Transdermal behaviors comparisons among Evodia rutaecarpa extracts with different purity of evodiamine and rutaecarpine and the effect of topical formulation in vivo

Aim

Evodiamine (EVO) and rutaecapine (RUT), the major active components from Evodia rutaecarpa extract (EE), are recognized as a depended analgesic agent. This study was designed to investigate the effect of purity and chemical enhancers on the transdermal behavior of EVO and RUT, and the pharmacological effect of their topical cream in vivo.

Material and methods

Transdermal delivery across a full thickness pig abdominal skin was detected in vitro by Franz-type diffusion cell, with HPLC for quantification of the permeation of EVO and RUT. The activity of topical cream in vivo was evaluated by a mice pain model induced by formalin and hot plate.

Results

Transdermal characters of EVO and RUT showed a low transdermal rate, long lag time and low cumulative amount. The transdermal rate and cumulative amount could be promoted by lipophilic enhancers, whereas lag time was shortened by hydrophilic surfactant, but these permeation parameters were not markedly influenced by purity of EE (p > 0.05). The effect in vivo was confirmed by analgesic models in topical cream of EE, which produced a significant (p < 0.05) inhibitory effects on pain response in dose-dependent manner.

Conclusion

The purity of EVO and RUT from EE has no significant effect on their permeation through porcine skin, but oleic acid or nerolidol can markedly elevate the transdermal rate of EVO and RUT. High purity of EE is the best choice for topical preparation to increase the drug loading. The effect of EE in vivo is verified by formalin model and hot plate test.     

A Novel Approach to the Treatment and Prevention of Laminitis: Botulinum Toxin Type A for the Treatment of Laminitis

Laminitis is an inflammation of the lamina of hoofed animals. According to the United States Department of Agriculture (USDA), laminitis impacts approximately 2% of the horse population each year. Because of the severity of the inflammation and chronic pain, it is frequently necessary to euthanize these horses. Surviving horses may be left useless, with resultant economic and social impact on the industry. Current interventions for laminitis are based on supportive care and alteration of biomechanical forces on the digit. The transition from laminitis to laminar failure (founder) is believed to be caused by the “weight of the horse and the forces of locomotion driving the bone down into the hoof capsule.” We hypothesize that an important factor is the torsional forces placed on the distal phalanx (coffin bone) by the deep digital flexor muscle and tendon. The paralyzing effect of botulinum toxin will result in a decrease of these torsional forces and therefore will aid in the prevention or treatment of the sequelae of laminitis. Seven horses with varying degrees of laminitis were evaluated. Each underwent pretreatment and posttreatment radiographs as well as pretreatment and posttreatment Obel grading. Each horse received botulinum toxin type A injected into the belly of the deep digital flexor muscle. In all cases there was radiographic stabilization of pedal displacement from the dorsal hoof wall. Obel scores showed improvement of 1 to 2 grades during the time monitored.     

鲫鱼中4种非甾体抗炎药残留的分析研究

[目的]建立一种微波超声波辅助提取-高效液相色谱法同时检测鲫鱼中氟尼辛葡甲胺、美洛昔康、酮洛芬和双氯芬酸钠4种非甾体抗炎药残留的分析方法。[方法]样品前处理采用磷酸酸化的乙醇为提取溶剂,微波超声波辅助提取,硅藻土层析柱净化,甲醇洗脱。[结果]采用的流动相为乙腈-0.1%三乙胺水溶液（磷酸调节pH值为3.5）,流动相体积比乙腈∶0.1%三乙胺水溶液=60∶40,流速0.8ml/min,检测波长为255nm。4种非甾体抗炎药的检出限为5～10μg/kg（S/N=3）,定量限15～30μg/kg（S/N=10）。添加回收率为72.5%～93.8%（n=5）,相对标准偏差（RSD）小于15%。[结论]该方法操作简单、快速、灵敏度高、特异性强,能满足定性定量分析要求。     

Development of a lameness model in sheep for assessing efficacy of analgesics

Objective To develop a lameness model to assess the efficacy of analgesics for alleviating pain, swelling and systemic signs of inflammation in sheep. Procedures The response to subcutaneous injection of 0.1 or 0.2 mL turpentine in a forelimb pastern (n = 4 ewes per dose) was examined at 0, 3, 6, 24, 48 and 72 h. In a second experiment, responses were measured at 0, 2, 4, 6, 8, 10, 12 and 24 h in ewes receiving 0.1 mL turpentine ± meloxicam 1 mg/kg IV at 0 h (n = 6 per group). Responses measured included forceplate pressure, skin temperature, limb circumference, nociception, leucocyte count, neutrophil : lymphocyte ratio, haptoglobin and daily feed intake. Results Turpentine injection caused a decrease in weight borne on the treated limb, increased skin temperature, increased sensitivity at the injection site and leucocytosis by 2 h and increased limb circumference by 4 h. Weight borne and sensitivity of the injected limb returned to control levels after around 24 h, whereas tissue swelling, elevated skin temperature and elevated haptoglobin levels persisted for at least 72 h. Treatment with meloxicam improved weight borne by and tolerance to pressure exerted on the turpentine‐injected limb. Conclusions The local and systemic signs of inflammation and pain, temporary reduction in function of the affected limb and partial amelioration of some of these changes by the dose of meloxicam used here suggest that injection of turpentine in the lower forelimb provides a suitable model for examining the efficacy of analgesics for alleviation of pain and inflammation in sheep.     

Pharmacokinetics of the novel COX‐2 selective inhibitor vitacoxib in cats: The effects of feeding and dose

The purpose of this study was to determine the pharmacokinetics and dose‐scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC‐MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a T_max of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MAT_fed). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg^?1 hr^?1) was 95.22 ± 23.53 ml kg^?1 hr^?1. Plasma concentrations scaled linearly with dose, with C_max (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study.     

Pharmacokinetics of transdermal flunixin in sows

The objective of this study was to describe the pharmacokinetics (PK) of flunixin in 12 nonlactating sows following transdermal (TD) flunixin (3.33 mg/kg) and intravenous (IV; 2.20 mg/kg) flunixin meglumine (FM) administration using a crossover design with a 10‐day washout period. Blood samples were collected postadministration from sows receiving IV FM (3, 6, 10, 20, 40 min and 1, 3, 6, 12, 16, 24, 36, and 48 hr) and from sows receiving TD flunixin (10, 20, 40 min and 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hr). Liquid chromatography and mass spectrometry were used to determine plasma flunixin concentrations, and noncompartmental methods were used for PK analysis. The geometric mean ± SD area under the plasma concentration–time curve (AUC) following IV injection was 26,820.59 ± 9,033.88 and 511.83 ± 213.98 hr ng/ml for TD route. Mean initial plasma concentration (C₀) was 26,279.70 ± 3,610.00 ng/ml, and peak concentration (C_max) was 14.61 ± 7.85 ng/ml for IV and TD administration, respectively. The percent mean bioavailability of TD flunixin was 1.55 ± 1.00. Our results demonstrate that topical administration is not an efficient route for delivering flunixin in mature sows.     

Evaluation of the adverse effects of subcutaneous carprofen over six days in healthy cats

This study evaluated the adverse effects of carprofen in seven healthy cats. Values for CBC, biochemical profiles and platelet aggregation were measured before and at seven days after SID treatment with subcutaneous carprofen: 4 mg/kg (day 1), 2 mg/kg (day 2 and 3) and 1 mg/kg (day 4 and 6) (CG) or 0.35 ml of saline (SG) for six days in a randomized, blinded, cross-over study with a four-week washout period. No treatment was given on day 5. Endoscopy of the GI tract was performed pre-treatment and on day 7 post-treatment. There were no significant changes in hematological profiles, biochemical profiles and endoscopy grading scores within nor between groups, except for lower albumin values at baseline than on day 7 (CG), and globulin and ALP values were higher at baseline than on day 7 in CG and SG. SC administration of carprofen over six days did not cause any adverse effects on gastrointestinal, hematological, or serum biochemical variables.     

Evaluation of cyclooxygenase-1 and cyclooxygenase-2 expression and the effect of cyclooxygenase inhibitors in canine prostatic carcinoma

Prostatic carcinoma occurs primarily in older castrated male dogs and is typically a fatal disease (most dogs die within few months after the initial diagnosis). Surgery, i.e., total prostatectomy, or radiation therapy is often not pursued due to risks of complications and a high rate of distant metastasis. Cyclooxygenase‐2 (Cox‐2) expression has been documented in several malignancies, including canine prostatic carcinoma. Cox‐2 inhibition has been reported to have preventative effects on several human malignancies and has therapeutic effects on both laboratory and spontaneous tumour models. The purpose of this retrospective study was to evaluate Cox expression and the effects of Cox inhibitors on survival in dogs with prostatic carcinoma. 94.1 and 88.2% of the tumours expressed Cox‐1 and Cox‐2, respectively. Furthermore, dogs treated with Cox inhibitors (piroxicam or carprofen) lived significantly longer than untreated dogs, 6.9 versus 0.7 months (P < 0.0001), suggesting that Cox inhibitors may have an important role in canine prostate cancer therapy.