The combined effect of tranilast 8% liposomal gel on the final cosmesis of acne scarring in patients concomitantly treated by isotretinoin: prospective, double-blind, split-face study.

BACKGROUND: Tranilast [N-(3,4-dimethoxycinnamoyl) anthranilic acid] has never been investigated for the prevention and treatment of acne scars. AIM: To evaluate the efficacy and safety of tranilast 8% gel in improving the final appearance of patients with acne scarring concomitantly treated by isotretinoin. METHODS: This was a prospective, double-blind, split-face study, which enrolled 40 otherwise healthy participants (aged 18-49 years) with facial acne scars. For each patient, one half of the face were treated with tranilast 8% liposomal gel and the other half with a water-based placebo. Using the Global Aesthetic Improvement Scale (GAIS), acne scars were evaluated by two dermatologists and by the patients, and the patients also rated their satisfaction with the treatment and reported adverse effects. RESULTS: In total, 32 participants completed the trial. The mean GAIS scores at 5 months post-treatment were significantly lower (better outcome) for the tranilast-treated side than the placebo-treated areas in patients concomitantly treated with isotretinoin (P < 0.001). All the isotretinoin-treated patients reported greater satisfaction and better general improvement in the skin's appearance and texture, and also greater improvement of pigment and redness on the tranilast 8% gel-treated side compared with the control side. CONCLUSION: Combined topical application of tranilast 8% gel twice daily with oral isotretinoin treatment in the active phase of acne vulgaris may result in fewer scars, finer skin texture and enhanced appearance.

Phototoxic risk assessment of dermally-applied chemicals with structural variety based on photoreactivity and skin deposition.

Combined use of photochemical and pharmacokinetic (PK) data for phototoxic risk assessment was previously proposed, and the system provided reliable phototoxic risk predictions of chemicals in same chemical series. This study aimed to verify the feasibility of the screening system for phototoxic risk assessment on dermally-applied chemicals with wide structural diversity, as a first attempt. Photochemical properties of test chemicals, 2-acetonaphthalene, 4'-methylbenzylidene camphor, 6-methylcoumarin, methyl N-methylanthranilate, and sulisobenzone, were evaluated in terms of UV absorption and reactive oxygen species (ROS) generation, and PK profiles of the test chemicals in rat skin were characterized after dermal co-application. All test chemicals showed strong UVA/B absorption with molar extinction coefficients of over 3000 M-1⋅cm-1, and irradiated 2-acetonaphthalene, 6-methylcoumarin, and methyl N-methylanthranilate exhibited significant ROS generation. Dermally-applied 2-acetonaphthalene and 4'-methylbenzylidene camphor indicated high and long-lasting skin deposition compared with the other test chemicals. Based on the photochemical and PK data, 2-acetonaphthalene was predicted to have potent phototoxic risk. The predicted phototoxic risk of the test chemicals by integration of obtained data was mostly consistent with their in vivo phototoxicity observed in rat skin. The screening strategy employing photochemical and PK data would have high prediction capacity and wide applicability for photosafety evaluation of chemicals.

Pharmacokinetics of tolfenamic acid in green sea turtles (Chelonia mydas) after intravenous and intramuscular administration.

The present study aimed to evaluate the pharmacokinetic features of tolfenamic acid (TA) in green sea turtles, Chelonia mydas. Green sea turtles were administered single either intravenous (i.v.) or intramuscular (i.m.) injection of TA, at a dose of 4 mg/kg body weight (b.w.). Blood samples were collected at preassigned times up to 168 hr. The plasma concentrations of TA were measured using a validated liquid chromatography tandem mass spectrometry method. Tolfenamic acid plasma concentrations were quantifiable for up to 168 hr after i.v. and i.m. administration. The concentration of TA in the experimental green sea turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 55.01 ± 8.34 µg/ml following i.m. administration. The elimination half-life values were 32.76 ± 4.68 hr and 53.69 ± 3.38 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 72.02 ± 10.23%, and the average binding percentage of TA to plasma protein was 19.43 ± 6.75%. Based on the pharmacokinetic data, the i.m. administration of TA at a dosage of 4 mg/kg b.w. might be sufficient to produce a long-lasting anti-inflammatory effect (7 days) for green sea turtles. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats.

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration-time curve (AUC0-∞ ), elimination half-life (t1/2ʎz ), total clearance (ClT ) and volume of distribution at steady state (Vdss ) were 6.64 ± 0.81 hr* µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h-1  kg-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t1/2ʎz , increased dose-normalized AUC0-∞ , and decreased ClT . In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.

Pharmacokinetics of tolfenamic acid in Hawksbill turtles (Eretmochelys imbricata) after single intravenous and intramuscular administration.

To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for Hawksbill turtles. Therefore, the present study aimed to assess the pharmacokinetic features of tolfenamic acid (TA) in Hawksbill turtles, Eretmochelys imbricata, after single intravenous (i.v.) and intramuscular (i.m.) administration at dosage 4 mg/kg body weight (b.w.). The study (parallel design) used 10 Hawksbill turtles randomly divided into equal groups. Blood samples were collected at assigned times up to 144 hr. The concentrations of TA in plasma were quantified by a validated liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). The concentration of TA in the experimental turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 89.33 ± 6.99 µg/ml following i.m. administration. The elimination half-life values were 38.92 ± 6.31 hr and 41.09 ± 9.32 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 94.46%, and the average binding percentage of TA to plasma protein was 31.39%. TA demonstrated a long half-life and high bioavailability following i.m. administration. Therefore, the i.m. administration is recommended for use in clinical practice because it is both easier to perform and provides similar plasma concentrations to the i.v. administration. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep.

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Changes in novel gastrointestinal and renal injury markers in the blood plasma of sheep following increasing intravenous doses of tolfenamic acid.

The administration of high doses of non-steroidal anti-inflammatory drugs (NSAID), such as tolfenamic acid (TA), has undesirable effects on different organs. Some novel biomarkers have been reported that can determine the gastrointestinal and renal injury caused by a high dose of NSAIDs or other toxic substances. This study was aimed at determining the changes in gastrointestinal (TFF2 and HYP), renal (NGAL and KIM-1) and cardiac (cTn-I, CK-MB) injury markers after the use of increasing intravenous doses of TA in sheep. TA was administered intravenously to groups of six sheep each, at the dose levels of 0 (Group 0, i.e., G0), 2 (G2), 4 (G4), 8 (G8) and 16 (G16) mg/kg. The concentrations of the studied biomarkers were measured at 3, 9, 18 and 36 h after administration of TA. The TFF2 and NGAL concentrations in G16 were found to be significantly higher (P < 0.05) than in the other groups except for G8 at different sampling times. HYP concentration in G16 was observed to be significantly (P < 0.05) lower than that in all other groups at 36 h. KIM-1 level in G16 was significantly (P < 0.05) higher than in all other groups at different sampling times. An increase in the renal markers, KIM-1 and NGAL, in G8 was observed before any change in plasma creatinine and urea. The cardiac marker cTn-I in G16 was significantly (P < 0.05) higher than in other groups at different sampling times. The results showed that the novel biomarkers (HYP, TFF2, NGAL, and KIM-1) can be used to determine gastric and renal injury in sheep.

Identification of novel plasminogen activator inhibitor-1 inhibitors with improved oral bioavailability: Structure optimization of N-acylanthranilic acid derivatives.

Novel plasminogen activator inhibitor-1 (PAI-1) inhibitors with highly improved oral bioavailability were discovered by structure-activity relationship studies on N-acyl-5-chloroanthranilic acid derivatives. Because lipophilic N-acyl groups seemed to be important for the anthranilic acid derivatives to strongly inhibit PAI-1, synthesis of compounds in which 5-chloroanthranilic acid was bound to a variety of highly lipophilic moieties with appropriate linkers was investigated. As the result it appeared that some of the derivatives possessing aryl- or heteroaryl-substituted phenyl groups in the acyl chain had potent in vitro PAI-1 inhibitory activity. Oral absorbability of typical compounds was also evaluated in rats, and compounds 40, 55, 60 and 76 which have diverse chemical structure with each other were selected for further pharmacological evaluation.

Exploration of toxicological impacts following acute and sub-chronic exposure to ethyl anthranilate-loaded mosquito repellent patch.

In the recent years, growing concern about the potential toxicity of synthetic repellents has led to the development of environmentally safe non-toxic insect control methods. Present investigation explores the toxicological impacts of ethyl anthranilate-loaded mosquito repellent patch (EAMRP) on respiratory system following acute and sub-chronic inhalation exposure in Wistar rats. Lungs parameters such as enhanced pause, tidal volume, respiration rate, inspiration time, and expiration time were determined using whole body plethysmograph. X-ray, scanning electron microscopy and histology were utilized to study the morphology and microscopical architecture of lungs. Hematological and serum biochemical markers were estimated. Cytokines such as IL-1ß, IL-2, and IL-12 were also estimated in bronchoalveolar lavage fluid using ELISA kits. Finally, acute oral and dermal toxicity studies were carried out to study the accidental or intentional poisoning due to the ingestion and skin contact of EAMRP, respectively. The findings demonstrate that inhalation exposure to EAMRP did not pose any significant dose related toxicity in above mentioned experiments. Further, no appreciable toxicity was observed in both acute oral and dermal exposure. Thus, these results revealed the non toxic nature of EAMRP in preclinical studies. Hence, EAMRP can be used successfully as an alternative to existing synthetic repellents without any potential health hazards.

Pharmacokinetics and bioavailability of tolfenamic acid in sheep.

The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration-time curves (AUC0-∞ ), elimination half-life (t1/2ʎz ), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax ) and time to reach Cmax (Tmax ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0-∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT ) decreased depending on dose, the volume of distribution at steady-state (Vss ) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.

Combination Ointment Containing Solid Tranilast Nanoparticles and Dissolved Sericin Is Efficacious for Treating Skin Wound-Healing Deficits and Redness in Diabetic Rats.

We attempted to design a combination ointment containing solid tranilast nanoparticles and dissolved sericin as a wound-healing drug (TS-combination ointment), and evaluated its usefulness as therapy for wound-healing deficits in streptozotocin-induced diabetic rat (STZ rat) using kinetic analyses as an index. Solid tranilast nanoparticles were prepared by bead mill methods with low-substituted methylcellulose; the mean particle size of the tranilast nanoparticles was 70 nm. The ointment was designed to contain the tranilast nanoparticles plus sericin powder and/or Carbopol® 934. Skin wound healing in STZ rats begins significantly later than in normal rats. Although the skin wound healing rate in STZ rats treated with an ointment containing tranilast nanoparticles was lower than in STZ rats treated with vehicle, the ointment was effective in reducing redness. An ointment containing sericin enhanced the skin-healing rate, but the preventive effect on redness was weak. On the other hand, the combination of tranilast and sericin increased both the skin healing rate and reduction in redness. In conclusion, we have adapted kinetic analyses to skin wound healing in rats, and found these analyses to be useful as an index of wound healing ability by a wound-healing drug. In addition, we show that treatment with the TS-combination ointment enhances the skin wound healing rate and reduces redness. These findings provide information significant to the search for new wound-healing therapies and for the design of wound-healing drugs.

The Effect of Tranilast 8% Liposomal Gel Versus Placebo on Post-Cesarean Surgical Scars: A Prospective Double-Blind Split-Scar Study.

BACKGROUND: Tranilast (N-[3, 4-dimethoxycinnamoyl] anthranilic acid), an antiallergic drug, has been shown to attenuate scar formation possibly through inhibition of transforming growth factor beta 1 activity and consequent suppression of collagen synthesis in fibroblasts. OBJECTIVE: The authors aimed at evaluating the efficacy and safety of tranilast 8% gel in improving the appearance and symptoms of new post-cesarean section surgical wounds. METHODS: In this prospective double-blind split-scar study, the authors treated each half scar of 26 women with either tranilast 8% liposomal gel or tranilast-free liposomal gel (placebo). Treatment was applied twice daily for 3 months. Twenty women completed the trial. Scar halves were evaluated by 2 investigators and by the patients 9 months after the last application using the Patient and Observer Scar Assessment Scale (POSAS). The participants also rated overall satisfaction and recorded side effects of the treatment. RESULTS: The mean POSAS scores at 9 months post-treatment were significantly lower for tranilast-treated half scars compared with placebo-treated half scars (p < .001). The women were significantly more satisfied with the tranilast-treated half-scar appearance (p = .002). Three participants reported itching and erythema on the tranilast-treated side. CONCLUSION: Topical tranilast 8% gel provided significantly better postcaesarian section scar cosmesis and user satisfaction compared with placebo.

Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients.

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product.

Tranilast stimulates endochondral ossification by upregulating SOX9 and RUNX2 promoters.

Endochondral ossification is an essential process for reparative phase of fracture healing, which starts with the differentiation of mesenchymal cells into chondrocytes followed by substitution of bone tissue. It is strictly controlled by the expression of crucial transcriptional factors: SOX9 in the early phase and RUNX2 in the late phase. Screening of FDA-approved compounds revealed that an anti-allergic drug, tranilast, that has been used for more than 30 years in clinical practice, enhanced the SOX9 promoter in chondrogenic cells and the RUNX2 promoter in osteoblastic cells. We observed that tranilast increased mRNA expression of both Sox9 and Runx2 in differentiating ATDC5 chondrogenic progenitor cells. Tranilast upregulated mRNA expression of chondrogenic marker genes (Col2a1, Acan, Col10a1, and Mmp13) in differentiating ATDC5 cells. Moreover, tranilast upregulated mRNA expression of essential signaling molecules involved in endochondral ossification (Pthrp, Ihh, and Axin2). In the later phase of differentiation of ATDC5 cells, tranilast increased synthesis of matrix proteoglycans, induced the alkaline phosphatase activity, and tended to accelerate mineralization. Tranilast is a potential agent that accelerates fracture repair by promoting the regulatory steps of endochondral ossification.

Avenanthramide supplementation attenuates eccentric exercise-inflicted blood inflammatory markers in women.

PURPOSE: Rigorous exercise is known to generate reactive oxygen species (ROS) and inflict inflammatory response. The present study investigated whether dietary supplementation of avenanthramides (AVA) in oats would increase antioxidant protection and reduce inflammation in humans after an acute bout of eccentric exercise. METHODS: Young women (age 18-30 years, N = 16) were randomly divided into two groups in a double-blinded fashion, receiving two cookies made of oat flour providing 9.2 mg AVA (AVA) or 0.4 mg AVA (Control, C) each day for 8 weeks. Before and after the dietary regimen each group of subjects ran downhill (DR) on a treadmill at -9% grade for 1 h at a speed to elicit 75% of maximal heart rate. Blood samples were collected at rest, immediately and 24 h post-DR. RESULTS: Before dietary supplementation plasma creatine kinase activity and tumor necrosis factor (TNF)-α concentration were increased immediately after DR (P < 0.05), whereas neutrophil respiratory burst (NRB) was elevated 24 h post-DR (P < 0.05). CK and TNF-α response to DR was abolished during post-supplementation tests in both AVA and C groups, whereas NRB was blunted only in AVA but not in C. Plasma interleukin-6 level and mononuclear cell nuclear factor (NF) κB activity were not affected by DR either before or after dietary supplementation, but were lowered 24 h post-DR in AVA versus C (P < 0.05). Both groups increased plasma total antioxidant activity following 8-week dietary regimen (P < 0.05), whereas only AVA group increased resting plasma glutathione (GSH) concentration (P < 0.05), decreased glutathione disulfide response to DR, and lowered erythrocyte GSH peroxidase activity (P < 0.05). CONCLUSIONS: Our data of pre- and post-supplementation difference reflect an interaction between repeated measure effect of eccentric exercise and AVA in diet. Long-term AVA supplementation can attenuate blood inflammation markers, decrease ROS generation and NFkB activation, and increased antioxidant capacity during an eccentric exercise bout.

Oat avenanthramide-C (2c) is biotransformed by mice and the human microbiota into bioactive metabolites.

BACKGROUND: Avenanthramides (AVAs), which are found exclusively in oats, may play an important role in anti-inflammation and antiatherogenesis. Although the bioavailability of AVAs has been investigated previously, little is known about their metabolism. OBJECTIVES: The aim of the present study was to investigate the metabolism of avenanthramide-C (2c), one of the major AVAs, in mice and by the human microbiota, as well as to elucidate the bioactivity of its major metabolites with the goal of finding new exposure markers to precisely reflect oat consumption. METHODS: For the mouse study, 10 CF-1 female mice were divided into control (vehicle-treated) and 2c intragastrically treated (200 mg/kg) groups (5 mice/group). Twenty-four-hour urine and fecal samples were collected with use of metabolic cages. For the batch culture incubations, 2c was cultured with fecal slurries obtained from 6 human donors. Incubated samples were collected at various time points (0, 12, 24, 48, 72, 96, and 120 h). Metabolites were identified via HPLC with electrochemical detection and LC with electrospray ionization/mass spectrometry. To investigate whether 2c metabolites retain the biological effects of 2c, we compared their effects on the growth of and induction of apoptosis in HCT-116 human colon cancer cells. RESULTS: Eight metabolites were detected from the 2c-treated mouse urine samples. They were identified as 5-hydroxyanthranilic acid (M1), dihydrocaffeic acid (M2), caffeic acid (M3), dihydroferulic acid (M4), ferulic acid (M5), dihydroavenanthramide-C (M6), dihydroavenanthramide-B (M7), and avenanthramide-B (M8) via analysis of their MS(n) (n = 1-3) spectra. We found that the reduction of 2c's C7'-C8' double bond and the cleavage of its amide bond were the major metabolic routes. In the human microbiota study, 2c was converted into M1-M3 and M6. Moreover, interindividual differences in 2c metabolism were observed among the 6 human subjects. Subjects B, C, E, and F could rapidly metabolize 2c to M6, whereas subject D metabolized little 2c, even up to 120 h. In addition, only subjects A, B, and F could cleave the amide bond of 2c or M6 to form the cleaved metabolites. Furthermore, we showed that 2c and its major metabolite M6 are bioactive compounds against human colon cancer cells. M6 was more active than 2c with the half-inhibitory concentration (IC50) of 158 µM and could induce apoptosis at 200 µM. CONCLUSION: To our knowledge, the current study demonstrates for the first time that avenanthramide-C can be extensively metabolized by mice and the human microbiota to generate bioactive metabolites.

Sublethal effects of insecticide seed treatments on two nearctic lady beetles (Coleoptera: Coccinellidae).

Predatory insects often feed on plants or use plant products to supplement their diet, creating a potential route of exposure to systemic insecticides used as seed treatments. This study examined whether chlorantraniliprole or thiamethoxam might negatively impact Coleomegilla maculata and Hippodamia convergens when the beetles consumed the extrafloral nectar of sunflowers grown from treated seed. We reared both species on eggs of Ephestia kuehniella and then switched adult H. convergens to a diet of greenbugs, Schizaphis graminum, in order to induce oviposition in this species. Excised sunflower stems, either treated or control and refreshed every 48 h, were provided throughout larval development, or for the first week of adult life. Exposure of C. maculata larvae to chlorantraniliprole and thiamethoxam applied as seed treatments delayed adult emergence by prolonging the pupal period. When adults were exposed, thiamethoxam reduced the preoviposition period compared to chlorantraniliprole, whereas the latter treatment cause females to produce fewer clutches during the observation period. Larvae of C. maculata did not appear to obtain sufficient hydration from the sunflower stems and their subsequent fecundity and fertility were compromised in comparison to the adult exposure experiment where larvae received supplemental water during development. Exposure of H. convergens larvae to thiamethoxam skewed the sex ratio in favor of females; both materials reduced the egg viability of resulting adults and increased the period required for eclosion. Exposure of H. convergens adults to chlorantraniliprole reduced egg eclosion times compared to thiamethoxam and exposure to both insecticides reduced pupation times in progeny. The results indicate that both insecticides have negative, sublethal impacts on the biology of these predators when they feed on extrafloral nectar of sunflower plants grown from treated seed.

Timing Spring Insecticide Applications to Target both Amyelois transitella (Lepidoptera: Pyralidae) and Anarsia lineatella (Lepidoptera: Gelechiidae) in Almond Orchards.

Amyelois transitella (Walker) (Lepidoptera: Pyralidae) and Anarsia lineatella Zeller (Lepidoptera: Gelechiidae) are key Lepidoptera pests of almonds in California. Spring insecticide applications (early to mid-May) targeting either insect were not usually recommended because of the potential to disrupt natural enemies when broad-spectrum organophosphates and pyrethroids were applied. The registration of reduced risk compounds such as chlorantraniliprole, methoxyfenozide, and spinetoram, which have a higher margin of safety for natural enemies, makes spring (early to mid-May) application an acceptable control approach. We examined the efficacy of methoxyfenozide, spinetoram, and chlorantraniliprole at three spring application timings including the optimum spring timing for both A. lineatella and A. transitella in California almonds. Our study also examined the possibility of reducing larval populations of A. lineatella and A. transitella simultaneously with a single spring insecticide application. There were no significant differences in the field efficacy of insecticides targeting either A. lineatella or A. transitella, depending on application timing for the three spring timings examined in this study. In most years (2009-2011), all three timings for each compound resulted in significantly less A. transitella and A. lineatella damage when compared with an untreated control, though there was some variation in efficacy between the two species. Early to mid-May applications of the reduced-risk insecticides chlorantraniliprole and spinetoram can be used to simultaneously target A. transitella and A. lineatella with similar results across the potential timings.

Effect of pH, polymer concentration and molecular weight on the physical state properties of tolfenamic acid.

Tolfenamic acid (TA) has been transformed from crystalline to amorphous state through freeze-drying by using varying ratios of polyacrylic acid (PA) at various pH values. The characterization of the films has been carried out using X-ray diffraction, differential scanning calorimetry, Fourier transform infrared (FTIR) spectrometry and scanning electron microscopy. The results showed a gradual change in the solid state properties of TA and a complete transformation into its amorphous form in 1:8, 1:4, 1:2 and 1:1 ratios at pH 3, 4, 5 and 6, respectively. FTIR spectrometry reveals the formation of a yellow polymorphic form of TA. Polymer molecular weight has also been observed to affect the drug transformation and interaction as the low molecular weight PA (Mw ∼ 1800) was found to be most effective followed by its medium (Mv ∼ 450 000) and high molecular weight (Mv ∼ 3 000 000) forms. No signs of recrystallization in the TA-PA films were noted during the 12-week storage period. PA of low molecular weight has also been found more effective in inhibiting the recrystallization of the melt upon cooling thus proving a valuable polymer in producing stable amorphous solid dispersions of TA.

Tamoxifen and tranilast show a synergistic effect against breast cancer in vitro.

OBJECTIVE: This study was aimed at examining a separate or combined effect of tamoxifen and tranilast drugs on growth and proliferation of breast cancer cells. BACKGROUND: Breast cancer is one of the most common cancers and the second leading cause of cancer death among women worldwide. Tamoxifen is the most widely used anti-estrogen for the treatment of breast cancer. Studies show that a combination therapy with other drugs enhances the activity of tamoxifen. Tranilast is an anti-inflammatory drug. We hypothesize that tranilast plus tamoxifen can work synergistically and help getting better result from this anticancer drug. METHODS: Two breast cancer cell lines, MCF-7 and MDA-MB-231, were treated with graduated concentrations of tamoxifen and tranilast alone or in combination at 24, 48 or 72 hours for MCF-7, and 48 hours for MDA-MB-231 cells. We used the MTT assay and lactate dehydrogenase leakage (LDH) assay to evaluate cell viability and cytotoxicity, respectively. RESULTS: In both ER-positive and ER-negative breast cancer cell lines, the combination of tranilast and tamoxifen was more effective in growth inhibition than single drug exposure. CONCLUSION: We have demonstrated that by means of a synergistic/additive inhibitory effect, tranilast was capable of enhancing the in vitro activity of tamoxifen on breast cancer cell lines. Based on the results obtained in this study, tranilast could be a candidate drug for combination therapy in resistant breast cancer patients (Fig. 9, Ref. 17). KEYWORDS: breast cancer, Tamoxifen, Tranilast, LDH release, MTT.