Escinosome thermosensitive gel optimizes efficacy of CAI-CORM in a rat model of rheumatoid arthritis.

Rheumatoid arthritis is among the most common disabling diseases associated with chronic inflammation. The efficacy of the current therapeutic strategies is limited; therefore, new pharmacological agents and formulation approaches are urgently needed. In this work, we developed a thermosensitive gel incorporating escinosomes, innovative nanovesicles made of escin, stabilized with 10% of tween 20 and loaded with a Carbonic Anhydrase Inhibitor (CAI) bearing a Carbon Monoxide Releasing Moiety (CORM) (i.e., CAI-CORM 1), previously synthesized by some of the authors as a new potent pain-relieving agent. The light scattering analysis of the developed formulation showed optimal physical parameters, while the chromatographic analysis allowed the quantification of the encapsulation efficiency (90.1 ± 5.91 and 91.6 ± 8.46 for CAI-CORM 1 and escin, respectively). The thermosensitive gel, formulated using 23% w/v of poloxamer 407, had a sol-gel transition time of 40 s and good syringeability. Its stability in simulated synovial fluid (SSF) was morphologically evaluated by electron microscopy. Nanovesicles were physically stable in contact with the medium for two weeks, maintaining their original dimensions and spherical shape. The viscosity increased by about 30- to 100-fold with the temperature change from 25 °C to 37 °C. The gel erosion in SSF occurred within 9 h (88.2 ± 0.743%), and the drug's passive diffusion from escinosomes lasted 72 h, allowing a potential sustained therapeutic effect. The efficacy of a single intra-articular injection of the gel containing escinosomes loaded with CAI-CORM 1 (3 mg/mL; 30 µL, CAI-CORM 1 formulation) and the gel containing unloaded escinosomes (30 µL, blank formulation) was evaluated in a rat model of Complete Freund's Adjuvant (CFA)-induced rheumatoid arthritis. CAI-CORM 1 formulation was assessed to counteract mechanical hyperalgesia, spontaneous pain, and motor impairments on days 7 and 14 after treatment. The histological evaluation of the joints stressed the improvement of several morphological parameters in CFA + CAI-CORM 1 formulation-treated rats. In conclusion, the hybrid molecule CAI-CORM 1 formulated in escinosome-based thermosensitive gel could represent a new valid approach for managing rheumatoid arthritis.

Topical hydrogels with escin ß-sitosterol phytosome and escin: Formulation development and in vivo assessment of antihyperalgesic activity.

The physicochemical properties, stability, in vivo antihyperalgesic activity, and skin irritation potential of the carbomer hydrogels with the new chemical entity escin ß-sitosterol (ES) phytosome were characterized and compared with those containing escin. Physicochemical characterization of the hydrogels (performed 48 hr after preparation) included organoleptic examination, pH measurement, light microscopy, differential scanning calorimetry analysis and rheological tests. The obtained results showed that increasing concentration of the active substances within 1-5% affected the appearance (color and transparency) of the hydrogels, their pH, consistency, and rheological behavior. Unlike acidic escin, which was dissolved in the liquid phase of the pseudoplastic hydrogels E1-E5 and reduced their maximal apparent viscosity (ηmax ), minimal apparent viscosity (ηmin ), and hysteresis area (H) in comparison to the plain carbomer hydrogel, amphiphilic ES-enhanced ηmax , ηmin , and thixotropy of the hydrogels ES1-ES5, which is favorable for prolonged retention at skin surface. Evaluation of in-use stability of the hydrogels showed that organoleptic characteristics, flow behavior, and pH values could be preserved for 3 months under ambient conditions. The rat ear test results suggested that the hydrogels are safe to be used on human skin. Both escin and ES-loaded hydrogels exerted significant, concentration-dependent antihyperalgesic effect in inflammatory pain model in rats. ES-loaded hydrogels were significantly more effective than those loaded with escin. This is a first report on the antihyperalgesic effect of topically applied escin as well as ES in a model of inflammatory pain.

A two-center, assessor-blinded, prospective trial evaluating the efficacy of a novel hypertonic draining cream for cellulite reduction: A Clinical and instrumental (Antera 3D CS) assessment.

INTRODUCTION: Gynoid lipodystrophy, also known as cellulite, is a very common skin alteration representing mainly a cosmetic problem rather than a real disease. An effective treatment of cellulite has not been well established. The initial phase of cellulite is characterized by subdermal tissue edema with interstitial fluids retention. A new hypertonic topical product with draining action (HTC) containing NaCl 13%, escine, caffeine, and beta-sitosterol has been recently developed. A 28-day double-blind placebo-controlled study has shown that this cream is able to reduce thigh circumference and the thickness of adipose tissue. No data so far are available regarding an objective evaluation of skin appearance for a longer application period. STUDY AIM: To evaluate the clinical efficacy of 2-month HCT treatment with clinical and instrumental assessments. SUBJECTS AND METHODS: In a prospective, 2-center, assessor-blinded trial 20 women (mean age 34 years) with cellulite of Grade I-III in severity were enrolled after their informed consent. HTC was applied once daily for 60 days. Primary outcomes of the trial were the evolution of thigh circumference measurements (assessed at baseline, after 1 and 2 months) and the computer-analysis of skin profilometry (ie, skin volumes) of a prespecified target area evaluated by means of Antera 3D CS digitalized images (assessed at baseline and at the end of the trial). Secondary outcome was the orange peel severity score (from 0 to 5) before and after pitch test. RESULTS: All subjects concluded the study period. Thigh circumference was reduced by -0.88 (right)/-1.2 cm (left) and by -1.8(right)/-2.1 (left) cm, after 30 and 60 days of treatment, respectively (P = .001, Wilcoxon test vs baseline). Antera 3D profilometry of the target zone showed a significant reduction in skin depression expressed in mm3 of -56% (from 59.7 to 26.73 mm3 ) after HTC application. Orange peel (no pitch test) mean (SD) score was 2.3 (1) at baseline, 2.0 (1) and 1.8 (0.8) after 1 and 2 months (P = .0031), respectively. After-pitch orange peel score was significantly reduced after treatment (from 3.3 to 2.2). CONCLUSION: Once daily application of HTC for 2 months has confirmed its efficacy in the improvement of objective and subjective assessments of cellulite parameters.(Trial Number registration: ISRCTN15111614).

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.

Effects of escin on indinavir crystallization time in the urine of patients with HIV-I infection: a multicenter, randomized, open-label, controlled, four-period crossover trial.

BACKGROUND: The combination of indinavir, a protease inhibitor, and reverse-transcriptase inhibitors is widely used in the treatment of HIV-1 infection. However, precipitation of indinavir crystals in the renal tubular lumen due to the drug's aqueous insolubility may result in characteristic symptoms of flank pain or classic renal colic. An in vitro study has shown that addition of escin to synthetic urine containing indinavir delayed the crystallization time of indinavir. OBJECTIVE: This study examined the efficacy and tolerability of the addition of escin to highly active antiretroviral therapy containing indinavir to delay the crystallization time of indinavir in urine. METHODS: This was a multicenter, randomized, open-label, controlled, 4-period crossover trial in which each period lasted 4 weeks. HIV-1-infected adults receiving treatment with indinavir plus 2 nucleoside analogue reverse-transcriptase inhibitors in whom plasma viral loads had been undetectable (HIV-1 RNA <200 copies/mL) for at least 6 months were randomly assigned to 1 of 2 groups based on the timing of the initiation of escin. Group I received escin during the second and third treatment periods, and group II received escin during the first and fourth treatment periods. The primary end point was the in vitro crystallization time of indinavir in 24-hour urine specimens, determined at the end of each 4-week period. Tolerability was assessed based on the number of patients with a rebound in plasma viral load and on the numbers of clinically and biologically relevant adverse events (including those requiring discontinuation of treatment). Clinical and laboratory evaluations were performed throughout each 4-week period. RESULTS: Fifty HIV-1-infected patients were enrolled, 47 were randomized to treatment (40 [85.1%] men, 7 [14.9%] women; median [interquartile range] age, 36 [34-45] years), and 30 completed the study. Urine pH and plasma and urine indinavir concentrations were unaffected by the addition of escin to antiretroviral treatment. The mean time to the onset of crystallization was 14.7 minutes with escin (95% Cl, 11.8-17.5) and 9.9 minutes without it (95% Cl, 6.7-13.1). Therefore, the addition of escin increased the mean crystallization time by 5.5 minutes (95% Cl, 1.5-9.5; P = 0.008), representing the overall capacity of study treatment to inhibit indinavir crystallization in the urine. Three of 47 patients had mild gastrointestinal symptoms associated with escin treatment. No episodes of nephrolithiasis were recorded during the study or after the completion of study treatment. CONCLUSION: The results of this prospective clinical trial of the effect of escin on indinavir crystallization time support the possibility that indinavir-associated nephrolithiasis may be prevented by means other than overhydration. Further research is needed in greater numbers of patients over longer follow-up times.

Rational therapy of chronic venous insufficiency--chances and limits of the therapeutic use of horse-chestnut seeds extract.

BACKGROUND AND METHODS: We report two clinical studies, one already published, performed in patients with early and advanced chronic venous insufficiency (CVI). In both, compression therapy and oral therapy with horse-chestnut seeds extracts (HCSE) were compared to placebo. RESULTS: The published study in early CVI (Grade I) showed HCSE and compression to be superior to placebo and to be equivalent to each other in reducing lower leg volume, a measure for oedema. In the study, in advanced CVI (Grade II and IIIa), compression appeared to be superior to placebo, whereas HCSE was not. HCSE fared better in Grade II than in Grade IIIa patients. These results are discussed in the light of data from an in vitro model, where HCSE has been able to close the intercellular gaps in the venular endothelium. Not fully specified factors lead to an opening of these gaps, resulting in oedema as well as in local coagulation and thrombosis. The subsequent inflammation keeps these gaps open and initiates and maintains a chronic disease process, which may be the starting point of CVI. CONCLUSION: Due to its ability to close the venular endothelial gaps, HCSE seems to be a suitable and protecting therapy during the early stages of CVI. In later more severe stages compression therapy is indicated. Taking into account the observed negative impact of compression on quality of life, pharmacological CVI therapy should start early to avoid progress and to spare patients compression therapy.

Three treatments for chronic venous insufficiency: escin, hydroxyethylrutoside, and Daflon.

Escin, hydroxyethylrutoside (HR), and Daflon have been shown to be safe and effective for the treatment of chronic venous insufficiency (CVI). They seem to work differently than compression therapy, suggesting that they would usefully augment this therapy. All three phlebotonics attenuate the drop in adenosine triphosphate in venous endothelial cells during hypoxia. This attenuates (1) the inflammation response, (2) the attraction of neutrophils, (3) damage to the veins, and (4) the release of growth factors. These factors otherwise would perpetuate venous insufficiency and contribute to varicose veins. Additional independent effects that would be useful for the treatment of CVI are that they reduce permeability and fragility; HR, Daflon, and perhaps escin increase venous tone; escin inhibits hyaluronidase; Daflon and probably HR are attracted to the veins. With regard to similarity, no differences in effect have been established among these phlebotonics.

Efeito de antiinflamatórios enzimáticos (bromélina, escina e papaína) no desenvolvimento de crânios e fêmures de ratas / The effect of enzymatic anti-inflammatory drugs (bromelain, aescin, and papain) on the development of skull and femur of rats

Neste trabalho estudou-se p efeito de antiinflamatórios enzimáticos de origem vegetal (bromelina, escina e papaína) no desenvolvimento de crânios e fêmures de ratas. Os antiinflamatórios foram injetados intraperitonealmente, em doses terapêuticas, em ratas prenhas e em filhotes (desde o desmame até atingirem a maturidade óssea - subgrupos IIB, IIIB e IVB). As três drogas antiinflamatórias de origem vegetal - bromelina, escina e papaína - causaram reduçäo do crescimento de crânios e fêmures de ratas

[Therapeutic regional anesthesia following an accidental intra-arterial injection. A case report on anesthesiologic care following incorrect injection of Reparil (sodium escinate)]. / Therapeutische Regionalanaesthesie nach irrtümlicher intraarterieller Injektion. Ein Fallbericht zur anaesthesiologischen Betreuung nach Fehlinjektion von Reparil (Natriumaescinat).

Symptomatology and therapeutic measures after accidental brachial intra-arterial injection of sodium escinate were explained by means of a case report. We obtained long-acting analgesia and sympathicolysis in the upper extremity by an anaesthesia of the ganglion stellatum followed by repeated interscalene plexus brachialis blockade. Even in very severe cases of accidental intra-arterial drug injection surgical procedures should be accompanied with therapeutic regional anaesthesia technics.

[Acute posttraumatic renal failure following therapy with antibiotics and beta-aescin (author's transl)]. / Akutes posttraumatisches Nierenversagen nach Antibiotika- und beta-Aescintherapie.

A case of acute renal insufficiency after therapy with gentamycin and beta-Aescin is reported. The role of these two agents in the causation of the acute renal failure is discussed. Renal function was restored using the REDY-Hemodialization System.

[Renal function under parenteral application of aescinat (author's transl)]. / Nierefunktion unter parenteraler Aescin-Behandlung

18 persons with unimpaired renal function were examined, if the parenteral application of aescinat was followed by disturbances of renal function. 10 of these persons got for 3 days 10 mg of sodium-aescinat per day administered intravenously. The other test persons got for 6 days 20 mg of aescinat administered. There was no alteration in any of these cases either of serum electrolytes, blood sugar, creatinine, urea, urine analysis, creatinine clearance or hippuran clearance. We come to the conclusion that there has to be a strict indication for the application of aescinat in patients with threatening or apparent renal failure and a cautious dosage on the other hand. Patients with unimpaired renal function can be treated in normal dosage without great danger of renal or other side effects with aescinat for avoiding oedema while passing renal calculi or after plastic surgery.

[Drug induced acute renal failure after heart surgery (author's transl)]. / Medikamentös bedingtes post-operatives Nierenversagen nach herzchirurgischen Eingriffen

The incidence of acute renal failure following cardiac surgery was markedly increased during the last years in our medical center. There was no correlation to known etiologic factors such as preexisting disease, hemolysis, low perfusion rates, post-operative low output syndrome etc. Post-operative renal failure was mainly seen in children between 2 and 10 years and was noted after 3-4 days of normal renal function. Peritoneal dialysis was carried out in 39% of out patients and the overall mortality was 10.7%. Careful analysis of our cases exhibited a correlation of the post operative acute renal failure to the intravenous application of Aescin. After abandoning this drug from our post-operative therapy we did not observe a similar case since almost one year.