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Abstract Picotamide is a thromboxane A2 (TXA2) receptor antagonist and TXA2 synthase inhibitor. In clinical studies, it has been considered as a platelet aggregation inhibitor and improved renal function. In vitro studies suggested inhibition of smooth muscle contraction by picotamide, which is poorly understood. Here, we examined effects of picotamide on contractions of renal interlobar and coronary porcine arteries, induced by different vasoconstrictors. Contractions were induced in an organ bath by agonists or electric field stimulation (EFS). Picotamide inhibited EFS‐induced contractions of interlobar arteries around 50% using concentrations of 100 and 300 µM. In interlobar arteries, concentration response curves for contractions induced by three different α1‐adrenoceptor agonists were shifted to the right by picotamide (2–10‐fold increases in EC50). In coronary arteries, α1‐adrenergic contractions were inhibited without right shift (approx. 50%). Contractions induced by two different cholinergic agonists in coronary arteries were inhibited by picotamide (≥50%) withouth right shift. Inhibition of serotonin‐induced contractions by picotamide showed features of a right shift, whereas contractions induced by the TXA2 analog U46619, angiotensin‐II, and endothelin‐1 were inhibited by picotamide in interlobar and coronary arteries without right shifts and to different degree. Picotamide inhibits a wide spectrum of vasoconstrictor‐induced contractions in porcine interlobar and coronary arteries. Inhibition of vasocontraction may contribute to beneficial effects of picotamide in the cardiovascular system and kidney.

Picotamide is a thromboxane A2 (TXA2) receptor antagonist and TXA2 synthase inhibitor. In clinical studies, it has been considered as a platelet aggregation inhibitor and improved renal function. In vitro studies suggested inhibition of smooth muscle contraction by picotamide, which is poorly understood. Here, we examined effects of picotamide on contractions of renal interlobar and coronary porcine arteries, induced by different vasoconstrictors. Contractions were induced in an organ bath by agonists or electric field stimulation (EFS). Picotamide inhibited EFS‐induced contractions of interlobar arteries around 50% using concentrations of 100 and 300 µM. In interlobar arteries, concentration response curves for contractions induced by three different α1‐adrenoceptor agonists were shifted to the right by picotamide (2–10‐fold increases in EC50). In coronary arteries, α1‐adrenergic contractions were inhibited without right shift (approx. 50%). Contractions induced by two different cholinergic agonists in coronary arteries were inhibited by picotamide (≥50%) withouth right shift. Inhibition of serotonin‐induced contractions by picotamide showed features of a right shift, whereas contractions induced by the TXA2 analog U46619, angiotensin‐II, and endothelin‐1 were inhibited by picotamide in interlobar and coronary arteries without right shifts and to different degree. Picotamide inhibits a wide spectrum of vasoconstrictor‐induced contractions in porcine interlobar and coronary arteries. Inhibition of vasocontraction may contribute to beneficial effects of picotamide in the cardiovascular system and kidney. [ABSTRACT FROM AUTHOR]

With the help of spatial quantitative structure‐activity relationships (QSAR) contour maps obtained by comparative molecular field analysis (CoMFA), a series of 4‐ethoxyisophthalamide compounds were prepared and some of them with higher activity were found. This paper continues the structural design, preparation, spectral confirmation of thirteen new 4‐ethoxyisophthalamide compounds and completes their preliminary screening of activity in response to the following inducers: adenosine diphosphate (ADP) and collagen. Among them, when ADP was used as an inducer, compounds whose activities are higher or close to picotamide, the IC50 value also were calculated and revealed that one compound 16 (IC50 : 0.26 μmol L−1) was more than three times more active than positive control drug picotamide. Meanwhile, cytotoxic effects in vitro of compound 11* and compound 16 on L929 cells were analyzed. The structure‐activity relationship showed that when electron‐withdrawing groups nitro or trifluoromethyl are introduced at the meta‐ or para‐ position of the two side chain benzene rings, it is beneficial on the whole to the improvement of antiplatelet activity. [ABSTRACT FROM AUTHOR]

In our present investigation, a series of novel 4-methoxy-1,3-benzenediolyl-hydrazones were designed and synthesized, and their ability to inhibit platelet aggregation was evaluated by adenosine diphosphate (ADP) and arachidonic acid (AA). The structures of the synthesized compounds were confirmed by spectral data. Results demonstrated that the activities of all compounds excelled the positive drug Picotamide (25.1% inhibition rate) and seven compounds (PNN01, PNN03, PNN05, PNN07, PNN09, PNN12, and PNN14) have efficiently inhibited platelet aggregation even higher than Clopidogrel (37.6% inhibition rate) induced by AA. Among them, PNN07 (39.8% inhibition rate) was considered as the most potent analogue. Evaluation of cytotoxic activity of the compounds against L929 cell line revealed that none of the compounds have significant cytotoxicity. Thus, diolylhydrazones derives are potential to be antiplatelet aggregation inhibitors and maybe working in AA-induced selectively. [ABSTRACT FROM AUTHOR]

To obtain more active and selective anti-platelet candidate drugs, we tried to introduce a methyl group at the 5-position and 6-position of the parent benzene ring first time, respectively or simultaneously. The idea could inspect compound with tetra-substituted or penta-substituted characteristics rather than retained classical 1,3,4-position triple substitutions characteristic whether it continues to have anti-platelet activity in vitro. The biological evaluation revealed that most of compounds with this novel structure were more potent than the positive control drug Picotamide. At the concentration of 1.3 μmol/L, using Arachidonic acid as an inducer, it was found that the anti-platelet activity in vitro of five compounds 1a, 1b, 1c, 2f, and 3d was higher than that of Picotamide and the series 1 compounds were generally higher than that of the series 2 and 3. And with ADP as an inducer, the activity in vitro of nine compounds 2a, 2b, 2d, 2f, 2g, 2h, 3a, 3b, and 3c was more elevated than that of Picotamide and the compounds of series 2 and 3 were all evidently even more active than that of series 1. The proportion of newly designed target compounds with active is higher than that of previously developed series of compounds. Based on the in vitro activity results, a preliminary analysis of the structure–activity relationship was deduced. Meanwhile, cytotoxic effects in vitro of 11 target compounds 1b, 1c, 2f, 2a, 2b, 3a, 3b, 3c, 2d, 2g, and 2h on L-929 cells were analyzed, but the data analysis shows that at two concentrations, target compounds have higher effect on L-929 cells than that of control drug Picotamide. The reason or mechanism for obtaining higher in vitro activity and higher cytotoxicity of the target compound under tetra- or penta- substitutions requires further relevant research work before conclusion can be drawn. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. In order to discover novel compounds with anti-platelet aggregation activities, a series of novel 4-methoxy-1,3-phthalamidesamides (1a–1i) and a series of novel 4-methoxy-1,3-benzenedisulfon-amides (2a–2i) were synthesized and their anti-platelet aggregation activities were evaluated by the turbidimetric method in response to the following agonists: adenosine diphosphate (ADP), arachidonic acid (AA), and Collagen. Those compounds that have better in vitro activities were subjected to cell toxicity tests via cell counting kit-8 (CCK-8) assay. The inhibition rates of anti-platelet in vitro of five compounds 1g (39.45%), 2d (38.87%), 2g (38.55%), 2h (44.56%), and 2i (43.93%) were higher than that of two reference drugs picotamide (36.12%) and aspirin (38.45%) when ADP was selected as an inducer. The inhibition rates of seven compounds 1c (43.63%), 1d (40.02%), 1g (47.42%), 1i (40.45%), 2c (40.11%), 2d (40.45%), and 2i (49.05%) were higher than that of picotamide (34.89%) and aspirin (39.43%) when AA was selected as inducer. And the inhibition rates of five compounds 1d (47.22%), 1i (45.01%), 2d (38.74%), 2e (42.21%), and 2f (39.94%) were higher than picotamide (38.45%) and aspirin (37.08%) when collagen was selected as inducer. Moreover, the effect of cell toxicity exhibited that none of the compounds had obvious cell toxicity against L-929 cells. Therefore, 4-methoxy-1,3-phthalamidesamides (1a–1i) and 4-methoxy-1,3-benzenedisulfon-amides (2a–2i) have the potential to become a novel kind of anti-platelet drugs and deserve further study. [ABSTRACT FROM AUTHOR]

A series of 4-methoxyisophthalamides (1d-1w) were designed and synthesized and their chemical structures were confirmed by IR, MS, 1H-NMR, and 13C-NMR. The in vitro on anti-platelet aggregation activities of these compounds were assessed by using Born method. Compounds with higher activities were selected to continue research via Cell Counting Kit-8 (CCK-8) assays of their cytotoxicities. Biological screening results revealed four compounds 1h, 1i, 1q, and 1v exhibited higher activities than the control drugs on against the platelet aggregation induced by adenosine triphosphate (ADP). Moreover, compounds 1p and 1q exhibited higher in vitro activities than picotamide induced by collagen at the concentration of 1.3 μM. Compound 1p also possessed anti-platelet aggregation activity superior to the control drug picotamide induced by arachidonic acid (AA) at the concentration of 1.3 μM. At the same time, the result of cytotoxicities exhibited that none of the compounds have significant cytotoxicities. Therefore, 4-methoxyisophthalamides are potential to become novel anti-platelet drugs with high activities and minimum toxicities. [ABSTRACT FROM AUTHOR]

Male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction are characterized by abnormal smooth muscle contractions in the lower urinary tract. Alpha 1 -adrenoceptor antagonists may induce smooth muscle relaxation in the outflow region and represent the current gold standard of medical treatment. However, results may be unsatisfactory or inadequate. Apart from α 1 -adrenoceptor agonists, smooth muscle contraction in the outflow region may be induced by thromboxane A 2 (TXA 2 ), endothelins, or muscarinic receptor agonists. Here, we studied effects of the thromboxane A 2 receptor (TP receptor) antagonist picotamide on contraction in the human male bladder trigone and prostate. Carbachol, the α 1 -adrenoceptor agonist phenylephrine, the thromboxane A 2 analog U46619, and electric field stimulation (EFS) induced concentration- or frequency-dependent contractions of trigone tissues in an organ bath. Picotamide (300 µM) inhibited carbachol-, phenylephrine-, U46619-, and EFS-induced contractions. Endothelins 1-3 induced concentration-dependent contractions of prostate tissues, which were inhibited by picotamide. Analyses using real time polymerase chain reaction and antibodies suggested expression of thromboxane A 2 receptors and synthase in trigone smooth muscle cells. Thromboxane B 2 (the stable metabolite of thromboxane A 2 ) was detectable by enzyme immune assay in trigone samples, with most values ranging between 50 and 150 pg/mg trigone protein. Picotamide inhibits contractions induced by different stimuli in the human lower urinary tract, including cholinergic, adrenergic, thromboxane A 2 - and endothelin-induced, and neurogenic contractions in different locations of the outflow region. This distinguishes picotamide from current medical treatments for LUTS, and suggests that picotamide may induce urodynamic effects in vivo. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (DM) and peripheral arterial disease (PAD) are two very relevant cardiovascular (CV) risk factors, which can often be found concurrently in the same patient. The DAVID trial, a double-blind, randomized, aspirin(ASA)-controlled study, has demonstrated that the use of picotamide, a thromboxane A2 synthase and receptor dual inhibitor, is associated with lesser CV morbidity and mortality in this type of patients in comparison to ASA, considered the standard antiplatelet agent. In order to estimate clinical and economic impacts of picotamide in the Italian health care setting, we developed a pharmacoeconomic model based on clinical data from DAVID and national economic parameters and demographics. The base case scenario, which reflects current prices and reimbursement policy (i.e. ASA fully paid for, picotamide out-of-pocket for patients) yielded an incremental cost/effectiveness ratio (ICER) of about 8,500 euro/year of life (YOL) saved, which falls below conventionally adopted willingness to pay thresholds. This cost, however, is totally born by the patient, while the savings on health care expenditures for avoided events (and less ASA) benefit the national health service (NHS). These results may help the physician in explaining the consequences of this choice to his/her patients, facilitating a fully-informed choice. The availability of a theoretical model allowed to explore some alternative scenarios, that indicate that the ICER can be further lowered and the economical burden better distributed through policy changes. In conclusion, the pharmacoeconomic model indicated that picotamide is likely to be a cost/effective option for CV mortality and morbidity prevention in patients with concurrent type 2 DM and PAD and that the level of adoption of this strategy will depend on willingness to pay and policy priorities of the NHS and patients themselves.

Inhibition of prostate smooth muscle contraction is an important strategy for medical treatment of lower urinary tract symptoms (LUTS). Besides α1-adrenoceptors, prostate smooth muscle contraction is induced by activation of thromboxane (TXA2) receptors (TXA2-R). Here, we examined the effects of the TXA2-R antagonist picotamide on contraction of human prostate tissue. Prostate tissues were obtained from radical prostatectomy. The effects of picotamide (300 μM), L-665,240 (3 μM), and seratrodast (3 μM) on U46619-, electric field stimulation- (EFS-), phenylephrine-, and norepinephrine-induced contractions were studied in organ baths. Expression of TXA2-R and TXA2 synthase (TXS) was examined by fluorescence stainings. Picotamide, seratrodast, and L-655,240 inhibited concentration-dependent contractions induced by the TXA2 analog U46619. Picotamide, but not seratrodast or L-655,240, inhibited frequency-dependent contractions induced by EFS. Picotamide inhibited concentration-dependent contractions induced by norepinephrine or by the selective α1-adrenoceptor agonist phenylephrine. In prostate strips, where only submaximal contraction by a low dose of phenylephrine was induced, application of U46619 raised tone to maximum phenylephrine-induced tension. Immunoreactivity for TXA2-R and TXS was observed in the stroma and in epithelial cells of glands. Colocalization of both immunoreactivites was observed with the smooth muscle markers calponin and smooth muscle actin, with the epithelial marker pan-cytokeratin, and with prostate-specific antigen in the stroma and glands. The receptor antagonist picotamide inhibits α1-adrenergic, TXA2-mediated, and EFS-induced contractions in the human prostate. To the best of our knowledge, this is the first antagonist able to inhibit two different contraction systems in the prostate. [ABSTRACT FROM AUTHOR]

Abstract: On the purpose of searching for the structure–activity relationship (SAR) and obtaining novel anti-platelet drugs, 41 4-methoxybenzene-1,3-isophthalamides have been described the synthesis process and in vitro activities on anti-platelet aggregation. The target compounds have been classified into four series: series 1 (ortho-substituted phenyl: 1a–1j), series 2 (meta-substituted phenyl: 2a–2k), series 3 (para-substituted phenyl: 3a–3l) and series 4 (aromatic of no substituted group and aromatic heterocyclic substituted groups: 4a–4h). The chemical structures of the target compounds were confirmed by MS, IR, 1H NMR, and their in vitro activities on anti-platelet aggregation were tested and assessed by using Born test. The result showed that thirteen compounds 1c, 1d, 1i, 1j, 2g, 3a, 3c, 3d, 3f, 3h, 3l, 4b and 4c have superior anti-platelet aggregation activities than the reference drug Picotamide. [Copyright &y& Elsevier]

Migraine with aura (MwA) is a primary headache that affects up 30% of migraine patients. Although the frequency of MwA attacks is usually low and the majority of migraine sufferers do not need prophylactic treatment(s), same particular patients do. This occurs when the neurological symptoms, that characterize the auras, determine anxiety to the migraine sufferers and when the frequency of MwA attacks is or becomes high. In this study, we review the few therapeutic conventional options specifically devoted to cure MwA attacks present in the literature together with those, recent, non-conventional. [ABSTRACT FROM AUTHOR]

Migraine with aura (MwA) sufferers, at times, need specific treatments. This is the case when the auras are frequent, prolonged and cause anxiety and distress. Abnormal release of glutamate, that may trigger auras, and abnormal platelet behaviour, that constitute a possible predisposing factor to MwA, may be possible targets for MwA specific prophylactic therapy. Here we present results obtained by using lamotrigine, an agent known to inhibit glutamate release, and picotamide, an antiplatelet drug. Both drugs significantly reduced, in two open label trials, the frequency and the duration of auras. In comparison with lamotrigine, the therapy with picotamide may offer some advantages, such as the use of the therapeutical dose from the first day of treatment (lamotrigine needs one month to reach such a dose) and the possibility to prevent cerebral ischaemic events and migraine stroke, a rare but severe complication of MwA attacks. [ABSTRACT FROM AUTHOR]

We evaluated the capacity of anti-aggregating agents to influence thromboxane A2 and prostacyclin formation, arachidonic acid-endoperoxide redirection, platelet aggregation and vessel tone, in isolated rabbit aorta incubated with homologous platelets. Picotamide (N,N′bis(3-pyridinylmethyl)-4-methoxy-isophthalamide), the only dual thromboxane A2-synthase inhibitor/receptor antagonist in clinical use, inhibited arachidonic acid-induced platelet aggregation with low potency, increased 180-fold by aorta presence. It inhibited thromboxane A2 formation in platelets and, in aorta presence, increased prostacyclin formation. Ozagrel (OKY-046, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propenoic acid), a pure thromboxane A2-synthase inhibitor, behaved similarly to picotamide, although the aorta caused a higher (600-fold) shift. The potency of the antagonist SQ 29,548 (1S-(1α,2β(5Z),3β,4α))-7-(3((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid) was unaffected by aorta. In coincubation experiments, arachidonic acid-challenge increased thromboxane A2-dependent vessel tone; picotamide increased prostacyclin and reduced thromboxane A2 formation and vasoconstriction. Ozagrel mimicked picotamide; aspirin (acetylsalicylic acid) reduced aorta contractility, thromboxane A2 and prostacyclin formation. SQ 29,548 reduced vasoconstriction without affecting eicosanoids. We demonstrate the importance of redirection of eicosanoids in the mechanism of action of thromboxane A2 inhibitors/antagonists within platelet–vascular wall interactions. These findings bear relevance in the development of novel anti-thrombotic drugs. [Copyright &y& Elsevier]

Picotamide (G 137), a new non prostanoid inhibitor of in vitro arachidonic acid induced platelet aggregation, has been further characterized in in vitro and ex vivo studies. When whole blood was activated with collagen in the presence of picotamide 5×10 M, thromboxane B production was decreased, and 6-keto-PGFα generation was significantly increased, suggesting a reorientation of platelet endoperoxide metabolism following blockade of thromboxane synthetase. Picotamide also inhibited platelet aggregation and clot retraction induced by the endoperoxide analogue U46619 in human platelets, indicating thromboxane A-receptor antagonism, possibly of competitive nature. A single oral dose of picotamide 1 g in 24 healthy volunteers produced a significant inhibition of collagen, arachidonic acid and U46619-induced platelet aggregation. Serum levels of thromboxane B were also reduced. Chronic administration of picotamide 1.2 g/d to patients with vascular disease resulted in a prompt and persistent fall in their increased plasma levels of β-thromboglobulin. The results indicate that picotamide is a combined thromboxane B-synthetase inhibitor and thromboxane A-receptor antagonist in human platelets, and that it may prove useful as an antithrombotic agent. [ABSTRACT FROM AUTHOR]

The effect of picotamide on platelet function has been studied in vitro and ex vivo. Picotamide at micromolar concentrations inhibited platelet aggregation induced by ADP, arachidonic acid and collagen, and it also inhibited the production of thromboxane A (TxA). Unlike aspirin, picotamide did not affect the synthesis of prostacyclin by blood vessels. In eight healthy subjects who took picotamide 1200 mg/d platelet aggregation and TxA production were inhibited. Picotamide appears to be an antiplatelet drug that reduces TxA synthesis without affecting cyclooxygenase activity. [ABSTRACT FROM AUTHOR]

In an open, preliminary trial we evaluated the use of picotamide, an antiplatelet drug, in the prophylactic treatment of migraine aura (MA). Twenty-two women suffering from migraine with typical aura or MA without headache, diagnosed according to International Headache Society criteria, entered a nine-month study. They underwent a three-month run-in period free of prophylactic drugs, followed by a six-month treatment period (subdivided in two trimesters, TI and TII) with 300 mg of picotamide administered twice daily. A detailed diary reporting neurological symptoms, duration and frequency of MA was compiled by patients along the trial time. The number of MA significantly decreased during treatment (from 6.85±3.82 in the run-in trimester to 2.85±2.72 during TI and to 2.55±2.89 during TII). Also, MA duration was decreased significantly, being 36.75±20.28 min during run-in, 20.00±16.94 during TI and 17.75±16.26 during TII. In 25% of patients MA totally disappeared. The number and the features of aura neurological symptoms were also positively modified by the use of picotamide. No serious adverse event was provoked by picotamide administration. Picotamide is effective in reducing MA frequency, duration and symptomatology. The effect is clearly evident in the first trimester of treatment and is maintained with no further modifications during the second trimester. [ABSTRACT FROM AUTHOR]

Migraine with aura (MwA) sufferers, at times, need specific treatments. This is the case when the auras are frequent, prolonged and cause anxiety and distress. Abnormal release of glutamate, which may trigger auras, and abnormal platelet behaviour, which constitutes a possible predisposing factor to MwA, are possible targets for MwA-specific prophylactic therapy. Here we present results obtained using lamotrigine (two open trials), an agent known to inhibit glutamate release, and picotamide, an antiplatelet drug, in the prophylactic treatment of MwA sufferers. Lamotrigine significantly reduced the frequency of MwA attacks, and picotamide together with lamotrigine reduced the duration and/or the occurrence of auras. In comparison to lamotrigine, the therapy with picotamide may have some advantages such as the use of the therapeutic dose from the first day of treatment (lamotrigine needs one month or more to reach such a dose) and the possibility to prevent cerebral ischaemic events and migraine stroke, a rare but severe complication of MwA attacks. [ABSTRACT FROM AUTHOR]