A sport cream (Harpago-Boswellia-ginger-escin) for localized neck/shoulder pain.

BACKGROUND: Neck/shoulder, sudden pain, or muscular pain (not associated to structural or bone/joints components), due to fascial or muscular strain is common in active subjects, in non-professional athletes and sports performers. The aim of this supplement registry was the evaluation of a cream based on natural, active ingredients for topical application in supporting the improvement of pain and improving head/neck mobility, possibly minimizing the use of systemic drugs. METHODS: The cream includes standardized active ingredients of natural origin as an extract of Harpagophytum procumbes, an extract from Boswellia serrata, a CO2 extract of ginger and escin. Subjects were divided into three groups, all using the standard management (SM) in combination with the Sport Cream or in addition to Flector (diclofenac) patch. RESULTS: The groups were comparable and homogeneous at the baseline. No side effects or skin tolerability issues were observed with the Sport Cream nor with the SM or diclofenac patches. Subjects receiving sport cream + SM reported a significant improvement in pain, stiffness, altered mobility and altered working capacity, with a reduced need for rescue medication (diclofenac) compared to subjects in the other two groups. CONCLUSIONS: Finally, subjects receiving sport cream + SM reported a more remarkable decrease in skin temperature in the affected area associated to an improvement in clinical symptoms.

Phytochemical, ethanomedicinal and pharmacological applications of escin from Aesculus hippocastanum L. towards future medicine.

Medicinal plants are used from ancient times for treatment of various ailments. Aesculus hippocastanum (Horse chestnut), is the popular and most valuable tree native to the South East Europe. It's seed extracts and their concentrates contain phytocompounds like flavonoids, polyphenols, triterpenoid saponin glycosides (escin), epicatechin, tannins, kaempferol, esculin, fraxin, carbohydrate, essential fatty acids (linoleic acid), oleic acid and purine bases (adenine and guanine). Due to these vital phyto-constituents, horse chestnut is used in phytomedicine for the prevention and treatment of diverse disorders as in venous congestion in leg ulcers, bruises, arthritis, rheumatism, diarrhoea, phlebitis etc. We collected the pharmacological applications of Aesculus hippocastanum L. extracts and escin as the cheif bioactive compound and their uses in traditionally and clinically for the management of various disorders. This review describes the efficacy of A. hippocastanum L. extracts and their bioactive compounds. So in the furtue this plant may be useful for the alternative treatment measure for various ailments via incorporating either extract or escin into novel delivery systems for improving the social health in future and would provide improved quality of life.

Aescin and diosmin each alone or in low dose- combination ameliorate liver damage induced by carbon tetrachloride in rats.

OBJECTIVE: This study evaluated hepatoprotective effect of aescin (AES) and diosmin (DIO), individually or in low-dose combination in chemically induced liver injury in rats. Rats were divided into 6 groups; Group 1, control, Group 2, injected with a single dose of a mixture of corn oil and carbon tetrachloride (CCl4) to induce hepatic toxicity. Before CCl4 injection, Groups 3-6 were treated daily for 14 days with silymarin (SIL) (200 mg/kg), aescin (AES; 3.6 & 1.75 mg/kg), Diosmin (DIO; 100 & 50 mg/kg). Serum samples were analyzed for different liver function, oxidative stress and antioxidant markers. Moreover, inflammation and tissue damage were confirmed by histological staining of liver tissue sections. RESULTS: Results indicated that CCl4 elevated serum levels of all assessed liver function markers and decreased levels of key antioxidants. Administration of AES and/or DIO significantly reversed all those CCl4-induced effects. Histopathological study showed disruption of the hepatic architecture, necrosis and inflammatory cells and depositions of glycogen and protein in the tissues of CCl4-treated group. Pretreatment with DIO and/or AES significantly improved histopathological structure of liver tissue. In conclusion, low-dose combination of AES and DIO exhibited significant and preferential hepatoprotective activity compared to individual treatment with AES or DIO.

Severe Acute Lung Injury Related to COVID-19 Infection: A Review and the Possible Role for Escin.

Acute lung injury (ALI) represents the most severe form of the viral infection sustained by coronavirus disease 2019 (COVID-19). Today, it is a pandemic infection, and even if several compounds are used as curative or supportive treatment, there is not a definitive treatment. In particular, antiviral treatment used for the treatment of several viral infections (eg, hepatitis C, HIV, Ebola, severe acute respiratory syndrome-coronavirus) are today used with a mild or moderate effect on the lung injury. In fact, ALI seems to be related to the inflammatory burst and release of proinflammatory mediators that induce intra-alveolar fibrin accumulation that reduces the gas exchange. Therefore, an add-on therapy with drugs able to reduce inflammation, edema, and cell activation has been proposed as well as a treatment with interferon, corticosteroids or monoclonal antibodies (eg, tocilizumab). In this article reviewing literature data related to the use of escin, an agent having potent anti-inflammatory and anti-viral effects in lung injury, we suggest that it could represent a therapeutic opportunity as add-on therapy in ALI related to COVID-19 infection.

Anti-inflammatory effect of external use of escin on cutaneous inflammation: possible involvement of glucocorticoids receptor.

Escin, as an internally applied anti-inflammatory agent, has been widely used in the treatment of inflammation and edema resulting from trauma or operation in the clinic. However, the effect of its external use on cutaneous inflammation and edema remains unexplored. In the present study, the anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats, paraxylene-induced ear swelling in mice, and cotton pellet-induced granuloma in rats. Effects of external use of escin gel on prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) were determined by ELISA. The anti-inflammatory mechanism was explored by detecting the expression of glucocorticoid receptor (GR) with Western blotting and Real-time PCR analyses, with further exploration of nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (P38MAPK) and activator protein-1 (AP-1) expressions. We demonstrated that external use of escin showed significant anti-inflammatory effects on acute and chronic inflammation in different animal models and its anti-inflammatory effects might be related to down-regulation of PGE2, TNF-α, and IL-1ß. The results also showed that escin exerted its anti-inflammatory effects by promoting the expression of GR, with the possible mechanism being inhibition of the expressions of GR-related signaling molecules such as NF-κB and AP-1.

A comparative study of the effectiveness of early and delayed loading of short tissue-level dental implants with hydrophilic surfaces placed in the posterior section of the mandible-A preliminary study.

The objective of the present study was to compare the primary and secondary stability of tissue-level short dental titanium implants with polished necks and hydrophilic surfaces of two different designs and manufacturers. The first implant system used (SPI®ELEMENT RC INICELL titanium implants, Thommen Medical AG, Grenchen, Switzerland), allowed functional loading 6 weeks after its placement, whereas the second implant system (RN SLActiv® tissue-level titanium implants, Straumann GmbH, Fribourg, Germany), was loaded after 15 weeks. The degree of primary and secondary stability was determined using an Osstell ISQ measuring device. Marginal bone loss (MBL) was evaluated radiographically 12 and 24 weeks after implantation and the Wachtel's healing index as well as the patient's satisfaction with the treatment was registered on a VAS scale. The intergroup comparison revealed significant differences in terms of primary stability as well as differences in MBL 3 months after the procedure, but no significant differences could be found after 6 months and for secondary stability. The primary stability was significantly higher for Thommen® compared to Straumann® implants. Insertion of short dental implants with a hydrophilic conditioned surface significantly shortens patient treatment time.

The positive clinical therapeutically effects of Escin on advanced thyroid cancer.

The incidences of thyroid cancer keep rising worldwide over the past few decades. Although most thyroid cancers are indolent and highly curable, the treatment for advanced thyroid cancer remains challengeable in clinical practice. We performed two separate cohorts to evaluate the safety and efficiency of Escin in patients with advanced thyroid cancer . In cohort 1, 120 patients were divided into four groups equally and were administrated with placebo or different dosages of Escin. The pharmacokinetics of Escin and the side effects were evaluated. In cohort 2, 120 patients were treated with Escin. Several biomarkers related to the progression of thyroid cancer were evaluated. Kaplan-Meier (KM) analyses were performed to evaluate progression-free survival (PFS) and overall survival (OS). The serum Escin concentrations were stable during the treatment. Escin (0.6 mg/kg/day for 9 days, intravenous injection) was tolerable for patients with thyroid cancer . Escin significantly reduced the serum levels of TSH, TgAb, Tg, and calcitonin and prolonged the PFS and OS for patients with advanced thyroid cancer. This study showed Escin is efficient and well tolerated in patients with advanced thyroid cancer. Future studies are needed to investigate the mechanism of Escin on thyroid cancer and the proper dosage of Escin clinically.

Successful treatment of pachydermoperiostosis patients with etoricoxib, aescin, and arthroscopic synovectomy: Two case reports.

RATIONALE: Pachydermoperiostosis (PDP) is a rare hereditary disorder that affects the skin and bones. PDP is characterized by periostosis, digital clubbing, and pachydermia. Previous studies demonstrated that increased prostaglandin E2 (PGE2) levels resulting from defective protein degradation pathways play a crucial role in PDP pathogenesis, and males were more commonly and severely affected than females. Moreover, nearly all PDP patients suffer from refractory arthralgia. Although several different treatment modalities are used for PDP, therapy for this disease remains challenging. PATIENTS CONCERNS: Two cases of PDP showing symptoms consistent with polyarthritis and arthralgia that mainly affected the knees and ankles. DIAGNOSES: The diagnostic criteria for PDP include digital clubbing, periostosis, and pachydermia. The 2 patients were diagnosed as PDP based on the finger clubbing, facial cutis furrowing, knee and ankle arthritis, and radiographic evidence of periosteal proliferation. INTERVENTIONS: Patient 1 had massive joint effusion that was treated by oral administration of etoricoxib and aescin combined with arthroscopic synovectomy, whereas Patient 2 had mild joint swelling and accepted only oral medication. OUTCOMES: Clinical symptoms of the 2 patients greatly improved after the treatment. During the 1-year follow-up, the patient experienced no adverse effects or recurrence. LESSONS: The therapeutic results showed that oral etoricoxib could reduce inflammation and retard progression of pachydermia, or even relieve facial skin furrowing, but had limited efficacy for arthralgia. However, oral aescin had satisfactory efficacy for arthralgia. Thus, etoricoxib combined with aescin is a safe and effective treatment for PDP. Meanwhile, arthroscopic synovectomy can be used to treat joint effusion, but had no therapeutic effect on arthralgia. Therefore, postoperative oral medications would be needed as subsequent therapy for joint problems. In conclusion, this study proposes an effective and safe treatment plan to address symptoms experienced by PDP patients.

Combined treatment with low dose prednisone and escin improves the anti-arthritic effect in experimental arthritis.

The present study was aimed at investigating whether low dose oral prednisone combined with escin could inhibit the progression of adjuvant-induced arthritis (AIA) in rats. Adjuvant arthritis was induced in SD rats began day 1 for 28 days. Prednisone at doses of 2, 10 mg/kg/day alone or escin at doses of 5, 10 mg/kg/day alone, or prednisone at dose of 2 mg/kg/day with escin at doses of 5 or 10 mg/kg/day were given to different groups of rats intragastrically from day 13 to 28 respectively. Paw swelling, arthritic index, histological and radiographic changes were assessed to evaluate the anti-arthritic effect. Weight growth, spleen and thymus indexes were also calculated. Serum samples were collected for estimation of pro-inflammatory cytokines. Rats developed erosive arthritis of the hind paw when immunized with adjuvant. Prednisone 2 mg/kg combined with escin 5 or 10 mg/kg significantly inhibited the paw swelling. Histopathological and radiographic analysis showed a marked decrease of synovial inflammatory infiltration, synovial hyperplasia and bone erosion by combination therapy, which also markedly suppressed the expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). No significant changes were found in monotherapy group except prednisone 10 mg/kg group. Furthermore, combined treatment rescued some of GCs' adverse effects evidenced by increase in body weight and decrease in index of spleen compared with untreated AIA rats. In conclusion, the combination therapy possessed synergistic anti-arthritic efficacy and reduced adverse effect, which may play a role in the management of human RA.

Treatment for superficial infusion thrombophlebitis of the upper extremity.

BACKGROUND: Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice. OBJECTIVES: To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity. SEARCH METHODS: The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015. SELECTION CRITERIA: RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment). DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome. MAIN RESULTS: We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. AUTHORS' CONCLUSIONS: The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.

Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress.

Here we explored the anti-oxidative and cytoprotective potentials of escin, a natural triterpene-saponin, against hydrogen peroxide (H2O2) in retinal pigment epithelium (RPE) cells. We showed that escin remarkably attenuated H2O2-induced death and apoptosis of established (ARPE-19) and primary murine RPE cells. Meanwhile, ROS production and lipid peroxidation by H2O2 were remarkably inhibited by escin. Escin treatment in RPE cells resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by transcription of anti-oxidant-responsive element (ARE)-regulated genes, including HO-1, NQO-1 and SRXN-1. Knockdown of Nrf2 through targeted shRNAs/siRNAs alleviated escin-mediated ARE gene transcription, and almost abolished escin-mediated anti-oxidant activity and RPE cytoprotection against H2O2. Reversely, escin was more potent against H2O2 damages in Nrf2-over-expressed ARPE-19 cells. Further studies showed that escin-induced Nrf2 activation in RPE cells required AKT signaling. AKT inhibitors (LY294002 and perifosine) blocked escin-induced AKT activation, and dramatically inhibited Nrf2 phosphorylation, its cytosol accumulation and nuclear translocation in RPE cells. Escin-induced RPE cytoprotection against H2O2 was also alleviated by the AKT inhibitors. Together, these results demonstrate that escin protects RPE cells from oxidative stress possibly through activating AKT-Nrf2 signaling.

Protective effects of escin against indomethacin-induced gastric ulcer in mice.

Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, is reported to have a potent antiulcer activity against ethanol-induced gastric mucosal lesions. This study investigated the possible mechanisms underlying the gastroprotective effect of escin against indomethacin-induced gastric ulcer in mice. Gastric ulceration was induced by a single intragastric administration of indomethacin (18 mg/kg). The mice underwent intragastric treatment with escin at doses of 0.45, 0.9 or 1.8 mg/kg. Gastric lesion was estimated morphometrically and histopathologically 6 h after the indomethacin administration. The antioxidative parameters in gastric mucosa were measured. Moreover, the activity of myeloperoxidase and the contents of TNF-α, P-selectin and VCAM-1 in gastric tissues were determined. The results showed that escin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from a reduction in the ulcer index and an attenuation of histopathologic changes. Escin caused significant reductions of the contents of malondialdehyde, TNF-α, P-selectin, VCAM-1 and myeloperoxidase activity. The altered activities of superoxide dismutase, catalase and glutathione peroxidase in the stomach tissues were also ameliorated by escin treatment. The present study demonstrated that escin had a protective effect against indomethacin-induced gastric ulcer in mice, not only by virtue of its antioxidant potential, but also due to its anti-inflammatory effect.

Corticosteroid transdermal delivery to target swelling, edema and inflammation following facial rejuvenation procedures.

BACKGROUND AND AIM: The use of transdermal therapeutic systems has spread worldwide since they allow effective local drug delivery. In the present study, we investigated the efficacy and safety of a new betamethasone valerate medicated plaster (Betesil®) to manage facial swelling, edema, inflammation, ecchymosis, and hematoma, when applied immediately after a facial rejuvenation procedure. MATERIALS AND METHODS: We applied the plaster to the skin of 20 healthy patients for 12 hours immediately after hyaluronic acid-based procedure performed with the aim of erasing facial wrinkles of perioral and nasolabial folds and improving chin and eye contour. A further 20 patients underwent the same cosmetic procedure, but they were treated with an aescin 10% cream (applied immediately after the procedure, in the evening, and the morning after) and served as control group. RESULTS: Betesil® application resulted in a significant improvement in swelling/edema/inflammation score, if compared with aescin 10% cream (P < 0.01). As for facial ecchymosis and hematoma around the needle injection track, only two patients in the active treatment group displayed minimal ecchymosis and hematoma. In the control group, two patients presented minimal ecchymosis and three slight hematoma. However, using the ecchymosis/hematoma score, no significant difference between Betesil® and aescin 10% cream groups was observed. Patients' satisfaction was significantly higher among subjects receiving Betesil®, if compared to patients receiving aescin 10% cream (P < 0.01). CONCLUSION: The present study supports the use of Betesil® plaster immediately after facial cosmetic procedures in order to safely control swelling, edema, and inflammation.

[Impact of combined therapy using glucosamine sulfate and anti-inflammatory agent on pain severity in patients with osteoarthritis: prospective, non-controlled postmarketing study].

UNLABELLED: Pain is one of the major symptoms of the osteoarthritis (OA). The objective of the study was to evaluate impact of combined therapy with diclofenac, aescin and original glucosamine sulfate on pain severity in patients with OA of different localizations in real life clinical settings in Russia and Ukraine. METHODS: Design--prospective, non-controlled, before and after post-marketing study. Study was performed in 38 cities across Russia and Ukraine in 2012. Registered anti-inflammatory and symptomatic slow acting drugs were used according to the registered indications and dosages. In Russian sites combined therapy A using diclofenac ("Dorosan" formulation, Rottapharm S.p.A., aerosole 1%, 3-4 times/day) for two weeks, original glucosamine sulfate ("Dona" formulation, Rottapharm S.p.A.) intramuscular (ampule 200 mg/ml, 2 ml 3 times/week) for 4 weeks and per os (powder 1500 mg, once/day) for 8 weeks was used. In Ukraine sites (scheme B) diclofenac was substituted with topical aescin ("Reparil-Gel" formulation, Madaus AG, tube 400 mg, 2-3 times/day) anti-inflammatory product. Physicians were free to change therapy and study organizers had no impact on prescribing and management practice. Patients with OA of different localizations were included into the study. Pain severity was assessed using numeric rating scale. Total duration of the study was 8 weeks. Questionnaires were distributed to patients via physician out-patient offices. The only endpoint was the difference in median pain severity at the end of the study compared with the baseline level. RESULTS: In total 4931 patients were included into the study (mean age 57 +/- 12 years, 75% were females). Scheme A was used in 3956 patients and scheme B in 975 patients. The median pain severity decreased from 0.7 at the baseline (interquartile range +/- 0.2) to 0.2 (interquartile range +/- 0.2) after 8 weeks of the study in both treatment regimens (p < 0.001). Limitations of the study include absence of the control group, collection of the questionnaires from physician offices, rather than directly from patients, limited range of clinical data collected and use of single instrument to assess pain severity. CONCLUSIONS: Post-marketing study of combined therapy of OA of different localizations using diclofenac, aescin and original glucosamine sulfate in Russia and Ukraine demonstrated decrease of the pain severity, assessed by numeric rating scale, after 8 weeks of the treatment.

Bioavailability of l-thyroxine and its metabolites after topical treatment with an emulsion containing 0.1% micronised l-thyroxine.

AIM: Aim of the study was to assess systemic effects of a cycle of treatment with a topical formulation of l-T4 and escin (Somatoline®) in healthy women based on changes in bioavailability of FT4, FT3, rT3, and TSH. METHODS: This study enrolled 20 healthy adult women with body mass index <30, not exposed to iodine-containing products. The study called for 28 consecutive days of treatment with Somatoline® followed by a 14-day follow-up period. Blood samples for FT4, FT3 and TSH levels were drawn at baseline, 5 and 24 hours after the first application and thereafter on days 14, 28 and 42. Levels of rT3 were measured during the first 24 hours postapplication. RESULTS: Subject mean age was 40.1±8.0 years and BMI from 19.1 to 29.8. Levels of FT4 always remained within normal range and did not change in a clinically relevant way from baseline (11±1.2 pg/dL), with maximum mean change from pretreatment values of 0.4 pg/mL (P=0.87). Likewise, FT3 and TSH levels did not change significantly from baseline (3±0.4 pg/dL and 1.8 ±0.9 µU/mL, respectively). Levels of rT3 behaved in a similar way, with modest changes from baseline (P=0.29). Local tolerability was defined "excellent" for 19 out of 20 women (95%) and "moderate" in one subject who experienced the onset of folliculitis, for which causal correlation with the treatment was considered "possible". CONCLUSION: Used at the posology foreseen for the marketed formulation, Somatoline® does not affect plasma levels of FT4, FT3, rT3 and TSH, either in the short term or after 28 days.

Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in pancreatic cancer both in vitro and in vivo.

PURPOSE: Pancreatic cancer is an aggressive malignancy, which generally develops resistance to chemotherapy. Agents that are safe and can sensitize cancer to chemotherapy are urgently needed. Escin, a natural mixture of triterpene saponins isolated from Aesculus wilsonii Rehd, has been demonstrated to possess anti-cancer activity both in vitro and in vivo. The anti-cancer activity of escin could be, in part, due to the inactivation of nuclear factor-κB (NF-κB). In contrast, chemotherapy including gemcitabine could activate NF-κB and lead to chemoresistance. Here, for the first time, we investigated whether escin, via the inactivation of NF-κB, would potentiate the antitumor activity of gemcitabine in pancreatic cancer. METHODS: Cell viability and proliferation, apoptosis, NF-κB activity and the expression of NF-κB-linked genes were all examined in vitro. The antitumor effect of escin with or without gemcitabine in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice. RESULTS: Escin not only potentiated the proliferation-inhibiting and apoptosis-inducing effect of gemcitabine in both BxPC-3 and PANC-1 cell lines in vitro, but also dramatically enhanced its suppressive effect on tumor growth in nude mice. The mechanism is at least partially due to the inhibition of NF-κB activity and consequent inhibition of c-Myc, COX-2, Cyclin D1, Survivin, Bcl-2 and Bcl-xL, and the activation of caspase-3. CONCLUSION: These data suggest that escin, via inactivation of NF-κB, could potentiate the efficacy of gemcitabine in combating pancreatic cancer, which could be a novel and potentially important therapeutic approach for the treatment for pancreatic cancer.

Intracellular drug delivery in Leishmania-infected macrophages: Evaluation of saponin-loaded PLGA nanoparticles.

Drug delivery systems present an opportunity to potentiate the therapeutic effect of antileishmanial drugs. Colloidal carriers are rapidly cleared by the phagocytic cells of the reticuloendothelial system (RES), rendering them ideal vehicles for passive targeting of antileishmanials. This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin ß-aescin. NPs were prepared using the combined emulsification solvent evaporation/salting-out technique. Confocal microscopy was used to visualise the internalisation and intracellular trafficking of fluorescein- and nile red-labelled PLGA NPs in J774A.1 macrophages infected with GFP-transfected Leishmania donovani. The in vitro activity of aescin and aescin-loaded NPs on L. infantum was determined in the axenic model as well as in the ex vivo model. The developed PLGA NPs were monodispersed with Z(ave)<300 nm, exhibited negative zeta potentials and had relatively high drug loadings ranging from 5.80 to 8.68% w/w PLGA. The fluorescent NPs were internalised by the macrophages and trafficked towards the lysosomes after 2 h in vitro incubation. Co-localisation of the NPs and the parasite was not shown. A two-fold increase in activity was observed in the ex vivo macrophage model by encapsulating ß-aescin in PLGA NPs (IC(50), 0.48-0.76 µg/mL vs. 1.55 ± 0.32 µg/mL for the free drug).

The antinociceptive effect of intrathecal escin in the rat formalin test.

This study investigated the antinociceptive effect of intrathecal escin and examined its effect on the formalin-induced activation of c-Fos and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) in the rat spinal cord. Rats were chronically implanted with lumbar intrathecal catheters, and the ability of intrathecal escin to alter nociceptive behaviours in the rat formalin test was examined. The expression of c-Fos and p-p38 MAPK in the dorsal horn of the spinal cord was detected in the control and escin (40µg) groups using immunohistochemical techniques. Intrathecal escin produced a dose-dependent reduction in formalin-evoked flinching behaviour in rats during the second phase; however, no effect was observed in the first phase. In addition, immunohistochemical experiments showed that the expression of c-Fos and p-p38 MAPK in the spinal cord dorsal horn increased after an injection of formalin into the paw. Interestingly, the 40µg dose of intrathecal escin, which was the larger of the two doses that blocked formalin-induced hyperalgaesia, attenuated the formalin-induced increases in c-Fos and p-p38 MAPK in the dorsal horn of the spinal cord. The decrease in pain-related behaviours and c-Fos expression indicated that escin produced antinociceptive effects in the rat formalin test. Although the specific mechanisms of these effects were not investigated, the reduction in p-p38 MAPK in the dorsal horn of the spinal cord may be involved.

Mixture designs in the optimisation of PLGA nanoparticles: influence of organic phase composition on ß-aescin encapsulation.

The objective of this study was to enhance the encapsulation of the antileishmanial saponin aescin in poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). We prepared the NPs by the O/W and W/O/W combined emulsification solvent evaporation/salting-out technique and investigated the influence of organic phase composition on the NPs' size, zeta potential and entrapment efficiency (EE%) using mixture designs. The obtained NPs were monodispersed with Z(ave)<300 nm and exhibited negative zeta potentials. For the single emulsion, the co-solvent concentration was shown to be the primary determinant of drug entrapment. The EE% increased from 14% to 22% by decreasing the amount of DMSO from 80% to 25% (v/v) in the organic polymer solution. For the double emulsion, EE% was 22% on average and independent of the organic phase composition. The double-emulsion technique did not enhance the aescin encapsulation as expected due to its amphiphilic nature. The optimised aescin-loaded NPs meet the requirements for further in vitro activity tests.

Aescin: microcirculatory activity. Effects of accessory components on clinical and microcirculatory efficacy.

AIM: This study was performed to test the hypothesis that the heparin and phosphatidylcholine (PDC) included in Aescin gel formulations had the main role of allowing a better penetration of Aescin without important pharmacodynamic effects. Heparin and PDC should be considered as "enhancers". They do not have - at the dosage used - a specific or independent action. An open, registry study of patients - a group with chronic venous insufficiency (CVI) and a group of patients with diabetic microangiopathy were completed. METHODS: In patients with CVI and in patients with diabetic microangiopathy, we used a commercial gel preparation containing Aescin, PDC and heparin (group A). The first group of patients used the full complex. The second group used the complex without PDC (group B) and the third (group C) used the complex without heparin. RESULTS: In both studies the different groups of patients were comparable. In CVI patients (mean age 44.5; SD 2.4; range 40-50) venous microangiopathy was present at the perimalleolar region. Aescin produced comparable microcirculatory results with and without the two other components. Transcutaneus PO2 [TcPO2] increased in all groups. Transcutaneus PCO2 (TcCO2) decreases. The increased Laser Doppler Flux (LDF) (typical of CVI) decreased towards normality. The local Plasma Free Radicals [PFR] levels decreased as the result of better skin perfusion (P<0.05). Comparable data were observed in subjects with diabetic microangiopathy (mean age 46.5; SD 3.1). In these patients the compound was applied at the dorsum of the foot. TcPO2 increased with treatment. TcPCO2, skin flux and PFR decreased towards normal levels (P<0.05). CONCLUSION: In conclusion Aescin improves the microcirculation and PFR. Heparin and PDC - included in the gel - have an ancillary role. An improved perfusion and nutrition of the skin was observed both in diabetic and venous microangiopathy. This may possibly contribute in the reduction of the incidence of ulceration associated with diabetic and venous microangiopathy. Aescin-based products may be included in a more complex management plan, including several systemic and local treatments.