Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10-5-10-4M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.
The constant increase in cardiovascular disease rate coupled with significant drawbacks of existing therapies emphasise the necessity to improve therapeutic strategies. Natural flavonoids exert innumerable pharmacological effects in humans. Here, we demonstrate the effects of chrysin, a natural flavonoid found largely in honey and passionflower on the modulation of platelet function, haemostasis and thrombosis. Chrysin displayed significant inhibitory effects on isolated platelets, however, its activity was substantially reduced under physiological conditions. In order to increase the efficacy of chrysin, a sulfur derivative (thio-chrysin), and ruthenium-complexes (Ru-chrysin and Ru-thio-chrysin) were synthesised and their effects on the modulation of platelet function were evaluated. Indeed, Ru-thio-chrysin displayed a 4-fold greater inhibition of platelet function and thrombus formation in vitro than chrysin under physiologically relevant conditions such as in platelet-rich plasma and whole blood. Notably, Ru-thio-chrysin exhibited similar efficacy to chrysin in the modulation of haemostasis in mice. Increased bioavailability and cell permeability of Ru-thio-chrysin compared to chrysin were found to be the basis for its enhanced activity. Together, these results demonstrate that Ru-thio-coupled natural compounds such as chrysin may serve as promising templates for the development of novel anti-thrombotic agents.
Platelets are small circulating blood cells that play essential roles in the maintenance of haemostasis via blood clotting. However, they also play critical roles in the regulation of innate immune responses. Inflammatory receptors, specifically Toll-like receptor (TLR)-4, have been reported to modify platelet reactivity. A plethora of studies have reported controversial functions of TLR4 in the modulation of platelet function using various chemotypes and preparations of its ligand, lipopolysaccharide (LPS). The method of preparation of LPS may explain these discrepancies however this is not fully understood. Hence, to determine the impact of LPS on platelet activation, we used ultrapure preparations of LPS from Escherichia coli (LPSEC), Salmonella minnesota (LPSSM), and Rhodobacter sphaeroides (LPSRS) and examined their actions under diverse experimental conditions in human platelets. LPSEC did not affect platelet activation markers such as inside-out signalling to integrin αIIbβ3 or P-selectin exposure upon agonist-induced activation in platelet-rich plasma or whole blood whereas LPSSM and LPSRS inhibited platelet activation under specific conditions at supraphysiological concentrations. Overall, our data demonstrate that platelet activation is not largely influenced by any of the ultrapure LPS chemotypes used in this study on their own except under certain conditions.
Flavonoids exert innumerable beneficial effects on cardiovascular health including the reduction of platelet activation, and thereby, thrombosis. Hence, flavonoids are deemed to be a molecular template for the design of novel therapeutic agents for various diseases including thrombotic conditions. However, the structure-activity relationships of flavonoids with platelets is not fully understood. Therefore, this study aims to advance the current knowledge on structure-activity relationships of flavonoids through a systematic analysis of structurally-related flavones. Here, we investigated a panel of 16 synthetic flavones containing hydroxy or methoxy groups at C-7,8 positions on the A-ring, with a phenyl group or its bioisosteres as the B-ring, along with their thio analogues possessing a sulfur molecule at the 4th carbon position of the C-ring. The antiplatelet efficacies of these compounds were analysed using human isolated platelets upon activation with cross-linked collagen-related peptide by optical aggregometry. The results demonstrate that the hydroxyl groups in flavonoids are important for optimum platelet inhibitory activities. In addition, the 4-C=O and B ring phenyl groups are less critical for the antiplatelet activity of these flavonoids. This structure-activity relationship of flavonoids with the modulation of platelet function may guide the design, optimisation and development of flavonoid scaffolds as antiplatelet agents.
INTRODUCTION: Cyclooxygenase (COX)-2 selective inhibitors are attractive candidates for treatment of ankle sprain because of their efficacy as anti-inflammatory and analgesic agents and their overall safety, including lack of effect on platelet aggregation. The objective of this study was to assess the efficacy and tolerability of celecoxib compared with diclofenac slow release (SR) in the treatment of acute ankle sprain in an Asian population.
METHODS: In this seven-day, multicentre, double-blind, randomised, parallel-group trial, 370 patients with first- or second-degree ankle sprain occurring at or less than 48 hours prior to the first dose of study medication were randomised to receive celecoxib 200 mg bid (189 patients) after a 400 mg loading dose or diclofenac SR 75 mg bid (181 patients). Patients were required to demonstrate moderate to severe ankle pain on weight bearing (45 mm or greater on a 100 mm visual analogue scale [VAS]) at baseline. The primary efficacy end point was the patient's assessment of ankle pain (VAS on full weight bearing) on day 4.
RESULTS: Celecoxib was as effective as diclofenac SR in improving the signs and symptoms of ankle sprain. At day 4, mean VAS scores for celecoxib and diclofenac SR had decreased to 28 mm and 30 mm, respectively. Treatment differences were not statistically significant. Incidence of upper gastrointestinal adverse events was low in both treatment groups (0.5 percent versus 2.2 percent for celecoxib and diclofenac SR, respectively).
CONCLUSION: Celecoxib, a COX-2 selective inhibitor, is as effective as diclofenac SR in treating ankle sprains. With its platelet-sparing properties, celecoxib may offer an advantage over diclofenac SR in managing musculoskeletal injuries.
OBJECTIVE: Thrombocytopenia in dengue fever is a common and serious complication. However, no specific treatment is available for dengue fever induced thrombocytopenia. In few countries (Pakistan, Malaysia, Sri Lanka and other Asian countries) the leaf extract of Carica papaya has been effectively used for thrombocytopenia. So, the study is planned to access effect of Carica papaya leaf extract on platelet count in dengue fever patients.
METHODS: All participants were randomised into two groups, study group and control group; the study group was given papaya leaf extract capsule of 500 mg once daily and routine supportive treatment for consecutive five days. The controls were given only routine supportive treatment. Daily complete blood counts, platelet counts and haematocrit level, liver function test, renal function test of both groups were observed.
RESULTS: On the first day platelet count of study group and control group was (59.82±18.63, 61.06±20.03 thousands, p value 0.36). On the 2nd day platelet count of both study and control groups was not significantly different (61.67±19.46 and 59.93±19.52 thousands, p value 0.20) but on 3rd day platelet count of study group was significantly higher than control group (82.96±16.72, 66.45±17.36 thousands, p value < 0.01). On 4th and 5th day platelet count of study group (122.43±19.36 and 112.47±17.49 thousands respectively) was also significantly higher than the control group (88.75±21.65 and 102.59±19.35 thousands) (p value < 0.01). On 7th day platelet count of study group and control group were not significantly different (124.47±12.35 and 122.46±19.76 thousands respectively, p value 0.08). Average hospitalization period of study group v/s control group was 3.65±0.97 v/s 5.42±0.98 days (p value < 0.01). Average platelet transfusion requirement in study group was significantly less than control group (0.685 units per patient v/s 1.19 units per patient) (p value <0.01).
CONCLUSIONS: It is concluded that Carica papaya leaf extract increases the platelet count in dengue fever without any side effect and prevents the complication of thrombocytopenia. So, it can be used in dengue fever with thrombocytopenia patients.
Normal platelet functions are critical for achieving primary haemostasis. Numerous medications have been shown to affect platelet functions. Pyridostigmine (Mestinon), an orally active cholinesterase inhibitor that is commonly used to treat myasthenia gravis has been documented to cause epistaxis and prolonged bleeding after a cut in anectodal reports. This study was initiated after a patient diagnosed to have myasthenia gravis, developed multiple bruises a week after being started on Mestinon. The objective of this study was to investigate the effect of Mestinon on platelet aggregation stimulated with various agonists in vitro.
Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.
Von Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD.
Following up a popular use of crude leaf preparations from Carica papaya for the treatment of dengue infections, a suspension of powdered Carica papaya leaves in palm oil has been investigated for its effect on thrombocyte counts in mice, administering by gavage 15 mg of powdered leaves per kg body weight to 5 mice. Equal numbers of animals received corresponding volumes of either palm oil alone or physiological saline solution. Thrombocyte counts before and at 1, 2, 4, 8, 10, 12, 24, 48 and 72 hours after dosing revealed significantly higher mean counts at 1, 2, 4, 8, 10 and 12 after dosing with the C. papaya leaf formulation as compared to the mean count at hour 0. There was only a non-significant rise of thrombocyte counts in the group having received saline solution, possibly the expression of a normal circadian rhythm in mice. The group having received palm oil only showed a protracted increase of platelet counts that was significant at hours 8 and 48 and obviously the result of a hitherto unknown stimulation of thrombocyte release. The results call for a dose-response investigation and for extending the studies to the isolation and identification of the C. papaya substances responsible for the release and/or production of thrombocytes.