Identification and structure-activity relationship exploration of uracil-based benzoic acid and ester derivatives as novel dipeptidyl Peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structure-activity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes.

Percutaneous absorption between frog species: Variability in skin may influence delivery of therapeutics.

Frogs have permeable skin, so transdermal delivery provides a practical alternative to traditional dosing routes. However, little is known about how frog skin permeability differs interspecifically, and there are different reported clinical outcomes following topical application of the same chemical in different frog species. This study collated in vitro absorption kinetic data previously reported for two frog species: the green tree frog (Litoria caerulea) and the cane toad (Rhinella marina), and used linear mixed-effects modelling to produce a model of absorption. Histology of skin samples from each species was performed to observe morphological differences that may affect absorption. Absorption kinetics differed significantly between species, with the logP of the applied chemical a better predictor of permeability than molecular weight. Application site also influenced permeability, with dorsal permeability consistently higher in cane toads. Ventral permeability was more consistent between species. Skin thickness differed between species and skin regions, and this may explain the differences in absorption kinetics. Guidelines for selecting chemicals and dosing site when treating frogs are presented. The permeability differences identified may explain the poor reproducibility reported in the treatment of disease across frog species, and reinforces the importance of considering interspecies differences when designing therapeutic treatments for frogs.

The dietary combination of essential oils and organic acids reduces Salmonella enteritidis in challenged chicks.

This study was conducted to determine the effects of essential oils and organic acids (EOA) on Salmonella Enteritidis (S. Enteritidis) challenged chickens. One-day-old specific pathogen-free (SPF) chicks (250) were randomly assigned to 5 groups, with 50 birds in each group. The treatment groups were as follows: 1) basal diet, negative control group (NC); 2) basal diet + S. Enteritidis, positive control group (PC); 3) PC + 4,000 g/t of enrofloxacin (5%), antibiotic group (ENR); 4) PC + 800 g/t of EOA1, thymol-benzoic acid group (TBA); and 5) PC + 800 g/t of EOA2, cinnamylaldehyde-caproic acid group (CCA). At 7 D of age, each bird, except those in NC, was orally gavaged with 0.4 mL of a suspension of 4.4 × 109 cfu S. Enteritidis/mL. Results revealed that ENR reduced bacterial counts in the liver and spleen on days 3, 5, and 7 post-challenge more (P < 0.05) than any other treatments. However, bacterial counts in cecal contents among ENR, TBA, and CCA were similar at 5 and 7 D post-challenge but lower than those of PC. Additionally, the bacterial counts in liver, spleen, and cecum contents in TBA were lower (P < 0.05) than in PC at 3, 5, and 7 D post-challenge; the bacterial counts in spleen contents in TBA were lower (P < 0.05) than in CCA at 7 D post-challenge. Tumor necrosis factor-α contents in TBA and CCA were lower (P < 0.05) than those in PC. Also, the ratio of villus height to crypt depth in the ileum of CCA was higher (P < 0.05) than that of PC and ENR; however, there was no difference in the secretory IgA content of the jejunum among the groups. In conclusion, EOA had a bacteriostatic effect on S. Enteritidis, and the effect of the thymol-benzoic acid complex surpassed that of the cinnamaldehyde-caproic acid complex. Therefore, EOA may act as an effective antibiotic substitute for animals in the prevention and treatment of Salmonella.

Enzymes and/or combination of organic acid and essential oils supplementation in pasture-fed free-range laying hens increased the digestibility of nutrients and non-starch polysaccharides.

Pasture intake can be a major challenge for free-ranging hens. This study was conducted to examine pasture digestion and to manage its negative effects. A total of 300 ISA Brown laying hens were used to investigate the effect of time on range (T) in short-term (6 wk) and long-term (12 wk) of 2 range types (R) (gravel vs. pasture) and dietary supplements (F) (T1 = xylanase; T2 = xylanase/beta-glucanase/pectinase/protease; T3 = xylanase/benzoic acid/essential oils) on crude protein, crude fiber, acid detergent fiber, neutral detergent fiber, non-starch polysaccharides (NSP), calcium and phosphorus digestibility, pH of the crop, and ileum digesta viscosity and morphology. Hens exposed to the range for 12 wk had lower (P < 0.05) digestibility of crude protein, insoluble rhamnose, ribose, and lower ileal pH compared to hens that ranged for 6 wk. Hens ranging on pasture had lower digestibility (P < 0.05) of crude protein, acid detergent fiber, neutral detergent fiber, insoluble arabinose, and insoluble xylose, but higher digestibility (P < 0.05) of insoluble mannose and glucose compared to hens that ranged on gravel. Hens fed T2 and T3 had higher digestibility (P < 0.05) of CP, acid detergent fiber, and neutral detergent fiber compared to hens fed T1. Hens fed T2 had higher digestibility (P < 0.05) of free oligosaccharide arabinose and xylose than those fed T1 or T3 diets. A significant interaction between T × R was detected for crude fiber digestibility and villus height. Digestibility of crude fiber was reduced and villus height was increased in hens ranged on pasture for 12 wk compared to 6 wk. An interaction between R × F was observed on phosphorus and soluble NSP digestibility (P < 0.05). Hens fed T2 and T3 diets had lower digestibility of phosphorus and NSP on gravel than on pasture. In conclusion, pasture consumption impaired the digestibility of nutrients. Supplementing free-range diets with a multi-enzyme or xylanase/benzoic acid/essential oil product reduced these negative effects and increased the ileal nutrient digestibility.

[Establishment of a rat model of premature ejaculation with 8-OH-DPAT].

OBJECTIVE: To explore the feasibility and practicability of establishing a rat model of premature ejaculation (PE) by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord segments. METHODS: Twenty-four male Wistar rats were equally randomized into a PE model and a blank control group. The PE model was established by injection of 8-OH-DPAT in 10 ml normal saline at 0.8 mg per kg of the body weight per day into the subarachnoid space of the lumbosacral spinal cord segments and the control rats were injected with the same volume of normal saline only, both for 4 weeks. Another 24 female Wistar rats were injected subcutaneously with benzoic acid estradiol at 20 µg to induce estrus at 36 hours before mated with the male animals. At 2 and 4 weeks, the male rats were mated with the female ones for 30 minutes each time and meanwhile observed for their mating behavior indicators, such as mount latency, intromission latency, ejaculation latency, mount frequency, intromission frequency, and ejaculation frequency. RESULTS: Compared with the controls, the PE model rats showed a significantly lower ejaculation latency (ï¼»712.35 ± 36.77ï¼½ vs ï¼»502.35 ± 46.72ï¼½ s, P<0.05), mount latency (ï¼»11.22 ± 3.60ï¼½ vs ï¼»8.69 ± 2.48ï¼½ s, P<0.05), mount frequency (13.28 ± 0.24 vs 7.53 ± 1.84, P<0.05), and intromission latency (ï¼»22.33 ± 2.45ï¼½ vs ï¼»12.08 ± 1.39ï¼½ s, P<0.05), but a remarkably higher ejaculation frequency (2.01 ± 0.48 vs 4.26 ± 0.89, P<0.05). No statistically significant difference was observed between the control and model animals in the intromission frequency (7.49 ± 2.21 vs 6.45 ± 1.89, P>0.05). CONCLUSIONS: A rat model of premature ejaculation was successfully established by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord segments, which is of great significance for further study of the mechanism of premature ejaculation.

Pasture, multi-enzymes, benzoic acid and essential oils positively influence performance, intestinal organ weight and egg quality in free-range laying hens.

1. The objective of this study was to investigate the effect of range type, multi-enzyme applications, and a combination of benzoic acid (BA) and essential oils (EO) on the productive performance, organ weight and egg quality of free-range laying hens. 2. Three hundred laying hens were evaluated for the short-term (6 weeks) and long-term (12 weeks) effects of range type (G = no pasture, P = pasture) and feed additives (T1 = control; T2 = betaglucanase/pectinase/protease; T3 = BA/EO). Body weight, feed intake (FI), feed conversion ratio (FCR), egg production (EP), digestive organ weight, and egg quality (EQ) were evaluated. Data were analysed using SPSS 2.2 in a 2×2×3 factorial arrangement. 3. Hens that ranged on pasture were significantly heavier (2043 g vs. 1996 g; p < 0.001), laid heavier eggs (61.9 g vs. 60.3 g; p < 0.001) and produced darker yolk colour (4.3 vs. 7.0; p < 0.001) compared to hens ranged on gravel. Hens fed T2 were significantly heavier (2050 g) compared to hens fed T1 (2005 g) or T3 (2008 g). Organ weights (gizzard, liver and pancreas) were significantly heavier in hens ranged on pasture (16.8 g/kg BW, 22.3 g/kg BW and 1.89 g/kg BW, respectively) compared to hens ranged on gravel (14.2 g/kg BW, 21.7 g/kg BW and 1.83 g/kg BW, respectively). Over time, body weight (1970-2070 g; p < 0.001) and egg weight (59.5-62.8 g; p < 0.001) increased, FI (123-120 g; p = 0.024) was reduced and FCR (2.36-2.10; p = 0.002) improved 4. In conclusion, hens housed on pasture and fed multi-enzyme supplemented diets had significantly heavier body weight and produced heavier eggs with darker yolk colour. Pasture intake and enzyme supplementation increased digestive organ weight significantly.

Pharmacokinetic data reduce uncertainty in the acceptable daily intake for benzoic acid and its salts.

The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg body weight. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical-specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity. Human clinical studies indicate that the pharmacokinetics of benzoic acid and its salts are similar in children and adults, and that there is a lack of adverse events in humans at doses comparable to the no observed adverse effect level (NOAEL) in rodents; this suggests that the pharmacokinetic UF for intraspecies variability, as well as the pharmacodynamic components of the UFs, may also be reduced, although we did not calculate to what degree. In conclusion, the total UF can be reduced to 50 (2 for interspecies differences in pharmacokinetics, 2.5 for interspecies differences in pharmacodynamics, and 10 for intraspecies variability), which would increase the ADI to 0-10 mg/kg body weight.

Insulinotropic action of 2, 4-dinitroanilino-benzoic acid through the attenuation of pancreatic beta-cell lesions in diabetic rats.

Beta cell destruction plays a key role in the pathogenesis of type 1 diabetes mellitus. It has also been argued that beta-cell mass is compromised in some cases of type 2 diabetes, although this is still debated. Currently, the failure of oral antidiabetic insulin secretagogue drugs to properly manage type 2 diabetes demands novel approaches for the treatment of this condition. The aim of the present study was to investigate the in vitro and in vivo antidiabetic effect in STZ-induced diabetic rats, and maximum tolerated dose (MTD) safety of novel anthranilic acid derivative, 2, 4-dinitroanilino-benzoic acid (1). Anthranilic acid derivative 1 was also evaluated for insulinotropic action on STZ-mediated pancreatic beta-cell lesions in diabetic rats. During an eight week study, oral glucose tolerance test, fasting blood glucose, and serum insulin levels, and pancreatic insulin contents were measured in four different groups of Wistar rats; control, STZ-induced diabetic, gliclazide-treated, and anthranilic acid derivative-treated diabetic rats. Beta-cell number and islet area were also quantified, and immunohistochemical study was performed. In vitro studies in cells showed that 2, 4-dinitroanilino-benzoic acid (1) did not adversely effect the cells viability. We found that the derivative 1 significantly improved the glucose tolerance, fasting blood glucose, and HbA1c levels, serum insulin levels, and pancreatic insulin contents (P < 0.05), comparable to gliclazide-treated group. The derivative 1 exhibited a significant insulinotropic action on diabetic pancreas, and caused an increased immunoreactivity for insulin, as compared to gliclazide-treated group. Together these results suggest that treatment of diabetic rats with 2, 4-dinitroanilino-benzoic acid (1) improved the glucose tolerance, fasting blood glucose, and HbA1c levels most probably by restoring the functional activities of the pancreas via its insulinotropic action. This indicates that the derivative 1 can serve as lead for the treatment of diabetes caused by low insulin levels.

Investigation of in-feed organic acids as a low cost strategy to combat Salmonella in grower pigs.

Salmonella carriage in pigs is a significant food safety issue. Dietary supplementation with organic acids has previously been shown to reduce shedding and transmission of Salmonella. Therefore, this study aimed to examine the effect of three commercially available organic acid-based products on Salmonella levels in grower pigs, using a model of experimental infection that closely mimics natural exposure to the organism. Seven week old trial pigs (n=40) with a mean weight of 14.7kg were placed in one of four pens with 10 pigs/pen. Pens had previously been contaminated with Salmonella Typhimurium 4,[5],12;i;- via seeder pigs. Trial pigs received one of four diets for 28days: 1, control diet; 2, sodium butyrate supplemented diet; 3, benzoic acid supplemented diet and 4, formic-citric acid supplemented diet. A further 10 pigs were placed in a Salmonella-free pen receiving the control diet. Pigs were weighed and blood sampled on days 0 and 28. Faeces was collected on day 0, 2, 3, 5, 7, 14, 21 and 28 and examined for Salmonella. On day 28, 5 pigs/group were euthanised and ileocaecal lymph nodes (ILN) and caecal contents sampled for culture. The remaining 5 pigs/pen were then fed the control diet and faeces were collected on days 35 and 42. On day 42 pigs were euthanised and ILN and caecal contents tested for Salmonella levels. The trial was repeated once. Within the first two days of exposure to the contaminated environment, 96% (77/80) of pigs became infected. Most pigs shed Salmonella at levels of between 100-103 CFU/g faeces for at least 7days post-exposure. A significant reduction in Salmonella faecal concentration was observed after supplementation with sodium butyrate (p=0.001) and a formic citric acid blend (p<0.0001). Average daily weight gain (ADWG) was significantly increased in all groups fed the supplemented feed when compared to the positive control group. The use of sodium butyrate or a blend of formic and citric acid in feed could be considered a cost-effective control measure to reduce Salmonella faecal shedding and improve ADWG in Salmonella infected herds.

Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations.

BACKGROUND: Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. METHODS: Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). RESULTS: A respirable dose of 59.9 ± 9.0 µg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 ± 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L·min-1. The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 ± 10.6 to 200.2 ± 19.9 µg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes-1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 ± 40.3 µg was produced. CONCLUSIONS: This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam.

Benzoic acid beneficially affects growth performance of weaned pigs which was associated with changes in gut bacterial populations, morphology indices and growth factor gene expression.

This study was conducted to investigate the effects of benzoic acid (BA) on growth performance, intestinal development and intestinal barrier function in weaned pigs. Ninety weaned pigs were randomly assigned to one of three treatments: a basal diet (CON), the basal diet supplemented with 2000 mg/kg benzoic acid (BA1) and 5000 mg/kg benzoic acid (BA2). At the end of days 14 and 42, six pigs per treatment were randomly selected to collect plasma and intestinal samples. Results showed that BA supplementation not only improved final body weight, daily growth and feed conversion ratio from days 15 to 42 and days 1 to 42, but also decreased the activity of plasma diamine oxidase (day 42) and the pH values of jejunal contents (day 14) (p < 0.05). Ileal Bacillus populations (day 14) were increased by BA, while Escherichia coli counts in the ileum and caecum (day 42) were decreased (p < 0.05). Higher Lactobacillus counts occurred in the ileum (day 14, 42) of BA1-fed piglets as compared to CON and BA2-fed piglets (p < 0.05). In addition, BA supplementation increased the ratio of villus height to crypt depth (day 14, 42) and decreased the crypt depth (day 14) (p < 0.05). Growth-stimulating factors (insulin-like growth factor-1, day 42; insulin-like growth factor-1 receptor, day 14, 42) and tight junction protein (occludin, day 14, 42; zonula occludens-1, day 42)-related gene mRNA levels were upregulated in the jejunum of piglets fed BA diets (p < 0.05). In conclusion, this study provides the first evidence that BA has beneficial effects on intestinal development and intestinal barrier function of weaned pigs, which can partly explain why growth performance of pigs was improved by dietary BA supplementation.

Bensal HP for Second Intention Healing Following Mohs Micrographic Surgery or Shave Skin Biopsy: An Open-label Pilot Study.

Dermatologists frequently create cutaneous defects that heal by second intention, yet there is no universal protocol for wound care in this setting. Several ointments commonly used for wound healing are not cost effective as they contain known contact allergens, contribute to antimicrobial resistance, and do not enhance the healing process. Recent studies indicate that Bensal HP, a commercially available ointment used for a variety of dermatologic conditions, may be useful for wound healing; although clinical data is currently limited. In this single-center open-label pilot study, Bensal HP was evaluated for second intention healing over 8 weeks following either Mohs micrographic surgery or shave skin biopsy in 20 patients. Results indicate that Bensal HP is effective for second intention healing as demonstrated by increased Global Assessment of Efficacy scores and decreased wound measurements, with 16 patients achieving full closure. Patient symptoms overall improved over the study period, and Bensal HP was well tolerated with no adverse effects associated with its use. By providing critical data regarding the safety and efficacy of Bensal HP, this study may provide useful information to guide further assessment in future large-scale comparative wound healing studies.

J Drugs Dermatol. 2016;15(10):1197-1202.

Bensal HP Attenuates the Inflammatory Response in Hair Shaving Associated Dermatitis.

Shaving is an ubiquitous practice, and cutaneous irritation and inflammation are common sequelae, which may be worsened by underlying skin conditions or poor hair removal techniques. Moisturizing shaving creams and aftershaves are available to help maintain or restore the epidermal barrier; however, many continue to suffer from post-shave redness, itching, and pain. To reduce post-shave inflammation, some products have included botanical and other natural ingredients, which are often favored by consumers. We evaluated Bensal HP, an ointment containing 3% oak bark extract, 3% salicylic acid, and 6% benzoic acid, which has documented anti-inflammatory and antimicrobial properties, in a murine model of shave irritation to determine whether it would be useful in this clinical setting. Shaving dermatitis was simulated using a depilatory agent and electric clippers, and the shaved area was photographed and treated with Bensal HP daily for four days. Compared to untreated controls, mice treated with Bensal HP experienced a visible reduction in skin irritation and inflammation. These findings were mirrored on histology, as Bensal HP-treated areas demonstrated increased epidermal integrity and decreased dermal inflammatory infiltrate compared to untreated skin. Using immunohistochemistry, fewer neutrophils and macrophages were noted, and cytokine analysis also revealed decreased IL-6 in Bensal HP-treated skin at 24 and 96 hours after shaving. These results highlight the potential of Bensal HP as an anti-inflammatory treatment for shave irritation. Given the product's application against a variety of inflammatory and infectious skin disorders, its use against shave irritation may also improve comorbid skin conditions, such as pseudofolliculitis barbae.

J Drugs Dermatol. 2016;15(7):836-840.

CLINICAL MANAGEMENT OF BILATERAL CUTANEOUS SQUAMOUS CELL CARCINOMA OF THE HIND FEET PADS IN A SOUTHERN WHITE RHINOCEROS (CERATOTHERIUM SIMUM SIMUM).

The current report describes the temporary regression, due to intensive symptomatic treatment, of ulcerative skin lesions caused by squamous cell carcinoma in a white rhinoceros. A captive, 40-yr-old southern white rhinoceros (Ceratotherium simum simum) developed profound, ulcerative skin lesions on the pads of both hind feet. At the peak of the disease, at least one quarter of the pads was affected. A diagnosis of squamous cell carcinoma was made via biopsy. Treatment included anti-inflammatory drugs, antibiotics, and local care. The lesions regressed on both feet until they seemed clinically healed. It was presumed that long-term, anti-inflammatory treatment and local bandaging had induced the temporary regression of the lesions. Two years later, however, a small ulcerative lesion reappeared on one pad and post mortem examination confirmed that the carcinoma was also histologically present in the clinically intact tissue. No metastasis was found and computed tomography showed normal digital bones.

Bensal HP Treatment for Burn and Excision Wounds: An In-Vivo Assessment of Wound Healing Efficacy and Immunological Impact.

Natural ingredients are of increasing interest within the field of dermatology. Bensal HP, an ointment containing 3% oak bark extract, 3% salicylic acid, and 6% benzoic acid, is believed to be efficacious against a variety of inflammatory and infectious dermatidites. Here we evaluate Bensal HP's ability to influence wound healing, which has yet to be studied in this setting. Bensal HP applied to burn wounds on the dorsal surface of BALB/c mice significantly attenuated wound expansion in the first few days post-injury as compared to controls. Histological analysis mirrored these findings with accelerated maturation of the wound bed and increased collagen deposition by the end of the study period. Cytokine analysis revealed decreased IL-6 and TNFα secretion in the Bensal HP-treated burns as compared to controls. Similarly, excisional wounds treated with Bensal HP demonstrated comparable wound healing as compared to controls with positive histologic features and increased collagen deposition. Furthermore, IL-6 production was attenuated in the Bensal-HP treated wounds at day 3, with no differences appreciated in IL-6 at day 7 or in TNFα at either time point. While Bensal-HP represents a therapeutic strategy to enhance the histologic and immunologic milieu in burn and excisional wounds, further study is needed to fully elucidate the full potential of this treatment.

Polysaccharide-based aerogel microspheres for oral drug delivery.

Polysaccharide-based aerogels in the form of microspheres were investigated as carriers of poorly water soluble drugs for oral administration. These bio-based carriers may combine the biocompatibility of polysaccharides and the enhanced drug loading capacity of dry aerogels. Aerogel microspheres from starch, pectin and alginate were loaded with ketoprofen (anti-inflammatory drug) and benzoic acid (used in the management of urea cycle disorders) via supercritical CO2-assisted adsorption. Amount of drug loaded depended on the aerogel matrix structure and composition and reached values up to 1.0×10(-3) and 1.7×10(-3) g/m(2) for ketoprofen and benzoic acid in starch microspheres. After impregnation, drugs were in the amorphous state in the aerogel microspheres. Release behavior was evaluated in different pH media (pH 1.2 and 6.8). Controlled drug release from pectin and alginate aerogel microspheres fitted Gallagher-Corrigan release model (R(2)>0.99 in both cases), with different relative contribution of erosion and diffusion mechanisms depending on the matrix composition. Release from starch aerogel microspheres was driven by dissolution, fitting the first-order kinetics due to the rigid starch aerogel structure, and showed different release rate constant (k1) depending on the drug (0.075 and 0.160 min(-1) for ketoprofen and benzoic acid, respectively). Overall, the results point out the possibilities of tuning drug loading and release by carefully choosing the polysaccharide used to prepare the aerogels.

Modification of digesta pH and intestinal morphology with the use of benzoic acid or phytobiotics and the effects on broiler chicken growth performance and energy and nutrient utilization.

Two experiments, each consisting of 2 trials, were conducted to investigate the effect of feeding benzoic acid (BA) and turmeric meal (TM) individually or in combination (Exp. 1) or garlic meal (GM) and TM individually or in combination (Exp. 2) on growth performance, digesta pH, gut morphology, and nutrient utilization in broiler chickens. Diets consisted of a nutrient-adequate control diet and the control diet with added BA (2 g/kg), TM (10 g/kg), BA (1 g/kg) plus TM (5 g/kg), and BA (2 g/kg) plus TM (10 g/kg) in Exp. 1. In Exp. 2, in addition to the same control diet as Exp. 1, the control diet with added GM (10 g/kg), TM (10 g/kg), GM plus TM at 5 g/kg each, and GM plus TM at 10 g/kg each were used. Each treatment had 6 replicate floor pens with 10 chickens per replicate. On d 14, 5 broiler chickens from each floor pen were transferred to metabolism cages and continued on their respective diets. Body weight and feed intake data were collected on d 0 and 21, excreta were collected from chickens in metabolism cages on d 19 and 20, and ileal digesta were collected on d 21. Digesta pH was measured at the crop, proventriculus, jejunum, and cecum. Jejunum sections were collected from chickens in Exp. 1 to study gut morphology. In Exp. 1, only the combination of BA and TM tended (P < 0.10) to improve weight gain but there were no effects on G:F. The combination of BA and TM at both inclusion rates decreased (P < 0.05) digesta pH in the crop, jenunum, and ceca. There were no treatment effects on ileal DM or total tract DM retention, but supplementation of BA or TM alone or in combination increased (P < 0.01) apparent ME (AME) and nitrogen-corrected AME (AMEn) relative to the control diet. In Exp. 2, TM alone or combined with GM improved (P < 0.05) weight gain and G:F compared to the control. Supplementation of TM alone or in combination with GM at the rate of 10 g/kg each reduced (P < 0.05) digesta pH in the crop, proventriculus, and ceca but had no effect at the jejunum. The combination of GM and TM improved (P < 0.01) ileal DE, AME, and AMEn. In conclusion, BA, TM, and GM individually or in combination with wheat-soybean meal based diets adequate in nutrients and energy selectively improved growth performance, modified digesta pH and intestinal growth, and increased the efficiency of dietary energy use.

In vitro effects of quercetin on oxidative stress mediated in human erythrocytes by benzoic acid and citric acid.

Benzoic acid (BA) and citric acid (CA) are food additives commonly used in many food products. Food additives play an important role in food supply but they can cause various harmful effects. The in vitro adverse effects of BA and CA and the protective effect of quercetin on human erythrocytes were investigated by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities. Erythrocytes were incubated with BA and CA, at three doses of 50, 100 and 200 microg/ml, and quercetin, at a concentration of 10 microM. After BA and CA application, a dose-dependent increase in MDA level and decreases in SOD, CAT, GST and GPx activities were found in erythrocytes. Among the two food additives, BA exerted a more harmful influence on human erythrocytes than CA. The protective effects of quercetin against oxidative stress--induction in the human erythrocytes by CA and BA, were found when these two food additives were applied at each of three doses of 50, 100 and 200 microg/ml. However, complete protection of quercetin against CA toxicity was only observed when this agent was applied at a lower dose of 50 microg/ml. Quercetin did not completely protect erythrocytes even at the lowest concentration of BA.

Ion-pair strategy for enabling amifostine oral absorption: rat in situ and in vivo experiments.

This study shows the effect of ion pair formation on intestinal absorption and oral bioavailability of amifostine. Amifostine is a prodrug used as a highly potent and selective radiotherapy and chemotherapy protectant but due to its low lipophilicity and charge at physiological pH range, its trans epithelial transport and its potential for oral drug delivery is very low. Ion pair formation with negatively charged counter ions was evaluated by in situ rat perfusion studies as a possible strategy to enhance intestinal absorption of amifostine. Succinic acid, phthalic acid and benzoic acid were used as counter ions. Rat intestinal perfusion studies confirmed a statistically significant increase in amifostine permeability in the presence of the counter ions in the order of succinic>phthalic>benzoic. Rat pharmacokinetic studies in vivo were performed to calculate oral absolute bioavailability of amifostine alone and with ion pairs in order to confirm the in situ perfusion results and the applicability of the ion pair approach. Intravenous and intraduodenal administrations were done in rats using a permanent jugular vein cannulation technique and a duodenal cannulation method to avoid drug degradation in stomach. In vivo oral bioavailability studies demonstrated a 20-30-fold increase in amifostine bioavailability with succinic acid depending on counter ion ratio and 10-fold increase with phthalic acid as ion pair. In summary ion pair strategy with succinic acid could enable amifostine oral administration on enteric coated formulations.

Effects of a blend of essential oil compounds and benzoic acid on performance of broiler chickens as revealed by a meta-analysis of 4 growth trials in various locations.

A series of growth trials with broiler chicks was conducted in various geographical locations to evaluate the efficacy of a novel eubiotic feed additive (EFA) at various dietary inclusion levels on performance of growing chicks. The EFA product consisted of a blend of essential oil compounds (thymol, eugenol, piperine) with benzoic acid, all belonging to the group of flavoring substances. Although variable in responses, the overall results indicated that 300 mg/kg of this EFA represented an optimum supplementation dose for generation of beneficial performance effects in broilers. A meta-analysis with all data from the 300 mg/kg EFA-supplemented treatments in comparison with the non-supplemented controls revealed that the eubiotic product significantly improved BW on d 21 (+2.0%; P = 0.0021) and on d 42 (+1.4%; P = 0.0151). Furthermore, the birds on the EFA 300 mg/kg treatment expressed a higher average daily gain in the starter phase (d 1-21; +2.1%; P = 0.0023) and over the entire experimental period (d 1-42; +1.5%; P = 0.0154). Feed conversion ratio was more favorable with dietary EFA supplementation (-0.6%; P = 0.0414), when compared with the control birds. Mortality was considered normal and was not affected by the dietary treatment (control = 3.09%; EFA 300 mg/kg = 3.26%). In conclusion, 300 mg/kg of this new eubiotic product demonstrated to effectively improve performance of broiler chicks under various husbandry conditions.