Safety Assessment of Capryloyl Salicylic Acid as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reassessed the safety of Capryloyl Salicylic Acid in cosmetic products; this ingredient is reported to function as a skin conditioning agent. The Panel reviewed relevant data relating to the safety of this ingredient in cosmetic formulations, and concluded that the available data are insufficient to make a determination that Capryloyl Salicylic Acid is safe under the intended conditions of use in cosmetic formulations.

Controlling Supramolecular Structures of Drugs by Light.

Controlling physicochemical properties of light-unresponsive drugs, by light, prima facie, a paradox approach. We expanded light control by ion pairing light-unresponsive salicylate or ibuprofen to photoswitchable azobenzene counterions, thereby reversibly controlling supramolecular structures, hence the drugs' physicochemical and kinetic properties. The resulting ion pairs photoliquefied into room-temperature ionic liquids under ultraviolet light. Aqueous solutions showed trans-cis-dependent supramolecular structures under a light with wormlike aggregates decomposing into small micelles and vice versa. Light control allowed for permeation through membranes of cis-ibuprofen ion pairs within 12 h in contrast to the trans ion pairs requiring 72 h. In conclusion, azobenzene ion-pairing expands light control of physicochemical and kinetic properties to otherwise light-unresponsive drugs.

Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion.

A microemulsion system was developed and investigated as a novel oral formulation to increase the solubility and absorption of Salicis cortex extract. This extract possesses many pharmacological activities, in particular, it is beneficial for back pain and osteoarthritic and rheumatic complaints. In this work, after qualitative and quantitative characterization of the extract and the validation of an HPLC/diode array detector analytical method, solubility studies were performed to choose the best components for microemulsion formulation. The optimized microemulsion consisted of 2.5 g of triacetin, as the oil phase, 2.5 g of Tween 20 as the surfactant, 2.5 g of labrasol as the cosurfactant, and 5 g of water. The microemulsion was visually checked, characterized by light scattering techniques and morphological observations. The developed formulation appeared transparent, the droplet size was around 40 nm, and the ζ-potential result was negative. The maximum loading content of Salicis cortex extract resulted in 40 mg/mL. Furthermore, storage stability studies and an in vitro digestion assay were performed. The advantages offered by microemulsion were evaluated in vitro using artificial membranes and cells, i.e., parallel artificial membrane permeability assay and a Caco-2 model. Both studies proved that the microemulsion was successful in enhancing the permeation of extract compounds, so it could be useful to ameliorate the bioefficacy of Salicis cortex.

Polyfluorinated salicylic acid derivatives as analogs of known drugs: Synthesis, molecular docking and biological evaluation.

We have developed the convenient methods for synthesis of polyfluorosalicylic acids and their derivatives. For the first time the biological properties of polyfluorosalicylates were investigated in vitro (permeability through the biological membranes, COX-1 inhibitory action) and in vivo (anti-inflammatory, analgesic activities, acute toxicity). Molecular docking of polyfluorinated salicylates confirmed in vitro and in vivo experiments.

Preliminary evaluation of military, commercial and novel skin decontamination products against a chemical warfare agent simulant (methyl salicylate).

Rapid decontamination is vital to alleviate adverse health effects following dermal exposure to hazardous materials. There is an abundance of materials and products which can be utilised to remove hazardous materials from the skin. In this study, a total of 15 products were evaluated, 10 of which were commercial or military products and five were novel (molecular imprinted) polymers. The efficacies of these products were evaluated against a 10 µl droplet of (14)C-methyl salicylate applied to the surface of porcine skin mounted on static diffusion cells. The current UK military decontaminant (Fuller's earth) performed well, retaining 83% of the dose over 24 h and served as a benchmark to compare with the other test products. The five most effective test products were Fuller's earth (the current UK military decontaminant), Fast-Act® and three novel polymers [based on itaconic acid, 2-trifluoromethylacrylic acid and N,N-methylenebis(acrylamide)]. Five products (medical moist-free wipes, 5% FloraFree™ solution, normal baby wipes, baby wipes for sensitive skin and Diphotérine™) enhanced the dermal absorption of (14)C-methyl salicylate. Further work is required to establish the performance of the most effective products identified in this study against chemical warfare agents.

Lamellar Liquid Crystal Improves the Skin Retention of 3-O-Ethyl-Ascorbic Acid and Potassium 4-Methoxysalicylate In Vitro and In Vivo for Topical Preparation.

The study aimed at increasing the skin retention of 3-O-ethyl-ascorbic acid (EA) and potassium 4-methoxysalicylate (4-MSK) via topical administration for effective skin-whitening. To achieve this goal, EA and 4-MSK were formulated into lamellar liquid crystalline (LLC) cream, and response surface methodology (RSM) was employed to optimize the formulation. Polarized light microscopy (PLM), differential scanning calorimetry (DSC), and rheological experiments were performed to confirm the presence of the LLC structure in the base of cream. In addition, a comparison analysis of the skin retention of the two drugs between the LLC cream and the common o/w (COW) cream was made through in vitro permeation and in vivo drug distribution experiments. As a result, the optimal formulation was defined as 1.2% of EA, 1.48% of 4-MSK, 14.05% of Schercemol™ DISM Ester (DISM) as the oil, 4.0% of Emulium® Delta as the emulsifier, and 3.0% of stearyl alcohol as the co-emulsifier. In comparison with the COW cream, the LLC cream significantly increased the skin retention of EA and 4-MSK both in vitro and in vivo. In conclusion, the LLC carrier serves as a promising choice for topical preparation by enhancing skin retention and providing desirable rheological characteristics.

Effect of food on the pharmacokinetics of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid, in healthy subjects.

OBJECTIVE: The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions. METHODS: The study participants (n=12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. RESULTS: The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 hxµg/mL for the fasting state and 22.20, 5,038 hxµg/mL for the fed state, the AUC0-∞ of triflusal and HTB were 19.79, 6,333 hxµg/mL for the fasting state and 22.44, 5,632 hxµg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB. CONCLUSION: High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects.

Comparative efficacy and bioequivalence of novel h1-antihistamine bepotastine salts (nicotinate and salicylate).

Bepotastine salts (nicotinate and salicylate) were investigated for their physicochemical properties to develop novel salt forms of bepotastine, bioequivalent to the bepotastine besilate-loaded tablet (Talion). These bepotastine salts of either nicotinate- or salicylate-loaded tablets were prepared by conventional wet granulation method, and dissolution profiles and pharmacokinetics in beagle dogs were compared to those of Talion. A novel bepotastine nicotinate has a higher solubility at varying pH levels (1.2, 4, or 6.8) than salicylate-loaded or besilate-loaded salt. In addition, those bepostastine salt forms (nicotinate and salicylate) are stable in heat, light, and water. Further, the novel nicotinate- and salicylate-loaded tablets showed similar dissolution rates to Talion in several selected dissolution media and were bioequivalent to Talion in beagle dogs in terms of area under the concentration-time curve (AUC) and maximum observed concentration (Cmax). A pharmacokinetic study performed in beagle dogs demonstrated that test and reference products were found to be bioequivalent in terms of safety, efficacy, and pharmacokinetic properties. These results suggest that bepostastine nicotinate and salicylate formulations are considered applicable candidates and are well tolerated versus the conventional bepostastine besilate formulation.

Percutaneous absorption, disposition, and exposure assessment of homosalate, a UV filtering agent, in rats.

Homosalate (HMS) is an ultraviolet (UV) filtering agent used in sunscreens and other cosmetics for skin protection purposes. Despite the widespread use of these products, absorption, disposition, and in vivo endocrine disrupting potential of HMS have not been characterized. Thus, the aim of this study was to examine the percutaneous absorption, disposition, and exposure assessment of HMS in rats. Initially, sunscreen preparations of petrolatum jelly, oily solution, lotion, and gel were prepared and evaluated for in vitro permeation of HMS across excised rat skin. Dermal permeability was greatest for gel, and this preparation was used in subsequent in vivo topical application investigations. After iv injection (0.5, 2, or 5 mg/kg), the pharmacokinetics of HMS was linear and was characterized by a large Vd(ss) (13.2-17 L/kg), high Cl(s) (4.5-6.1 L/h/kg), and long t½ (6.1-8.4 h). After topical application of gel, the bioavailability of HMS was 5.4 ± 1.1 and 4.2 ± 0.6% for high and low doses (10 and 20 mg), respectively. Consistent with the prolonged absorption (Tmax 11.2 ± 1.8 and 12 ± 0 h for low and high doses, respectively), the terminal t½ was longer after topical application (23.6-26.1 h) compared to iv injection. A population pharmacokinetic model was further developed to simultaneously fit the time courses of plasma concentrations and dermal content data after iv injection and topical application. Findings of this study may be useful to further examine the relationship between exposure and endocrine disrupting potential of HMS in risk assessment.

Formulation study of PLGA in situ films for topical delivery of salicylates.

A film-forming system (FFS) represents a convenient topical dosage form for drug delivery. In this study, a non-commercial poly(lactic-co-glycolic acid) (PLGA) was chosen to formulate an FFS containing salicylic acid (SA) and methyl salicylate (MS). This unique combination is advantageous from a therapeutic point of view, as it enabled modified salicylate release. It is beneficial from a technological perspective too, because it improved thermal, rheological, and adhesive properties of the in situ film. DSC revealed complete dissolution of SA and good miscibility of MS with the polymer. MS also ensures optimal viscoelastic and adhesive properties of the film, leading to prolonged and sustained drug release. The hydrolysis of MS to active SA was very slow at skin pH 5.5, but it apparently occurred at physiological pH 7.4. The film structure is homogeneous without cracks, unlike some commercial preparations. The dissolution study of salicylates revealed different courses in their release and the influence of MS concentration in the film. The formulated PLGA-based FFS containing 5 % SA and 10 % MS is promising for sustained and prolonged local delivery of salicylates, used mainly for keratolytic and anti-inflammatory actions and pain relief.

Pharmacokinetics of methyl salicylate-2-O-ß-D-lactoside, a novel salicylic acid analog isolated from Gaultheria yunnanensis, in dogs.

Methyl salicylate-2-O-ß-D-lactoside (MSL), a natural salicylate derivative of Gaultheria yunnanensis (Franch.) Rehder (G. yunnanensis), has been shown to provide a beneficial anti-inflammatory effect in animal models. Studies on the pharmacokinetics and bioavailability of MSL can provide both a substantial foundation for understanding its mechanism and empirical evidence to support its use in clinical practice. A simple and sensitive high-performance liquid chromatography (HPLC) method, coupled with ultraviolet analyte detection, was developed for determining the concentration of MSL and its metabolite in beagle plasma. Chromatographic separation was achieved on a Agilent Zorbax SB-C18 column (5 µM,4.6 × 250 mm). The mobile phase consisted of aqueous solution containing 0.1% phosphoric acid and acetonitrile (82:90, v/v), at a flow rate of 1 mL/min. Validation of the assay demonstrated that the developed HPLC method was sensitive, accurate and selective for the determination of MSL and its metabolite in dog plasma. After orally administering three doses of MSL, it could no longer be detected in dog plasma and its metabolite, salicylic acid, was detected. Salicylic acid showed a single peak in the plasma concentration-time curves and linear pharmacokinetics following the three oral doses (r(2) > 0.99). In contrast, only MSL was detected in plasma following intravenous administration. These results will aid in understanding the pharmacological significance of MSL. The developed method was successfully used for evaluation of the oral and intravenous pharmacokinetic profile of MSL in dogs.

Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer.

PURPOSE: S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). PATIENTS AND METHODS: In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. RESULTS: Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. CONCLUSION: The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

Pharmacokinetics of salsalate and salicylic acid in normal and diabetic rats.

The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto-Kakizaki rats. Three PK studies were conducted: (1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. (2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. (3) PK during 4 months feeding of SS-containing diet in both normal and diabetic rats. The disposition of SS and SA were evaluated simultaneously using a pharmacokinetic model comprising several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing of SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS-diet feeding, the diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F), possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in the future usage of SS in diabetes.

Modeling diabetes disease progression and salsalate intervention in Goto-Kakizaki rats.

Type 2 diabetes mellitus (T2DM) arises owing to insulin resistance and ß-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control groups (n = 6) and salsalate treatment groups (n = 6), which were fed a salsalate-containing diet from 5 to 21 weeks of age. Blood glucose and salicylate concentrations were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started at approximately 5 weeks, resulting in an increase by 15 to 25 mg/dl and a second phase at 14 to 15 weeks with an upsurge of more than 100 mg/dl. A mechanism-based model was proposed to describe the natural diabetes progression and salsalate pharmacodynamics by using a population method in S-ADAPT. Two transduction cascades were applied to mimic the two T2DM components: insulin resistance and ß-cell dysfunction. Salsalate suppressed both disease factors by a fraction of 0.622 on insulin resistance and 0.134 on ß-cell dysfunction. The substantial alleviation of diabetes by salsalate supports the hypothesis that chronic inflammation is a pathogenic factor of diabetes in GK rats. In addition, body weight and food intake were measured and further modeled by a mechanism-based growth model. Modeling results suggest that salsalate reduces weight gain by enhancing metabolic rate and energy expenditure in both GK and Wister-Kyoto rats.

Gastrointestinal safety of triflusal solution in healthy volunteers: a proof of concept endoscopic study.

PURPOSE: Triflusal is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. It was initially marketed as capsules containing 300 mg of active substance. In 2006 a new 600 mg (10 ml) oral solution form of triflusal was authorized in Spain. The primary aim of this study was to compare the gastrointestinal safety of the new triflusal oral solution with triflusal capsules in healthy volunteers. METHODS: Sixty healthy subjects were randomly assigned, in a 2.5:2.5: 1 ratio, into one of three groups, with 25 subjects receiving one bottle of triflusal oral solution (600 mg) daily, 25 subjects receiving two triflusal capsules (600 mg) once daily, and ten subjects receiving two placebo capsules once daily, respectively, during 7 consecutive days. Gastroscopy was performed at baseline before the administration of study drugs and after 4-8 h of the last dose of study drugs. Effects on the esophagus, stomach, and duodenum were measured in accordance with a modified Lanza scale. RESULTS: No differences between groups were detected at baseline. After treatment, median global scores in the placebo, triflusal solution, and triflusal capsules groups were, respectively, 0, 1, and 3 (p = 0.003 for comparison between placebo and triflusal capsules and p = 0.042 for comparison between triflusal solution and triflusal capsules). There were no significant differences between the scores on the triflusal solution and placebo groups. All treatments were well tolerated. CONCLUSION: In healthy subjects, triflusal solution induced less endoscopically apparent gastrointestinal mucosal damage than triflusal capsules and did not induce more damage than the placebo in healthy volunteers.

Evaluation of salicylic acid fatty ester prodrugs for UV protection.

The purpose of this study was to investigate the physicochemical properties and in vitro evaluation of fatty ester prodrugs of salicylic acid for ultraviolet (UV) protection. The physicochemical properties such as lipophilicity, chemical stability and enzymatic hydrolysis were investigated with the following fatty ester prodrugs of salicylic acid: octanoyl (C8SA), nonanoyl (C9SA), decanoyl (C10SA), lauroyl (C12SA), myristoyl (C14SA) and palmitoyl oxysalicylate (C16SA). Furthermore, their skin permeation and accumulation were evaluated using a combination of common permeation enhancing techniques such as the use of a lipophilic receptor solution, removal of stratum corneum and delipidization of skin. Their k' values were proportional to the degree of carbon-carbon saturation in the side chain. All these fatty esters were highly stable in 2-propanol, acetonitrile and glycerin, but unstable in methanol and ethanol. They were relatively unstable in liver and skin homogenates. In particular, C16SA was mostly hydrolyzed to its parent compound in hairless mouse liver and skin homogenates, suggesting that it might be converted to salicylic acid after its topical administration. In the skin permeation and accumulation study, C16SA showed the poorest permeation in all skins, suggesting that it could not be permeated in the skin. Furthermore, C14SA and C16SA were less accumulated in delipidized skin compared with normal skin or stripped skin, suggesting that these esters had relatively strong affinities for lipids compared with the other prodrugs in the skin. C16SA showed significantly higher dermal accumulation in all skins compared with its parent salicylic acid. Thus, the palmitoyl oxysalicylate (C16SA) might be a potential candidate for UV protection due to its absence of skin permeation, smaller uptake in the lipid phase and relatively lower skin accumulation.

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrations.

The cochlea's inaccessibility and complex nature provide significant challenges to delivering drugs and other agents uniformly, safely and efficiently, along the entire cochlear spiral. Large drug concentration gradients are formed along the cochlea when drugs are administered to the middle ear. This undermines the major goal of attaining therapeutic drug concentration windows along the whole cochlea. Here, utilizing a well-known physiological effect of salicylate, we demonstrate a proof of concept in which drug distribution along the entire cochlea is enhanced by applying round window membrane low-frequency micro vibrations with a probe that only partially covers the round window. We provide evidence of enhanced drug influx into the cochlea and cochlear apical drug distribution without breaching cochlear boundaries. It is further suggested that ossicular functionality is not required for the effective drug distribution we report. The novel method presented here of local drug delivery to the cochlea could be implemented when ossicular functionality is absent or impeded and can be incorporated in clinically approved auditory protheses for patients who suffer with conductive, sensorineural or mixed hearing loss.

Oral absorption and drug interaction kinetics of moxifloxacin in an animal model of weightlessness.

To investigate the effect of simulated weightlessness on the pharmacokinetics of orally administered moxifloxacin and the antacid Maalox or the antidiarrheal Pepto-Bismol using a tail-suspended (TS) rat model of microgravity. Fasted control and TS, jugular-vein-cannulated, male Sprague-Dawley rats received either a single 5 mg/kg intravenous dose or a single 10 mg/kg oral dose of moxifloxacin alone or with a 0.625 mL/kg oral dose of Maalox or a 1.43 mL/kg oral dose of Pepto-Bismol. Plasma concentrations of moxifloxacin were measured by HPLC. Pharmacokinetic data were analyzed using WinNonlin. Simulated weightlessness had no effect on moxifloxacin disposition after intravenous administration but significantly decreased the extent of moxifloxacin oral absorption. The coadministration of moxifloxacin with Maalox to either control or TS rats caused significant reductions in the rate and extent of moxifloxacin absorption. In contrast, the coadministration of moxifloxacin with Pepto-Bismol to TS rats had no significant effect on either the rate or the extent of moxifloxacin absorption. These interactions showed dose staggering when oral administrations of Pepto-Bismol and moxifloxacin were separated by 60 min in control rats but not in TS rats. Dose staggering was more apparent after the coadministration of Maalox and moxifloxacin in TS rats.

Salirasib in the treatment of pancreatic cancer.

The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.