Perspectiva histórica de la plaqueta y su conexión con la enfermedad tromboembólica y su tratamiento (pasado, presente y futuro) / Historical perspective of the platelet and its connection to thromboembolic disease and its treatment (past, present and future)

En este artículo se hace una revisión histórica, desde la mitad del siglo pasado hasta la actualidad, de la importancia de la plaqueta y de su actividad funcional en relación con la enfermedad tromboembólica. Esta revisión se inicia en la primera mitad del siglo pasado, cuando este «elemento forme» de la sangre era conocido, casi en exclusiva, por su participación en la hemostasia primaria. Sin embargo, en las décadas de los años ochenta y noventa, se convierte en un actor clave y central en la formación del trombo arterial para ser considerado, en la actualidad y los próximos años, en un factor importante, pero uno más, en la génesis y desarrollo de los procesos trombóticos. Se hace un repaso de los descubrimientos clave que han permitido esta evolución y como ello ha hecho posible el descubrimiento y desarrollo de fármacos capaces de inhibir la agregación plaquetaria, en particular el triflusal, un antiagregante plaquetario fruto de la investigación llevada a cabo en el Laboratorio Uriach. Es por este descubrimiento que la historia de la i+d en Uriach ha estado también unida, durante más de 4 décadas, a la historia evolutiva de la plaqueta y de la enfermedad tromboembólica (AU)

This article gives a historical review, from the middle of the last century to the present, of the importance of the platelet and its functional activity in thromboembolic disease. This review begins in the first half of the last century when this blood component was almost exclusively known for its role in primary haemostasis. However, in the nineteen-eighties and nineties, it becomes a key player in the formation of arterial thrombus. Currently and in the coming years it will be considered as an important factor, but just one more, in the formation and development of thrombotic processes. A review is done of the key events that have permitted this evolution and how this has enabled the discovery and development of platelet inhibitor drugs, in particular Trifusal, an anti-platelet agent obtained from research carried out by Uriach Laboratories. Due to this discovery, R&d history at Uriach has been linked, for over four decades, to the historical evolution of both the platelet and thromboembolic disease

Comparative bioavailability study of triflusal oral solution vs. triflusal capsules in healthy subjects. A single, randomized, two-way cross-over, open-label phase I study.

Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose. This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bioequivalence assessment included AUC(0-t), AUC(0-inf) and Cmax. The formulations were considered bioequivalent if the geometric mean ratios of AUC(0-t), AUC(0-inf) and Cmax were within the predetermined equivalence range (80% to 125%). Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC(0-t) (microg x h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC(0-infinity) (microg x h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; Cmax, (microg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; Cmax/AUC(0-infinity) (h(-1)): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC(0-infinity), AUC(0-t), and Cmax were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness. It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulations were well tolerated.

New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.

The synthesis and pharmacological evaluation of new water-soluble phosphoramidate derivatives of the COX-2 selective inhibitor cimicoxib (4) are described. The sulfonylphosphoramidic acid derivative 10 was converted to 4 in human plasma and showed excellent in vivo activity in the rat carrageenan-edema test. Pharmacokinetic evaluation in dogs indicated that 10 behaved as a prodrug, immediately converting to 4 and giving an identical profile to that of the parent compound. These results represent the first description of phosphoramidic acids as prodrugs for the sulfonamido group. Compound 10 also exhibited an important and sustained analgesic effect in the hyperalgesia test in rats and a high aqueous solubility at pH higher than 7. This profile led to the selection of 10 (UR-14048) for further development in the parenteral treatment of acute pain.

Rupatadine: a new selective histamine H1 receptor and platelet-activating factor (PAF) antagonist. A review of pharmacological profile and clinical management of allergic rhinitis.

Rupatadine is a new agent for the management of diseases with allergic inflammatory conditions, such as seasonal and perennial rhinitis. The pharmacological profile of rupatadine offers particular benefits in terms of a strong antagonist activity towards both histamine H1 receptors and platelet-activating factor (PAF) receptors. Rupatadine has a rapid onset of action, and its long-lasting effect (>24 h) permits once-daily dosing. Rupatadine should not be used in combination with the cytochrome P450 inhibitors, such as erythromycin or ketoconazole, due to an increase in AUC and Cmax for rupatadine, although no clinically relevant adverse events have been reported. In addition, rupatadine, at the recommended dose of 10 mg, has been shown to be free of sedative effects and not to cause significant changes in the corrected QT interval in special populations, including the elderly, nor when coadministered with erythromycin or ketoconazole. Preclinical data have also shown that rupatadine and its main active metabolites did not interfere with cloned human HERG channel and did not affect in vitro isolated dog Purkinje fibers at concentrations at least 2000 times greater than those obtained with therapeutic doses in humans. Rupatadine is clinically effective in relieving symptoms in patients with seasonal and perennial allergic rhinitis. Newly published data on its efficacy and safety suggest that this compound may improve the nasal and non-nasal symptoms in comparison to other currently available second generation H1 receptor antihistamines.

Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.

The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.