6 levels and PTTC emulsion significantly reduced IL-6 levels to 92.53 ± 12.74 pg/ml compared to basal levels (141.69 ± 8.41 pg/ml). CONCLUSION: PTTC can be delivered intradermally to potentially treat psoriasis.

Synthesis and evaluation of fluorinated fingolimod (FTY720) analogues for sphingosine-1-phosphate receptor molecular imaging by positron emission tomography.

Sphingosine-1-phosphate (S1P) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G-protein coupled receptors (GPCRs): S1P1-S1P5. S1P and its receptors (S1PRs) play important roles in the immune, cardiovascular, and central nervous systems and have also been implicated in carcinogenesis. Recently, the S1P analogue Fingolimod (FTY720) has been approved for the treatment of patients with relapsing multiple sclerosis. This work presents the synthesis of various fluorinated structural analogues of FTY720, their in vitro and in vivo biological testing, and their development and application as [(18)F]radiotracers for the study of S1PR biodistribution and imaging in mice using small-animal positron emission tomography (PET).

Effect of fingolimod (FTY720) on cerebral blood flow, platelet function and macular thickness in healthy volunteers.

AIM: Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral disease modifying therapy approved for the treatment of relapsing multiple sclerosis. The aim of this double-blind, placebo-controlled study was to evaluate the effect of fingolimod on cerebral blood flow, platelet function and macular thickness in healthy volunteers. METHODS: The study included 88 healthy volunteers who received fingolimod 0.5 mg or 1.25 mg or matched placebo over a period of 4 weeks. Transcranial colour coded sonography was performed to measure mean blood flow velocities, the platelet function was measured by the PFA-100® assay using a collagen/epinephrine cartridge and macular thickness was measured using optical coherence tomography. An assessment of non-inferiority of fingolimod vs. placebo was performed against a reference value (20% of the overall baseline value). RESULTS: All 88 randomized participants completed the study. At day 28 compared with baseline value, for 0.5 mg, 1.25 mg and placebo treatments, the mean middle cerebral artery blood flow velocity decreased by 4, 1 and 3.7 cm s(-1), respectively. The platelet function analyzer closure time increase was not significant (7.8, 7.5 and 10.4 s, respectively). The mean percentage change in the central foveal thickness from baseline for both eyes was below 3% for all groups. The safety profile of fingolimod in this study was found consistent with the previous reports. CONCLUSIONS: In healthy volunteers, the changes seen with both fingolimod doses were found to be within normal variability, non-inferior and comparable with those observed with placebo for all the pharmacodynamic parameters assessed.