Limitations of conventional anticoagulant therapy and the promises of non-heparin based conformational activators of antithrombin

Rashid, Qudsia; Singh, Pratap; Abid, Mohammad; Jairajpuri, Mohamad Aman

doi:10.1007/s11239-012-0712-z

Cited by 15 publications

(10 citation statements)

References 67 publications

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“…A dual agent should be advantageous, due to expected pharmacokinetics, likely lower incidence of side effects, and less demanding clinical studies. Furthermore, combining anticoagulant and antiplatelet effects into a single molecule will prevent and treat concomitantly venous and arterial thrombosis; This emerging class of dual acting compounds could lead to a novel approach in cardiovascular diseases …”

Section: Emerging Bioactive Sulfated Phenolic Small Moleculesmentioning

confidence: 99%

Emerging Sulfated Flavonoids and other Polyphenols as Drugs: Nature as an Inspiration

2013

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Nature uses sulfation of endogenous and exogenous molecules mainly to avoid potential toxicity. The growing importance of natural sulfated molecules, as modulators of a number of physiological and pathological processes, has inspired the synthesis of non-natural sulfated scaffolds. Until the 1990s, the synthesis of sulfated small molecules was almost restricted to derivatives of flavonoids and aimed mainly at structure elucidation and plant biosynthesis studies. Currently, the synthesis of this type of compounds concerns structurally diverse scaffolds and is aimed at the development of potential drugs and/or exploitation of the biological effects of sulfated metabolites. Some important hit compounds are emerging from sulfated flavonoids and other polyphenols mainly as anticoagulant and antiviral agents. When compared with polymeric macromolecules such as heparins, sulfated small molecules could be of value in therapeutics due to their hydrophobic nature that can contribute to improve the bioavailability. This review highlights the synthetic approaches that were applied to obtain monosulfated or polysulfated phenolic small molecules and compiles the diverse biological activities already reported for this type of derivatives. Toxicity and pharmacokinetic parameters of this emerging class of derivatives will also be considered, emphasizing their value for therapeutic applications.

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Section: Emerging Bioactive Sulfated Phenolic Small Moleculesmentioning

confidence: 99%

Emerging Sulfated Flavonoids and other Polyphenols as Drugs: Nature as an Inspiration

2013

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“…AT and HCII are the most critical endogenous anticoagulant molecules that regulate coagulation by inhibiting procoagulant proteases, namely, thrombin, fXa, fIXa, and fXIa (AT) and thrombin (HCII). Both AT and HCII require heparin as a cofactor to inhibit these proteases at physiologically relevant rates, underlying the principal use of heparin as anticoagulant [ 35 – 37 ]. Heparin binding domain of AT and HCII comprises of positively charged residues of the helix D of both AT and HCII and helix A of AT [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Polysulfated Trehalose as a Novel Anticoagulant Agent with Dual Mode of Action

Rashid

Abid

Gupta

et al. 2015

BioMed Research International

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Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. An in vitro analysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5′-Diphosphate (ADP) induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.

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“…Os anticoagulantes são substâncias utilizadas para preservação de amostras de sangue, uma vez que evitam a formação de coágulos e trombos e preservam estruturas celulares e moleculares (Tecles et al, 2004). Sabe-se que os anticoagulantes têm diferentes mecanismos de ação sobre as plaquetas e sobre a cascata de coagulação em si, que por sua vez podem interferir na funcionalidade dos leucócitos e sobre a AL (Rashid et al, 2012). O uso de conservantes para a preservação, refrigeração e a estocagem de sangue canino para a análise da expressão de CD11b e da atividade da explosão respiratória foram avaliados; contudo, para estudos funcionais de neutrófilos não foram recomendadas (Ruaux e Williams, 2000).…”

Section: Discussionunclassified

Adesão leucocitária e MDA sérico em cães naturalmente infectados por Leishmania infantum

Santos¹,

Lima²,

Lopes-Neto³

et al. 2016

RBCV

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ResumoO presente estudo avaliou o estresse oxidativo e a adesão de leucócitos (AL) em cães naturalmente infectados por Leishmania infantum. Foram utilizados cães saudáveis (CN = 10) e cães acometidos por leishmaniose visceral na forma sintomática (CS = 10), submetidos previamente a exames de imunofluorescência indireta (IFI), ensaio imunoenzimático (ELISA) e pesquisa do parasito em aspirados de medula óssea. Soro foi utilizado para avaliação de malondialdeído (MDA) no ensaio para espécies reativas ao ácido tiobarbitúrico (TBARS) e AL foi determinada pelo método da coluna de náilon em sangue em EDTA, heparina e citrato. Os dados de AL foram expressos em porcentagem e MDA em média ± desvio padrão, submetidos ao teste T de student não pareado (p < 0,05). Amostras em heparina apresentaram níveis mais elevados de AL no grupo CS (55,62%, p < 0,05) quando comparadas com EDTA e citrato (10,46% e 5,28%). Citrato e EDTA inibiram AL em cães doentes e saudáveis, enquanto a heparina preservou a AL. A proporção neutrofílica se apresentou reduzida nas amostras em heparina (85% para 67%, p <0,05) quando comparadas com citrato e EDTA, que por sua vez mantiveram-se estáveis (83% para 80%). Os níveis de MDA apresentaram-se mais elevados em CS (0,0117µM ± 0,002) quando comparado com CN (0,0057µM ± 0,001) (p <0,05). Estes dados dão suporte à conclusão de que na LVC ocorre elevação do estresse oxidativo e aumento da expressão das moléculas de adesão nos leucócitos, evidenciando resposta inflamatória sistêmica. A escolha do anticoagulante é importante para a implementação do ensaio de AL.Palavras-chave: agregação leucocitária, anticoagulantes, estresse oxidativo, leishmaniose visceral canina. AbstractThe present study evaluated the oxidative stress and leukocyte adhesion (LA) in dogs naturally infected by Leishmania infantum. Healthy dogs (HD = 10) and dogs affected by canine visceral leishmaniasis (CVL) in symptomatic form (SD= 10) were previously submitted to indirect immunofluorescence reaction (IIF), enzyme-linked immunosorbent assay (ELISA) and detection of parasites in bone marrow aspirates. Serum was used to assess malondialdeid (MDA) by thiobarbituric acid reactive species (TBARS) assay and AL was determined by nylon column method using whole blood stored in EDTA, citrate and heparin. AL data was expressed as percentage and MDA data as mean ± standard deviation, both submitted to the unpaired student's T test (p < 0.05). Heparin samples showed higher levels of AL in CS group (55.62 %, p < 0.05) when compared with EDTA and citrate (10.46% and 5.28%). Citrate and EDTA inhibit AL in healthy and sick dogs, while heparin preserved AL in both groups. Neutrophil proportion in heparin samples were lower (85% to 67%, p <0.05) compared with citrate and EDTA, which in turn remained practically unchanged (83% to 80%). MDA levels were higher in SD (0.0117μM ± 0.002) when compared to HD (0.0057μM ± 0.001) (p <0.05). These data support the conclusion that CVL induces oxidative stress enhance and leukocyte adhesion increase, indicating systemi...

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Limitations of conventional anticoagulant therapy and the promises of non-heparin based conformational activators of antithrombin

Cited by 15 publications

References 67 publications

Emerging Sulfated Flavonoids and other Polyphenols as Drugs: Nature as an Inspiration

Emerging Sulfated Flavonoids and other Polyphenols as Drugs: Nature as an Inspiration

Polysulfated Trehalose as a Novel Anticoagulant Agent with Dual Mode of Action

Adesão leucocitária e MDA sérico em cães naturalmente infectados por Leishmania infantum

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