I have decided to add the horse chestnut to the ginkgo as I'm too excited to stop!!!!
Of course this is not at all scientific but I am impatient to sort the vascular problems out and I think the combination is going to be spectacular. Fingers crossed.
Here's more horse chestnut research on angiogenesis and permeability etc:
1: Vascul Pharmacol. 2008 Jul 30. [Epub ahead of print] Links
Effect of beta-escin sodium on endothelial cells proliferation, migration and apoptosis.Wang XH, Xu B, Liu JT, Cui JR.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University 100083, Beijing China.
beta-Escin, the major active compound in extracts of the horse chestnut Aesculus hippocastanum seed, has shown clinically significant activity in chronic venous insufficiency (CVI). Our previous studies had shown that beta-escin sodium inhibited angiogenesis in chick chorioallantoic membrane (CAM) and in aortic disk assay. In this study, we explored the direct effect of beta-escin sodium on proliferation, migration and apoptosis in human umbilical vein endothelial cells (HUVECs) and ECV304 cells. Sulforhodamine B (SRB) assay showed that beta-escin sodium (10, 20, 40 mug/ml) inhibited endothelial cells (ECs) proliferation dose-dependently. beta-escin sodium also induced ECs apoptosis at 40 mug/ml. Cell migration was evaluated by an improved wound assay: barren spot assay. And the direct effect on cell motility excluding influence of cell proliferation was examined by High Content Screening (HCS, Cellomics) assay. The data indicated that beta-escin sodium suppressed ECs migration and cell motility. Western blot results suggested that beta-escin sodium acts on ECs possibly by increasing expression of thrombospondin-1 (TSP-1), and decreasing expression of PKC-alpha and activation of p44/42 mitogen-activated protein kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK). Our findings give the evidence that beta-escin sodium might have potential anti-angiogenic activity via its direct effects on ECs.
PMID: 18718875 [PubMed - as supplied by publisher]
aescin seems to have contradictory effects:
1: Vascul Pharmacol. 2007 Jul;47(1):68-73. Epub 2007 Apr 21. Links
Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta.Carrasco OF, Vidrio H.
Department of Pharmacology School of Medicine, Universidad Nacional Autónoma de México, Apartado Postal 70297, 04510 Mexico, D.F. Mexico.
The triterpene saponin escin is the active component of the extract of seeds of Aesculus hippocastanum used in the treatment of chronic venous insufficiency. Escin is also used experimentally to increase membrane permeability in isolated cells. Since endothelial dysfunction is postulated to be involved in venous insufficiency, the possible endothelium-protectant effect of escin was explored in rat aortic rings, a model widely used to study such effects with cardiovascular agents. Escin enhanced endothelium-dependent relaxation induced by acetylcholine when such relaxation had been reduced by exposure to the superoxide ion generator pyrogallol. This effect was attributed to enhanced nitric oxide production by endothelial nitric oxide synthase, a calcium-dependent enzyme, activated by the increased endothelial cell permeability to calcium induced by escin. Another effect of escin thought to contribute to its therapeutic activity is its ability to produce venous contraction. The compound was found to induce concentration-related contraction also in rat aortic rings. This response was partially inhibited by removal of the endothelium or by preincubation with indomethacin, and was completely abolished by incubation in a calcium-free perfusion fluid. Contraction was considered to be due mainly to the aforementioned effect on calcium permeability, with some mediation by release of endothelial vasoconstrictor prostanoids. It was concluded that, in rat aorta, escin possesses an endothelium-protectant action and a direct contractile effect. The former could contribute to its beneficial effect in the treatment of venous insufficiency, while the latter could constitute a limiting side effect.
PMID: 17512261 [PubMed - indexed for MEDLINE]
here horsechesnut inhibits the reduction in VCAM and PECAM of an insult to the vasculature. Not sure that is good. Think we want to reduce both VCAM and PECAM.
1: Planta Med. 2007 Mar;73(3):285-8. Epub 2007 Feb 19.Links
Aescin protection of human vascular endothelial cells exposed to cobalt chloride mimicked hypoxia and inflammatory stimuli.Montopoli M, Froldi G, Comelli MC, Prosdocimi M, Caparrotta L.
Department of Pharmacology and Anaestesiology, University of Padova, Padova, Italy.
Human vascular endothelial cells (HUVECs) were exposed to CoCl2 as an in vitro model of hypoxia. Expression of VCAM-1 (vascular cell adhesion molecule), reduction of PECAM-1 (platelet endothelial cell adhesion molecule) and cytoskeletal changes without alterations in cell viability were observed. HUVECs were also exposed to Escherichia coli lipopolysaccaride (LPS) as an in vitro model of inflammation: significant IL-6 release was measured. Pre-treatment of HUVECs with aescin prevented, in a concentration-dependent fashion (0.1-1 microM), the action of CoCl2 on VCAM-1 and PECAM-1, also preserving endothelial cell morphology. Furthermore, aescin pre-treatment reduced IL-6 release from LPS-activated vascular endothelium.
PMID: 17310430 [PubMed - indexed for MEDLINE]
However this suggests a very positive action on the vasculature:
1: Eur J Pharmacol. 1996 Nov 14;315(2):227-33. Links
Effect of aescine on hypoxia-induced activation of human endothelial cells.Arnould T, Janssens D, Michiels C, Remacle J.
Laboratoire de Biochimie Cellulaire, Facultés Universitaires Notre dame de la Paix, Namur, Belgium.
Phlebotonic drugs are very often old drugs which improve symptoms in chronic venous insufficiency but their precise mechanism remains unclear. One reason for this lack of information is our poor understanding of the aetiology of the varicose vein. One hypothesis which is being more and more substantiated is that the origin of the disease lies in the activation of the endothelium during blood stasis, leading to a cascade of reactions which, in the long term, alter the structure of the vein wall. In this work, we tested aescine (Reparil i.v. form), a phlebotonic drug, in an in vitro model which mimics this situation, i.e. human endothelial cells exposed to hypoxic conditions. Aescine was shown to inhibit 2 important steps of the activation of endothelial cells incubated 120 min under hypoxia the decrease in ATP content, which is the starting point of the activation cascade, and the increase in the activity of phospholipase A2, an enzyme responsible for the release of precursors of inflammatory mediators. Hypoxia-activated endothelial cells also increase their adhesiveness for neutrophils. This process could also be prevented in a dose-dependent manner if endothelial cells were incubated in the presence of aescine. This inhibition was confirmed by morphological observations in scanning electron microscopy. All 3 effects were already evidenced at 100 ng/ml and were maximal at 750 ng/ml. These effects obtained at very low concentrations probably represent one of the main molecular and cellular mechanisms that underlie, among others, protection of the vessel wall. Objective criteria for our understanding of the preventive action of this phlebotonic drug are, thus, provided.
PMID: 8960888 [PubMed - indexed for MEDLINE]
here it reduces edema in the brain which is a feature of relapse:
To investigate the inhibiting effect of β-Aescin on nuclear factor-κB (NF-κB) activation and the expression of tumor necrosis factor-α (TNF-α) protein after traumatic brain injury (TBI) in the rat brain, 62 SD rats were subjected to lateral cortical impact injury caused by a free-falling object and divided randomly into four groups: (1) sham operated (Group A); (2) injured (Group B); (3) β-Aescin treatment (Group C); (4) pyrrolidine dithocarbamate (PDTC) treatment (Group D). β-Aescin was administered in Group C and PDTC treated in Group D immediately after injury. A series of brain samples were obtained directly 6 h, 24 h and 3 d respectively after trauma in four groups. NF-κB activation was examined by Electrophoretic Mobility Shift Assay (EMSA); the levels of TNF-α protein were measured by radio-immunoassay (RIA); the water content of rat brain was measured and pathomorphological observation was carried out. NF-κB activation, the levels of TNF-α protein and the water content of rat brain were significantly increased (P<0.01) following TBI in rats. Compared with Group B, NF-κB activation (P<0.01), the levels of TNF-α protein (P<0.01) and the water content of brain (P<0.05) began to decrease obviously after injury in Groups C and D. β-Aescin could dramatically inhibit NF-κB activation and the expression of TNF-α protein in the rat brain, alleviate rat brain edema, and that could partially be the molecular mechanism by which β-Aescin attenuates traumatic brain edema.
Keywords: Brain injuries, β-Aescin, Nuclear factor-κB, Tumor necrosis factor-α, Rats
Good for intestinal motility too. Interesting since starting the salvia/ginkgo I've really noticed improved gastrointestinal motility.
1: World J Surg. 2005 Dec;29(12):1614-20; discussion 1621-2. Links
Escin: inhibiting inflammation and promoting gastrointestinal transit to attenuate formation of postoperative adhesions.Fu F, Hou Y, Jiang W, Wang R, Liu K.
Department of Pharmacology, School of Pharmacy, Yantai University, Yantai, P.R., 264005, China. fufenghua@Sohu.com
Postoperative peritoneal adhesions are common, serious complications of general abdominal and gynecologic surgery that can lead to chronic abdominal pain, intestinal obstruction, and infertility. As yet, there are no ideal drugs that may be prescribed for patients to prevent adhesion formation effectively. In this study the effects of escin, a natural drug, on the various steps of adhesion formation were investigated. The effects of escin on increased vascular permeability induced by acetic acid in a mouse model of acute inflammation, granuloma formation in a subchronic inflammatory rat model, gastrointestinal transit in rats with intestinal paralysis, intestinal motility in postoperative patients, and postoperative adhesion formation in a rat model were observed. It was shown that escin could inhibit acute inflammation and granuloma formation, cause acceleration of gastrointestinal transit, help recover intestinal motility, and attenuate the formation of postoperative adhesions. The findings suggest that escin attenuates the formation of postoperative adhesions by inhibiting inflammation and promoting gastrointestinal transit.
Thus it may be concluded that both inhibition of inflammation and increased gastrointestinal motility during the early postoperative period have a positive effect on decreasing the formation of adhesions.
PMID: 16311848 [PubMed - indexed for MEDLINE]
I like the idea of using horsechestnut as this is a plant that is probably suited to the higher latitude diseases.
Here's more good stuff:
1: Acta Pharmacol Sin. 2004 Jul;25(7):869-75.Links
Effects of sodium beta-aescin on expression of adhesion molecules and migration of neutrophils after middle cerebral artery occlusion in rats.Hu XM, Zhang Y, Zeng FD.
Institute of Clinical Pharmacology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
AIM: To investigate the effects of sodium beta-aescin on neutrophil migration and expression of adhesion molecules (ICAM-1 and E-selectin) after middle cerebral artery occlusion (MCAO) in rats. METHODS: Rats were pretreated with sodium beta-aescin for 7 d and then subjected to cerebral ischemia/reperfusion (I/R) injury induced by an MCAO. After a 2-h ischemia and a 24-h reperfusion, the infarct volume and neurological deficit were determined by the method of TTC staining and the Longa's score. The effect of sodium beta-aescin on the migration of neutrophils was evaluated by measuring the activity of myeloperoxidase (MPO) enzyme. The expressions of adhesion molecules were determined by immunohistochemistry and Western blot. RESULTS: Sodium beta-aescin significantly reduced the cerebral infarct volume and ameliorated the neurological deficit (P<0.05 or P<0.01). The MPO activity and the expressions of ICAM-1 and E-selectin in the vehicle-treated rats were increased significantly (P<0.01) after cerebral I/R. After treatment with sodium beta-aescin, the enzymatic activity of MPO and the expressions of these adhesion molecules were significantly reduced compared with the vehicle-treated group (P<0.05 or P<0.01). CONCLUSION: Sodium beta-aescin can attenuate brain injury, down-regulate the protein expressions of ICAM-1 and E-selectin, and reduce the migration of neutrophils after cerebral I/R.
PMID: 15210059 [PubMed - indexed for
1: Angiology. 2004 May-Jun;55 Suppl 1:S1-5. Links
Microcirculatory efficacy of topical treatment with aescin + essential phospholipids gel in venous insufficiency and hypertension: new clinical observations.Belcaro G, Cesarone MR, Dugall M.
Irvine2 Vascular Laboratory, Department of Biomedical Sciences, G. D'Annunzio University, Italy. email@example.com
Aescin + essential phospholipids (AEPL) topical gels are used for local treatment of venous and microcirculatory alterations (varicose veins, chronic venous insufficiency). Bruises, swelling, thrombophlebitis, and contusions are effectively treated with AEPL. Active ingredients are escinate and essential phospholipids (EPL). The aim of this new study was the evaluation of the efficacy of the effects of AEPL gel on the microcirculation in subjects with chronic venous insufficiency, venous hypertension (CVH), and venous microangiopathy. Patients were assessed measuring skin flux with laser-Doppler flowmetry (LDF). After 2 weeks of local treatment, all individual values (100%) were significantly decreased (p < 0.05), indicating an improvement in the microcirculation. In all treated patients, flux decreased at least 30% (indicating a decrease in the level of venous microangiopathy) (p < 0.05). Considering these observations, topical treatment with AEPL in areas of venous microangiopathy is beneficial, can prevent ulceration, and improves the skin healing processes.
PMID: 15156249 [PubMed - indexed for MEDLINE]
but this is less reassuring:
Responsiveness of human varicose saphenous veins to vasoactive agents.
British Journal of Clinical Pharmacology. 51(3):219-224, March 2001.
Brunner, Friedrich 1; Hoffmann, Christine 2; Schuller-Petrovic, Sanja 2
Aims : To test in vitro the constrictor and relaxation responsiveness of variously diseased segments of human saphenous vein from patients with varicose vein disease.
Methods : The vein segments were derived (i) from the inguinal saphenous vein (valvularly incompetent and slightly dilated; tissue A); (ii) from the distal end of the lower leg just above the medial ankle (competent; tissue B); (iii) from a tributary to the long saphenous vein just below the knee (dilated, incompetent and overtly varicose; tissue C). The contractile responses were tested with phenylephrine (an [alpha]-adrenergic receptor agonist) and aescin, a clinically used phlebotonic drug derived from horse chestnut extract. Relaxant responses were tested with acetylcholine and sodium nitroprusside.
Results : Both contractile agents contracted vein segments from the inguinal and ankle area with similar potency and efficacy, but were virtually without effect in the overtly varicose segments from the calf. E C50 values (molar concentration of the agonist that produces 50% of the maximum effect) in tissues A and B were 2.9 +/- 0.3 and 2.5 +/- 0.5 [micro]mol l-1 (phenylephrine) and 9.4 +/- 1.0 and 15.9 +/- 2.5 [micro]mol l-1 (aescin); the corresponding maximum effects (maximum effect, percent of KCl-induced contraction) were 76 +/- 3 and 70 +/- 4% (phenylephrine) and 70 +/- 2 and 71 +/- 3% (aescin) (P = NS in both cases for A vs B). In tissue C, the maximum effects were 5 +/- 5% (phenylephrine) and 10 +/- 7% (aescin) of KCl-induced contraction (not significantly different from zero). Acetylcholine-induced relaxation was similar for vein segments from locations A and B, whereas sodium nitroprusside was more effective in tissue B than A.
Conclusions : These findings support the notion that abnormalities within the venous wall affect venous smooth muscle contractility. Since competent and incompetent clinically normal vessels show normal contractile responses, whereas varicose vessels are not responsive to vasoactive drugs, it is likely that pharmacological treatment regimens are effective in early, but not in late stages of the disease.
The abstract isn't published but this looks very promising!!
1: Arzneimittelforschung. 1970 Jun;20(6):863-4.Links
[Studies of brain edema in the rat induced by triethyl tin sulfate. 6. Protective effect of aescin against the triethyl tin sulfate conditioned increase of permeability of blood-brain barrier]
1: Biol Pharm Bull. 1997 Oct;20(10):1092-5.Links
Effects of escins Ia, Ib, IIa, and IIb from horse chestnut, the seeds of Aesculus hippocastanum L., on acute inflammation in animals.Matsuda H, Li Y, Murakami T, Ninomiya K, Yamahara J, Yoshikawa M.
Kyoto Pharmaceutical University, Japan.
We investigated the effects of escins Ia, Ib, and IIb isolated from horse chestnut, the seeds of Aesculus hippocastanum L., and desacylescins I and II obtained by alkaline hydrolysis of escins on acute inflammation in animals (p.o.). Escins Ia, Ib, IIa, and IIb (50-200 mg/kg) inhibited the increase of vascular permeability induced by both acetic acid in mice and histamine in rats. Escins Ib, IIa, and IIb (50-200 mg/kg) also inhibited that induced by serotonin in rats, but escin Ia didn't. Escins Ia, Ib, IIa, and IIb (200 mg/kg) inhibited the hind paw edema induced by carrageenin at the first phase in rats. Escin Ia (200 mg/kg) and escins Ib, IIa, and IIb (50-200 mg/kg) inhibited the scratching behavior induced by compound 48/80 in mice, but escin Ia was weakest. Desacylescins I and II (200 mg/kg) showed no effect. With regard to the relationship between their chemical structures and activities, the acyl groups in escins were essential. Escins Ib, IIa, and IIb with either the 21-angeloyl group or the 2'-O-xylopyranosyl moiety showed more potent activities than escin Ia which had both the 21-tigloyl group and the 2'-O-glucopyranosyl moiety.
PMID: 9353571 [PubMed - indexed for MEDLINE]
1: Arzneimittelforschung. 1994 Jan;44(1):25-35.Links
Veinotonic effect, vascular protection, antiinflammatory and free radical scavenging properties of horse chestnut extract.Guillaume M, Padioleau F.
Lipha Group, Department of Pharmacology, Suresnes, France.
Horse chestnut extract (HCE), containing 70% escin, is the main active component of Veinotonyl 75. The aim of this work was to investigate pharmacological properties attempting to elucidate the efficacy of HCE in chronic venous insufficiency. Veinotonic and lymphagogue properties: HCE dose dependently contracts the canine saphenous isolated vein (cumulative doses 5 x 10(-8) to 5 x 10(-4) g/ml). Its action lasts more than 5 h. In the perfused canine saphenous vein, HCE (25-50 mg in bolus) increases the venous pressure of the normal vein and the pathological vein stenosed 8 days before, and the contractile response to noradrenaline is significantly potentiated. Moreover, during the perfusion in inverse direction of the blood stream, a clear contracting effect on the valves is also obtained with HCE. In the anaesthetized dog, HCE in situ improves the femoral vein compliance and opposes the venous distension obtained during clamping in a carotido-femoral perfusion with constant flow. In other respects, HCE significantly increases femoral venous pressure and flow, together with thoracic lymphatic flow, while respecting the arterial parameters (2.5 and 5 mg/kg i.v.). Vasculotropic action: HCE dose dependently diminishes the cutaneous capillary hyperpermeability induced either by injections of phlogistic agents as histamine and serotonin in the rat (100 to 400 mg/kg p.o.), or by an irritative agent (chloroform) application in the rabbit (50 to 300 mg/kg p.o. and 2.5 to 5 mg/kg i.v.). It significantly increases the vascular resistance in the guinea pig fed a scorbutigenic diet as measured by the petechia method (50 to 400 mg/kg p.o.). Antiedema and antiinflammatory properties: HCE decreases the formation of edemas induced in the rat's hind paw, one of lymphatic origin, the other of inflammatory origin (200 to 400 mg/kg p.o.). In an experimental model of pleurisy in the rat HCE suppresses plasmatic extravasation and leucocytes emigration into the pleural cavity (200 to 400 mg/kg p.o.; 1 to 10 mg/kg i.v.). It decreases the connective tissue formation in the subchronic model of inflammatory granuloma in the rat (400 mg/kg p.o. and 5-10 mg/kg s.c.). Antiradical mechanism of action both in vitro and in vivo: HCE dose dependently inhibits both enzymatic and non-enzymatic in vitro lipid peroxidation (5 x 10(-6) to 5 x 10(-4) g/ml).(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 8135874 [PubMed - indexed for MEDLINE]
1: Dtsch Med Wochenschr. 1986 Aug 29;111(35):1321-9.Links
[Effects of horse-chestnut seed extract on transcapillary filtration in chronic venous insufficiency][Article in German]
Bisler H, Pfeifer R, Klüken N, Pauschinger P.
The effect of horse-chestnut seed extract (standardized on aescin; Venostasin retard) was assessed in a randomized placebo-controlled crossover double-blind trial of 22 patients with proven chronic venous insufficiency by measuring the capillary filtration coefficient and the intravascular volume of the lower leg by venous-occlusion plethysmography. Three hours after taking two capsules of Venostasin (600 mg; each capsule containing 50 mg aescin) the capillary filtration coefficient had decreased by 22%, whereas after administration of an identical-looking placebo capsule it rose but slightly over three hours. The difference in the effect of Venostasin and placebo is statistically significant (P = 0.006). The intravascular volume was reduced 5% more after Venostasin than the placebo, but this is not statistically significant. It is concluded that Venostasin has an inhibitory effect on oedema formation via a decrease in transcapillary filtration and thus improves oedema-related symptoms in venous diseases of the legs.
PMID: 3527643 [PubMed - indexed for MEDLINE]
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,