Absorption,distribution, metabolism and excretion of loxoprofen after dermal application of loxoprofen gel to rats

Abstract

1. Loxoprofen (LX), is a prodrug of the pharmacologically active form, trans-alcohol metabolite (trans-OH form), which shows very potent analgesic effect. In this study, the pharmacokinetics and metabolism of [¹⁴C]LX-derived radioactivity after dermal application of [¹⁴C]LX gel (LX-G) to rats were evaluated.

2. The area under concentration-time curve (AUC_0–∞) of radioactivity in the plasma after the dermal application was 13.6% of that of the oral administration (p?<?0.05).

3. After the dermal application, the radioactivity remained in the skin and skeletal muscle at the treated site for 168?h, whereas the AUC_0–168?h of the radioactivity concentration in every tissue examined except the treated site was statistically lower than that after the oral administration (p?<?0.05).

4. The trans-OH form was observed at high levels in the treated skin site at 0.5?h. Metabolite profiles in plasma, non-treated skin site and urine after the dermal application were comparable with those after the oral administration.

5. Renal excretion was the main route of elimination after the dermal application.

6. In conclusion, compared to the oral administration, the dermal application of [¹⁴C]LX-G showed lower systemic and tissue exposure with higher exposure in the therapeutic target site. The radioactivity revealed similar metabolite profiles in both administration routes.     

Sedative effect of central administration of Coriandrum sativum essential oil and its major component linalool in neonatal chicks

Context Coriandrum sativum L. (Apiaceae) (coriander) is an herb grown throughout the world as a culinary, medicinal or essential crop. In traditional medicine, it is used for the relief of anxiety and insomnia. Systemic hydro-alcoholic and aqueous extract from aerial parts and seeds had anxiolytic and sedative action in rodents, but little is known about its central effect in chicks.

Objective To study the effects of intracerebroventricular administration of essential oil from coriander seeds and its major component linalool on locomotor activity and emotionality of neonatal chicks.

Materials and methods The chemical composition of coriander essential oil was determined by a gas-chromatographic analysis (>?80% linalool). Behavioural effects of central administration of coriander oil and linalool (both at doses of 0.86, 8.6 and 86?μg/chick) versus saline and a sedative diazepam dose (17.5?μg/chick, standard drug) in an open field test for 10?min were observed.

Results Doses of 8.6 and 86?μg from coriander oil and linalool significantly decreased (p?<?0.05) squares crossed number, attempted escapes, defecation number and distress calls, and significantly increased (p?<?0.05) the sleeping posture on an open field compared with saline and were similar to the diazepam group.

Discussion and conclusion The results indicate that intracerebroventricular injection of essential oil from Coriandrum sativum seeds induced a sedative effect at 8.6 and 86?μg doses. This effect may be due to monoterpene linalool, which also induced a similar sedative effect, and, therefore, could be considered as a potential therapeutic agent similar to diazepam.     

Evaluation of antinociceptive and antidiarrhoeal properties of Manilkara zapota leaves in Swiss albino mice

Context Manilkara zapota (L.). P. Royen. (Sapotaceae) has been used in folk medicine to treat pain, diarrhoea, inflammation, arthralgia, and other disorders.

Objective Screening of Manilkara zapota leaves ethanol extract and its different solvent soluble fractions for possible antinociceptive and antidiarrhoeal activities in Swiss albino mice.

Materials and methods The extract and various fractions (200 and 400?mg/kg body weight; p.o.) were tested for peripheral and central antinociceptive activity by acetic acid-induced writhing and radiant heat tail-flick method, respectively; castor oil-induced diarrhoeal model was used to evaluate antidiarrhoeal activity at both doses. All the samples were administered once in a day and the duration of study was approximately 5?h.

Results Ethanol extract (400?mg/kg), petroleum ether fraction (400?mg/kg), and ethyl acetate fraction (400?mg/kg) showed significant peripheral antinociceptive activity having 59.89, 58.24, and 46.7% (p?<?0.001) of writhing inhibition, respectively, which is comparable with that of standard diclofenac (59.34% inhibition). The ethanol extract (400?mg/kg) and petroleum ether fraction (400?mg/kg) also showed promising central analgesic activity having 74.15 and 82.15% (p?<?0.001) elongation of reaction time, respectively, at 90?min after administration of sample which is also similar to that obtained by morphine (85.84% elongation). In antidiarrhoeal activity screening, ethanol extract (200 and 400?mg/kg) showed significant inhibition of defecation by 53.57 and 60.71%, respectively (p?<?0.001) compared with that of loperamide (71.42%).

Discussion and conclusion The findings of the studies demonstrated antinociceptive and antidiarrhoeal activities of M. zapota leaves which could be the therapeutic option against pain and diarrhoeal disease.     

Epithelial transport of Noscapine across cell monolayer and influence of absorption enhancers on in vitro permeation and bioavailability: implications for intestinal absorption

Abstract

The purpose of this study was to investigate the permeation of Noscapine (Nos) across the Caco-2 and Madin–Darby canine kidney (MDCK) cell monolayers and to evaluate the influence of absorption enhancers on in vitro and in vivo absorption of Nos. The bidirectional transport of Nos was studied in Caco-2 and MDCK cell monolayers at pH 5.0–7.8. The effect of 0.5% w/v chitosan (CH) or Captisol (CP) on Nos permeability was investigated at pH 5.0 and 5.8. The effect of 1–5% w/v of CP on oral bioavailability of Nos (150?mg/kg) was evaluated in Sprague–Dawley rats. The effective permeability coefficients (P_eff) of Nos across Caco-2 and MDCK cell monolayers was found to be in the order of pH 5.0?>?5.8?>?6.8?>?7.8. The efflux ratios of P_eff?<?2 demonstrated that active efflux does not limit the absorption of Nos. The use of CH or CP have shown significant (***, p?<?0.001) enhancement in P_eff of Nos across cell monolayer compared with the control group. The CP (1–5% w/v) based Nos formulations resulted in significant (***, p?<?0.001) increase in the bioavailability of Nos compared with Nos solution. The use of CP represents viable approach for enhancing the oral bioavailability of Nos and reducing the required dose.     

Efficacy of Aloe vera/olive oil cream versus betamethasone cream for chronic skin lesions following sulfur mustard exposure: a randomized double-blind clinical trial

Background: Chronic pruritic skin lesions are among the common late complications of sulfur mustard intoxication. In the present randomized double-blind clinical trial, therapeutic efficacy of Aloe vera/olive oil combination cream in the alleviation of these lesions was evaluated and compared to that of betamethasone 0.1% cream.

Methods: Sixty-seven Iranian chemical warfare-injured veterans were randomized to apply A. vera/olive oil (n?=?34, completers?=?31) or betamethasone 0.1% (n?=?33, completers?=?32) cream twice daily for 6 weeks. Evaluation of pruritus severity was performed using a pruritic score questionnaire and visual analogue scale (VAS).

Results: Both treatments were associated with significant reductions in the frequency of pruritus (p?<?0.05), burning sensation (p?<?0.01 and p?<?0.001 in A. vera/olive oil and betamethasone group, respectively), scaling (p?<?0.01 and p?<?0.05) and dry skin (p?<?0.001) at the end of trial. Fissure and excoriation were only reduced in the A. vera group (p?<?0.05). The change in the frequency of hyper- and hypopigmentation lesions, blisters, erythema and lichenification did not reach statistical significance in any of the groups (p?>?0.05). Mean pruritus (p?<?0.05) and VAS scores (p?<?0.01 and p?<?0.05) were significantly decreased by the end of trial in both groups. The rate of improvement in the pruritus severity [defined as being classified in a less severe category (mild, moderate and severe)] was found to be comparable between the groups (p?>?0.05).

Conclusion: A. vera/olive oil cream was at least as effective as betamethasone 0.1% in the treatment of sulfur mustard-induced chronic skin complications and might serve as a promising therapeutic option for the alleviation of symptoms in mustard gas-exposed patients.     

Biological activities of salvianolic acid B from Salvia miltiorrhiza on type 2 diabetes induced by high-fat diet and streptozotocin

Abstract

Context: Salvia miltiorrhiza Bge. (Labiatae) has been widely used for treating diabetes for centuries. Salvianolic acid B (SalB) is the main bioactive component in Salvia miltiorrhiza; however, its antidiabetic activity and possible mechanism are not yet clear.

Objective: To investigate the effects of SalB on glycometabolism, lipid metabolism, insulin resistance, oxidative stress, and glycogen synthesis in type 2 diabetic rat model.

Materials and methods: High-fat diet (HFD) and streptozotocin-induced diabetic rats were randomly divided into model group, SalB subgroups (50, 100, and 200?mg/kg), and rosiglitazone group.

Results: Compared with the model group, SalB (100 and 200?mg/kg) significantly decreased blood glucose (by 23.8 and 21.7%; p?<?0.05 and p?<?0.01) and insulin (by 31.3 and 26.6%; p?<?0.05), and increased insulin sensitivity index (by 10.9 and 9.3%; p?<?0.05). They also significantly decreased total cholesterol (by 24.9 and 27.9%; p?<?0.01), low-density lipoprotein cholesterol (by 56.2 and 64.6%; p?<?0.01), non-esterified fatty acids (by 32.1 and 37.9%; p?<?0.01), hepatic glycogen (by 41.3 and 60.5%; p?<?0.01), and muscle glycogen (by 33.2 and 38.6%; p?<?0.05), and increased high-density lipoprotein cholesterol (by 50.0 and 61.4%; p?<?0.05 and p?<?0.01), which were originally altered by HFD and streptozotocin. In addition, SalB (200?mg/kg) markedly decreased triglyceride and malondialdehyde (by 31.5 and 29.0%; p?<?0.05 and p?<?0.01), and increased superoxide dismutase (by 56.6%; p?<?0.01), which were originally altered by HFD and streptozotocin.

Discussion and conclusion: The results indicate that SalB can inhibit symptoms of diabetes mellitus in rats and these effects may partially be correlated with its insulin sensitivity, glycogen synthesis and antioxidant activities.     

Pooled analysis of GI tolerability of 21 randomized controlled trials of celecoxib and nonselective NSAIDs

ABSTRACT

Objective: To compare the gastrointestinal (GI) tolerability of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at approved doses in patients with common musculoskeletal conditions.

Research design and methods: This was a retrospective, pooled analysis of studies selected from the Pfizer Corporate Clinical Trials Registry. Study selection criteria were: (1) Data available as of October 31, 2004; (2) Randomized, parallel-group study design and planned treatment duration of ≥?2 weeks; (3) At least one nonselective NSAID (naproxen, ibuprofen, or diclofenac) as a comparator; (4) At least one arm with 200?mg or 400?mg celecoxib per day; (5) Patients with osteoarthritis (OA), adult rheumatoid arthritis (RA), or ankylosing spondylitis (AS).

Data were pooled by treatment and by subject from the safety analysis population of each included study. Joint primary end points were the combined incidence of tolerability-related GI adverse events (AEs) (abdominal pain, dyspepsia, nausea, diarrhea, and flatulence), and time to study discontinuation due to any GI?AE.

Results: In all, 21 studies met the selection criteria. Across the safety analysis populations of the included studies, 7797 patients received celecoxib total daily dose 200?mg/day, 6653 received celecoxib total daily dose 400?mg/day, 2953 received naproxen, 499 received ibuprofen, and 5643 received diclofenac. Tolerability-related GI AEs were reported by significantly fewer celecoxib-treated patients (16.0%) than by those treated with naproxen (24.3%), ibuprofen (24.2%), or diclofenac (19.9%) (p?<?0.0001 vs. each comparator). Time to study discontinuation due to any GI?AE was significantly longer for celecoxib than for naproxen (p?<?0.0001), ibuprofen (p?=?0.002), or diclofenac (p?=?0.048). In the RA subpopulation (n?=?2857), there was no significant difference between the celecoxib and naproxen or ibuprofen groups in incidence of tolerability-related GI AEs and GI AEs.

Limitations: The limitations are inherent to the retrospective analysis design.

Conclusions: In this pooled analysis of celecoxib at approved doses in OA, RA, and AS, fewer celecoxib-treated patients in the overall population had tolerability-related GI AEs than patients treated with naproxen, ibuprofen, or diclofenac. In addition, celecoxib-treated patients had a significantly longer time to study discontinuation due to GI AEs.     

The application of 1,8-cineole,a terpenoid oxide present in medicinal plants,inhibits castor oil-induced diarrhea in rats

Abstract

Context: 1,8-Cineole, a terpene, characterized as a major constituent occurring in the essential oils of several aromatic plants. It is widely used in pharmaceutical industry, as a food additive and for culinary purposes.

Objective: This study investigates the inhibitory effect of 1,8-cineole on transit time and diarrhea in animal models.

Materials and methods: Acute toxicity and lethality of 1-8-cineole was determined by Lork’s guidelines. The antidiarrheal effect of 1,8-cineole was investigated by determining the intestinal transit and enterpooling in rats. In all experiments, different doses of 1,8-cineole (20–120?mg/kg), atropine, and loperamide were administered orally.

Results: The LD₅₀ of 1,8-cineole for oral administration was estimated to be 1280?mg/kg. 1,8-Cineole (20–120?mg/kg) did not show a significant decrease in small intestine transit (p?>?0.05); however, the highest dose displayed a significant decrease in comparison with atropine (p?<?0.05). This substance decreased the peristaltic index value to 68?±?0.36% at a dose of 120?mg/kg compared with the control group (85.22?±?4.31%) in the castor oil transit test. 1,8-Cineole significantly delayed the onset of diarrhea to ?142.33?±?6.08?min at 120?mg/kg, while the time was 103.66?±?20.73?min for the control and >240?min for the loperamide. Moreover, 1,8-cineole significantly decreased intestinal fluid accumulation (p?<?0.05).

Conclusions: This study demonstrated antispasmodic and antisecretory activities of 1,8-cineole and rationalized the traditional use of the plant containing various levels of this terpene in the treatment of gastrointestinal complains such as diarrhea.     

Comparison of rofecoxib and a multidose oxycodone/acetaminophen regimen for the treatment of acute pain following oral surgery: a randomized controlled trial

SUMMARY

Objective: To compare the efficacy of a single dose of rofecoxib 50?mg with a single dose of oxycodone/acetaminophen 10/650?mg over 6?h as well as with a multidose regimen of oxycodone/acetaminophen 10/650?mg followed by oxycodone/acetaminophen 5/325?mg over 24?h.

Research design and methods: In this double-blind, randomized, two-phase study, patients with moderate to severe pain after surgical extraction of ≥ 2 third molars, including one mandibular impaction, were treated with rofecoxib 50?mg, oxycodone/acetaminophen 10/650?mg (single-dose phase) followed by 5/325?mg every 6?h as needed (multidose phase), or placebo. Patients rated their pain relief and intensity at 18 time points over 24?h. Efficacy was measured over 6 and 24?h by total pain relief (TOPAR), sum of pain intensity difference (SPID), and patient global assessment of response to therapy (PGART). Primary endpoint for the single dose comparison was TOPAR over 6?h; SPID was the key 24-h endpoint. Onset of analgesic effect, peak analgesic effect, and duration of analgesic effect were also evaluated. Adverse experiences were recorded.

Results: 271 patients were randomized to treatment with rofecoxib (n = 121), oxycodone/acetaminophen (n = 120), or placebo (n = 30). For the single dose comparison, rofecoxib-treated patients achieved pain relief at least as effective as oxycodone/acetaminophen-treated patients as assessed by TOPAR6 (12.9 vs 11.3, 95% CI on difference = [–0.1, 3.2], p = 0.059). Patients also rated a single dose of rofecoxib as at least as effective as multidose oxycodone/acetaminophen over 24?h on SPID24 (21.9 vs 18.1, 95% CI on difference = [–1.0, 8.8], p = 0.122). Patients treated with oxycodone/acetaminophen had a shorter time to onset of analgesia than patients treated with rofecoxib (24 vs 35?min, p < 0.05). Patients in the active treatment groups achieved similar peak effects during the single-dose phase. Individuals treated with rofecoxib demonstrated a longer duration of analgesic effect than those treated with a single dose of oxycodone/acetaminophen. Patients on active treatment demonstrated better efficacy than patients on placebo on these prespecified endpoints (?p < 0.001 for both comparisons). Fewer rofecoxib than oxycodone/acetaminophen patients experienced adverse events (47.9 vs 75.8%, p < 0.001), including nausea (19.0 vs 42.5%, p < 0.001), vomiting (9.9 vs 24.2%, p < 0.01), and dizziness (7.4 vs 31.7%, p < 0.001).

Conclusion: Patients treated with a single dose of rofecoxib 50?mg achieved an overall analgesic effect at least as effective as patients treated with a single-dose of oxycodone/acetaminophen 10/650?mg over 6?h and multidose oxycodone/acetaminophen over 24?h, with fewer adverse experiences of nausea (?p < 0.001), vomiting (?p < 0.01), and dizziness (?p < 0.001).     

A randomized controlled study comparing rofecoxib,diclofenac sodium,and placebo in post-bunionectomy pain

SUMMARY

Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.

Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50?mg (N = 85), enteric-coated diclofenac sodium 100?mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50?mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24?h. Primary endpoint was total pain relief over 8?h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5.

Results: For TOPAR8 scores, rofecoxib 50?mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo (?p = 0.003) and diclofenac (?p = 0.019); proportion of patients achieving onset within 4?h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03?h vs. 4:02?h, p < 0.001 and 1:41?h vs. 4:02?h, p < 0.001). Rofecoxib patients used significantly less (?p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1?tablets/day vs. 2.1?tablets/day) and Days 2–5 (0.9?tablets/day vs. 1.8?tablets/day). No significant differences in adverse experiences between treatments were seen.

Conclusion: Rofecoxib 50?mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50?mg was significantly more effective than diclofenac sodium 100?mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.     

Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous biomarkers

Abstract

Context: Acetaminophen (APAP) leads to severe hepatic and renal necrosis and thus causes significant clinical problems. Artemisia pallens Walls ex D.C. (Asteraceae) possesses various pharmacological properties such as antidiabetic, antioxidant, analgesic, and anti-inflammatory activity.

Objective: The objective was to evaluate the protective effects of Artemisia pallens methanol extract (APME) in APAP-induced hepatic and nephro-toxicity.

Materials and methods: The methanolic extract of aerial parts of Artemisia pallens (APME) was prepared. Toxicity was induced in male Wistar rats (180–220?g) by administration of APAP (700?mg/kg, p.o., 14?d). APME (100, 200, and 400?mg/kg, p.o.) was administered to rats 2?h before APAP oral administration. Various biochemical and molecular parameters along with histopathological aberration were studied in the kidney and liver of rats.

Results: Pretreatment with APME (200 and 400?mg/kg, p.o.) significantly (p?<?0.01 and p?<?0.001) decreased aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, blood urea nitrogen (BUN), and serum creatinine as compared with APAP-treated rat. Decreased level of serum albumin, serum uric acid, and HDL were significantly (p?<?0.01 and p?<?0.001) restored by APME (200 and 400?mg/kg, p.o.) pre-treatment. Administration of APME (200 and 400?mg/kg, p.o.) significantly (p?<?0.01 and p?<?0.001) reduced the elevated level of cholesterol, LDL, LDH, triglyceride, and VLDL. It also significantly (p?<?0.01 and p?<?0.001) restored the altered level of hepatic and renal antioxidant enzymes (superoxide dismutase (SOD) and glutathione (GSH)). The increased level of malondialdehyde (MDA) and nitric oxide (NO) in hepatic as well as renal tissue was significantly (p?<?0.01 and p?<?0.001) decreased by APME (200 and 400?mg/kg, p.o.) administration. Histological alternation induced by APAP in liver and kidney was also reduced by the APME (200 and 400?mg/kg, p.o.) pre-treatment.

Conclusion: It is concluded that the methanol extract of Artemisia pallens alleviates APAP induced in rats toxicity through its antioxidative and anti-inflammatory actions.     

Enrichment of Bifidobacterium longum subsp. infantis ATCC 15697 within the human gut microbiota using alginate-poly-l-lysine-alginate microencapsulation oral delivery system: an in vitro analysis using a computer-controlled dynamic human gastrointestinal model

Abstract

This study evaluates alginate-poly-l-lysine-alginate Bifidobacterium longum subsp. infantis ATCC 15697-loaded microcapsules to enrich the human gut microbiota. The cell survival of alginate-poly-l-lysine-alginate microencapsulated B. infantis ATCC 15697 in gastric acid, bile, and through human gastrointestinal transit was investigated, as well as the formulation’s effect on the gut microbiota. Results show that microencapsulation increases B. infantis ATCC 15697 cell survival at pH1.0 (33.54?±?2.80% versus <1.00?±?0.00%), pH1.5 (41.15?±?2.06% versus <1.00?±?0.00%), pH2.0 (60.88?±?1.73% versus 36.01?±?2.63%), pH3.0 (75.43?±?1.23% versus 46.30?±?1.43%), pH4.0 (71.40?±?2.02% versus 47.75?±?3.12%) and pH5.0 (73.88?±?3.79% versus 58.93?±?2.26%) (p?<?0.05). In addition, microencapsulation increases cell survival at 0.5% (76.85?±?0.80% versus 70.77?±?0.64%), 1.0% (59.99?±?0.97% versus 53.47?±?0.58%) and 2.0% (53.10?±?1.87% versus 44.59?±?1.52%) (p?<?0.05) (w/v) bile. Finally, daily administration of alginate-poly-l-lysine-alginate microencapsulated B. infantis ATCC 15697 in a human gastrointestinal model induces a significant enrichment of B. infantis within the ascending (184.51?±?17.30% versus 53.83?±?17.82%; p?<?0.05), transverse (174.79?±?25.32% versus 73.17?±?15.30%; p?<?0.05) and descending (94.90?±?25.22% versus 46.37?±?18.93%; p?>?0.05) colonic microbiota.     

Antinociceptive effect of the essential oil of tarragon (Artemisia dracunculus)

Context: Tarragon [Artemisia dracunculus L. (Asteraceae)] is used as a commercial flavoring and in perfumery. In traditional folk medicine, tarragon has been used for treatment of pain and gastrointestinal disturbances.

Objective: This study investigated the antinociceptive effect of the essential oil of A. dracunculus (EOAD) in various experimental models.

Materials and methods: The median lethal dose (LD₅₀) of EOAD was estimated using the method of Lorke. The antinociceptive effect was assessed using chemical (formalin and acetic acid) and thermal (hot-plate) nociceptive tests in rats and mice. In all experiments, EOAD was administered intraperitoneally at the doses of 10, 30, 100 and 300?mg/kg.

Results: In the acute toxicity test, the value of estimated LD₅₀ for EOAD was 1250?mg/kg. EOAD (100 and 300?mg/kg) significantly reduced (p?p?Conclusions: This study reported the peripheral and central antinociceptive activity of the EOAD and rationalized the traditional use of the plant in the treatment of different painful conditions.     

Insecticidal Activities of Commercial Rosemary Oils (Rosmarinus officinalis.) Against Larvae of Pseudaletia unipuncta. and Trichoplusia ni. in Relation to Their Chemical Compositions

Abstract

Rosemary [Rosmarinus officinalis. L. (Lamiaceae)] essential oil has insecticidal properties and is the active ingredient in a number of commercial insecticides. Like other plant essential oils, the chemical composition of rosemary oil can vary based on genotype, geography, climate, and method of preparation. This study explored the relationship between chemical composition and insecticidal activity of 10 commercial samples of rosemary oil, based on laboratory bioassays with two agricultural pests, the armyworm Pseudaletia unipuncta. Haworth (Noctuidae) and the cabbage looper Trichoplusia ni. Hübner (Noctuidae). Nine major terpenoid constituents of rosemary oil were quantified in the samples by gas chromatography–mass spectrometry (GC-MS). The major constituents were 1,8-cineole, α-pinene, β-pinene, and camphor; on average 1,8-cineole made up 52% of the oil by weight. Bioassayed individually, camphor was the most toxic compound to the armyworm (LD₅₀ = 189.4 μ g larva^{? 1}) whereas μ-terpineol was the most toxic to the looper (LD₅₀ = 128.5 μ g larva^{? 1}). LD₅₀ values for the ten rosemary oils ranged from 167.1 to 372.1 μ g larva^{? 1}in the armyworm and from 58.9 to 335.9 μ g larva^{? 1} in the looper. Correlation analysis comparing rosemary oil toxicity to chemical composition revealed slight but significant correlation for d.-limonene and α-terpineol in bioassays with the looper but no correlations between constituents and toxicity with the armyworm. An “artificial” rosemary oil was prepared by mixing the nine major constituents in proportions reflecting the average proportion of each constituent in the 10 commercial oils. In the armyworm, this “artificial” oil was significantly less toxic than five of the intact oils; in the looper, the artificial oil was less toxic than three of the intact oils. Our results suggest that toxicity of rosemary oil, at least to lepidopteran larvae, is a consequence of the combined (and possibly synergistic) effects of several chemical constituents, with no individual compound making a dominating contribution.     

The analgesic effect of etoricoxib relative to that of two opioid-acetaminophen analgesics: a randomized,controlled single-dose study in acute dental impaction pain

ABSTRACT

Background: To compare the analgesic effect of single doses of etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg in acute pain using the dental impaction model.

Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6?h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences.

Results: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg, codeine/acetaminophen 60?mg/600?mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2?units) versus oxycodone/acetaminophen (10.2?units); and codeine/acetaminophen (6.0?units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (?p < 0.001) shorter for oxycodone/acetaminophen (20?min) and numerically but not significantly shorter (?p = 0.259) for codeine/acetaminophen (26?min) compared with etoricoxib (40?min). Etoricoxib (24?h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3?h), codeine/acetaminophen (2.7?h), and placebo (1.7?h) (?p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly (?p < 0.05) fewer episodes of nausea.

Conclusion: Etoricoxib 120?mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg.     

Combination of azelaic acid 5% and clindamycin 2% for the treatment of acne vulgaris

Context and objective: Acne vulgaris, an inflammatory skin disease with different clinical appearances, is a common problem in most adolescents. It seems that using combinations of topical agents can decrease resistance to the treatment and improve the efficacy. Therefore, we evaluated the effects of azelaic acid (AA) 5% and clindamycin (Clin) 2% combination (AA-Clin) on mild-to-moderate acne vulgaris.

Materials and methods: The efficacy and safety of 12-week treatment with AA-Clin in patients with mild-to-moderate facial acne vulgaris were evaluated by a multicenter, randomized, and double-blind study. A total of 88 male and 62 female patients were randomly assigned to one of these treatments: AA 5%, Clin 2%, and combination of them. Every 4 weeks, total inflammatory and noninflammatory lesions were counted, acne severity index (ASI) was calculated, and patient satisfaction was recorded.

Results: Treatment for 12 weeks with combination gel significantly reduced the total lesion number compared with baseline (p?<?0.01), as well as Clin 2% or AA 5% treatment groups (p?<?0.05 or p?<?0.01). The percentage of reduction in ASI in combination treated group (64.16?±?6.01) was significantly more than those in the Clin 2% (47.73?±?6.62, p?<?0.05) and 5% AA (32.46?±?5.27, p?<?0.01) groups after 12 weeks. Among the patients in the AA-Clin group, 75.86% of males were satisfied or very satisfied and 85.71% of females were satisfied or very satisfied. This trend was significant in comparison to the number of patients who were satisfied with AA 5% or Clin 2% treatment (p?<?0.01). Seven patients in AA-Clin group (incidence?=?22%) showed adverse effects that were not statistically significant compared to treatment with individual active ingredients.

Discussion and conclusion: The profound reduction in lesion count and ASI by combination therapy with AA-Clin gel in comparison to individual treatment with 5% AA or Clin 2% suggested the combination formula as an effective alternative in treatment of acne vulgaris.     

The anti-hyperalgesic and anti-inflammatory profiles of p-cymene: Evidence for the involvement of opioid system and cytokines

Abstract

Context: Pain corresponds to the most frequent reason for visits to physicians, and its control by conventional drugs is accompanied by several side effects, making treatment difficult. For this reason, new chemical entities derived from natural products still hold great promise for the future of drug discovery to pain treatment.

Objective: The objective of this study was to evaluate the antinociceptive and anti-inflammatory profiles of p-cymene (PC), a monocyclic monoterpene, and its possible mechanisms of action.

Materials and methods: Mice treated acutely with PC (25, 50, or 100?mg/kg, i.p.) were screened for carrageenan-induced hyperalgesia and the inflammatory components of its cascade (30–180?min), carrageenan-induced pleurisy (4?h), and tail-flick test (1–8?h). Also, we observed the PC effect on the generation of nitric oxide by macrophages and the activation of neurons in the periaqueductal gray (PAG) by immunofluorescence.

Results: PC reduced (p?<?0.001) the hyperalgesia induced by carrageenan, TNF-α, dopamine, and PGE₂. PC decrease total leukocyte migration (100?mg/kg: p?<?0.01), neutrophils (50 and 100?mg/kg: p?<?0.05 and 0.001), and TNF-α (25, 50, and 100?mg/kg: p?<?0.01, 0.05, and 0.001, respectively), besides reducing NO production (p?<?0.05) in vitro. PC produced antinociceptive effect in tail-flick test (p?<?0.05), which was antagonized by naloxone, naltrindole, nor-BNI, and CTOP, and increased (p?<?0.001) the number of c-Fos-immunoreactive neurons in PAG.

Discussion and conclusion: These results provide information about the anti-hyperalgesic and anti-inflammatory properties of PC suggesting a possible involvement of the opioid system and modulating some pro-inflammatory cytokines.     

The ginsenoside metabolite compound K exerts its anti-inflammatory activity by downregulating memory B cell in adjuvant-induced arthritis

Context: Compound K (CK, 20-O-d-glucopyranosyl-20(S)-protopanaxadiol), a novel ginsenoside metabolite, is structurally a member of the dammarane-type triterpene saponins. Several studies have identified the anti-inflammatory activity of CK. Our previous study demonstrated that CK exerted its anti-inflammatory effect via inhibition of abnormal activation and differentiation of T cells. However, its mechanism of action on B cells remains unclear.

Objective: The objective of this study is to investigate the effect and underlying mechanisms of CK’s effects on memory B cells in the setting of adjuvant-arthritis (AA).

Materials and methods: Complete Freund’s adjuvant was used to induce AA in rats. Rats were administered, either CK (10, 40, and 160?mg/kg), once daily for 15?d, or methotrexate (MTX; 0.5?mg/kg) once every 3?d, for a total of six times. To evaluate the anti-inflammatory effect of CK, a global assessment and a swollen joint count of AA rats were performed every 3?d. Spleen index and histopathology were examined. Subsets of B cells including CD45R⁺IgM⁺ (total B cells) and CD45R⁺CD27⁺ (memory B cells) and expression of CD40 and CD40L were assayed by flow cytometry.

Results: Compared with the AA rats, global assessment scores and swollen joint counts were significantly lower in the treated groups received CK (40 and 160?mg/kg; p?<?0.05 and p?<?0.01, respectively). CK (40 and 160?mg/kg) decreased the spleen index (p?<?0.01), and alleviated hyperplasia of lymph nodes (p?<?0.05 and p?<?0.01, respectively) and marginal zone (p?<?0.05) in the spleen. In addition, CK (40 and 160?mg/kg) suppressed memory B cell subsets (p?<?0.05), and suppressed CD40L expression on T cells and CD40 expression on B cells (p?<?0.05 and p?<?0.01, respectively).

Discussion and conclusion: This study demonstrated that CK downregulated memory B cells in AA rats, and this down-regulation may be T-cell dependent.     

Antidiabetic mechanism of Coptis chinensis polysaccharide through its antioxidant property involving the JNK pathway

Abstract

Context: Antidiabetic activity of Coptis chinensis Franch (Ranunculaceae) polysaccharide (CCPW) has been reported. However, its molecular mechanism remains unclear.

Objective: An attempt was made to further verify the antidiabetic activity of CCPW on type 2 diabetes mellitus (T2DM) and elucidate the mechanism of antidiabetic activity.

Materials and methods: Male Wistar rats were fed with high-fat diet (HFD) and injected with streptozotocin (STZ) to generate a T2DM model. Effects of CCPW on fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), glutathione (GSH), glutathione peroxidases (GSH-Px), superoxide dismutases (SOD), catalase (CAT), malondialdehyde (MDA), c-jun n-terminal kinase (JNK), phosphorylated insulin receptor substrate 1 (phospho-IRS1), phosphorylated phosphatidylinositol 3 kinase (phospho-PI3Kp85) and glucose transporter 4 (Glut4) were investigated.

Results: FBG level of diabetic rats could be significantly inhibited by 51.2, 42.7, and 23.3% through administration of CCPW at doses of 200, 100, and 50?mg/kg b.w., respectively (p?<?0.01). CCPW also could significantly reduce TG by 19.2, 12.1, and 7.4%, and TC by 24.2, 20.9, and 18.7%, respectively (p?<?0.05 or p?<?0.01). CCPW showed an obvious antioxidant effect through increasing GSH-Px, SOD, and CAT activities, and decreasing GSH and MDA contents (p?<?0.05 or p?<?0.01). Furthermore, CCPW could inhibit JNK and phospho-IRS1 expression and promote the expression of phospho-PI3Kp85 and Glut4 compared with those in the DM group (p?<?0.05 or p?<?0.01).

Discussion and conclusion: CCPW can produce antidiabetic activity in rats with T2DM through its antioxidative effect, which is closely related to the JNK/IRS1/PI3K pathway.     

Metabolic effect of repaglinide or acarbose when added to a double oral antidiabetic treatment with sulphonylureas and metformin: a double-blind,cross-over,clinical trial

ABSTRACT

Objective: To compare the metabolic effects of acarbose and repaglinide in type 2 diabetic patients who are being treated with a sulphonylurea–metformin combination therapy. The primary endpoint of the study was to evaluate which add-on treatment between acarbose and repaglinide is more efficacious in reducing PPG. The second endpoint was to evaluate which of these two treatment is more efficacious in the global management of glucose homeostasis in the enrolled patients.

Research design and methods: After a 4-week run-in period with a suplonylurea–metformin combination, 103 patients were randomised to receive in addition either repaglinide, up to 6?mg/day (2?mg three times a day) or acarbose, up to 300?mg/day (100?mg three times a day) with forced titration (independently of their glycaemic control, unless side-effects developed due to the drug dosage) for 15 weeks. The treatment was then crossed-over for further 12 weeks until the 27th week. We assessed body mass index (BMI), glycosylated haemoglobin (HbA_1c), fasting plasma glucoe (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostatic model assesssment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (Tg), at baseline and at 1, 2, 15 and 27 weeks of treatment.

Results: Seven patients did not complete the study, comprising one patient who was lost to follow-up and a further six through side-effects (two in week 1, one in week 15 and three after cross-over) Side-effects were classified as nausea (one in acarbose group), gastrointestinal events (four in acarbose group), and hypoglycaemia (one in repaglinide group). After 15 weeks of therapy, the repaglinide-treated patients experienced a significant decrease in HbA_1c (?1.1%, p?<?0.05), FPG (?9.5%, p?<?0.05), and PPG (?14.9%, p?<?0.05), when compared to the baseline values. However, the same treatment was associated with a significant increase in body weight (+2.3%, p?<?0.05), BMI (+3.3%, p?<?0.05) and FPI (+22.5%, p?<?0.05); The increase was reversed during the cross-over phase. After 15 weeks of therapy, the acarbose-treated patients experienced a significant decrease in body weight (?1.9%, p?<?0.05), BMI (?4.1%, p?<?0.05), HbA_1c (?1.4%, p?<?0.05), FPG (?10.7%, p?<?0.05), PPG (?16.2%, p?<?0.05), FPI (?16.1%, p?<?0.05), PPI (?26.9%, p?<?0.05), HOMA index (?30.1%, p?<?0.05), when compared to the baseline values. All these changes were reversed during the cross-over study phase, except those relating to HbA_1c, FPG and PPG. The only changes that significantly differed when directly comparing acarbose- and repaglinide-treated patients were those relating to FPI (?16.1% vs. +22.5%, respectively, p?<?0.05) and HOMA index (?30.1% vs. +2.7%, p?<?0.05).

Conclusion: In addition from having a similar effect to repaglinide on PPG, acarbose appeared to have a more comprehensive positive effect on glucose metabolism compared to repaglinide in this relatively small sample of type 2 diabetic patients when used as add-on therapy to sulphonylureas and metformin.