RESUMO
Fibrinogen concentrate use as a haemostatic agent has been increasingly explored. This study evaluates spontaneous reports of potential adverse drug reactions (ADRs) that occurred during postmarketing pharmacovigilance of Haemocomplettan P/RiaSTAP, and reviews published safety data. This descriptive study analysed postmarketing safety reports recorded in the CSL Behring pharmacovigilance database from January 1986 to December 2013. A literature review of clinical studies published during the same period was performed. Commercial data indicated that 2,611,294 g of fibrinogen concentrate were distributed over the pharmacovigilance period, corresponding to 652,824 standard doses of 4 g each, across a range of clinical settings and indications. A total of 383 ADRs in 106 cases were reported (approximately 1 per 24,600 g or 6,200 standard doses). Events of special interest included possible hypersensitivity reactions in 20 cases (1 per 130,600 g or 32,600 doses), possible thromboembolic events in 28 cases (1 per 93,300 g or 23,300 doses), and suspected virus transmission in 21 cases (1 per 124,300 g or 31,000 doses). One virus transmission case could not be analysed due to insufficient data; for all other cases, a causal relationship was assessed as unlikely due to negative polymerase chain reaction tests and/or alternative explanations. The published literature revealed a similar safety profile. In conclusion, underreporting of ADRs is a known limitation of pharmacovigilance. However, the present assessment indicates that fibrinogen concentrate is administered across a range of indications, with few ADRs and a low thromboembolic event rate. Overall, fibrinogen concentrate showed a promising safety profile.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Fibrinogênio/efeitos adversos , Hemostáticos/efeitos adversos , Farmacovigilância , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Contaminação de Medicamentos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Hepatite B/transmissão , Hepatite C/transmissão , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Medição de Risco , Fatores de Risco , Tromboembolia/induzido quimicamente , Tromboembolia/diagnóstico , Fatores de Tempo , Adulto JovemRESUMO
Structural analogs of leukotriene B4 (LTB4) were designed using a preferred conformation of LTB4 (1). Appending an aromatic ring scaffold between LTB4 carbons 7 and 11 led to quinoline analogs 3 and 15. A similar modification to the LTB4 structure between carbons 7 and 9 led to the pyridine analogs 41 and 46. The compounds of this study were evaluated in receptor binding assays using [3H]LTB4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline 3, displayed moderate potency in the LTB4 receptor binding assay (Ki = 0.9 microM). Modification of 3 by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, Ki = 0.01 microM); a further improvement in receptor binding was achieved in the pyridine series (e.g., 41; Ki = 0.001 microM). The LTB4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB4. Of the analogs prepared in this report only 47 demonstrated LTB4 receptor antagonist activity.
Assuntos
Leucotrieno B4/análogos & derivados , Piridinas/síntese química , Piridinas/metabolismo , Quinolinas/síntese química , Quinolinas/metabolismo , Receptores do Leucotrieno B4/metabolismo , Humanos , Leucotrieno B4/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Conformação Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Piridinas/farmacologia , Quinolinas/farmacologia , Receptores do Leucotrieno B4/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of trisubstituted pyridines have been prepared that exhibit in vitro leukotriene B4 (LTB4, 1) receptor antagonist activity. Previous disubstituted pyridines from these labs showed high affinity for the LTB4 receptor but demonstrated agonist activity in functional assays (e.g., 2, Ki = 1 nM). Compound 4, the initial lead compound of this new series, showed only modest affinity by comparison (Ki = 282 nM); however, 4 was a receptor antagonist with no demonstrable agonist activity up to 10 microM. Subsequent modifications of the lipid tail and aryl head group region led to the discovery of aniline 50 (SB 201146). This compound, also free of agonist activity, possesses high affinity for the LTB4 receptor (Ki = 4.7 nM).
Assuntos
Acrilatos/síntese química , Acrilatos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores do Leucotrieno B4/antagonistas & inibidores , Ligação Competitiva , Humanos , Leucotrieno B4/antagonistas & inibidores , Leucotrieno B4/metabolismo , Neutrófilos/metabolismo , Neutrófilos/ultraestrutura , Piridinas/metabolismo , Receptores do Leucotrieno B4/metabolismo , Relação Estrutura-Atividade , TrítioRESUMO
The isolation and structure determination of the naturally occurring LTB4 receptor antagonist Leucettamine A (1) was recently reported. Herein we describe the synthesis of this natural product, the preparation of several analogues, and their effectiveness as antagonists of [3H]LTB4 binding to intact human U-937 cells. Total synthesis of Leucettamine A (1) is achieved by a convergent route which takes advantage of the elements of symmetry within the molecule. Syntheses of analogues of 1, which lacked the same degree of symmetry, are achieved by a different approach starting from alpha-amino acids. The natural product 1 inhibits [3H]LTB4 binding to its receptors on intact human U-937 cells with a Ki = 3.5 +/- 0.8 microM and is devoid of measurable agonist activity at the concentrations tested. 2-Amino imidazole analogues of 1 lacking the dioxolane groups were prepared. Generally these are significantly less potent than 1. However, one (26), designed on the basis of a putative structural overlay with LTB4, demonstrated potency comparable to that of the natural product (Ki = 2.4 +/- 0.2 microM).
Assuntos
Dioxóis/síntese química , Dioxóis/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Leucotrieno B4/antagonistas & inibidores , Receptores do Leucotrieno B4/antagonistas & inibidores , Cálcio/sangue , Dioxóis/metabolismo , Humanos , Imidazóis/metabolismo , Cinética , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptores do Leucotrieno B4/metabolismo , Relação Estrutura-AtividadeRESUMO
(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocytes with a Ki of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.
Assuntos
Benzoatos/química , Piridinas/química , Receptores do Leucotrieno B4/antagonistas & inibidores , Benzoatos/farmacologia , Ligação Competitiva , Cálcio/sangue , Cristalografia por Raios X , Grânulos Citoplasmáticos/efeitos dos fármacos , Humanos , Leucotrieno B4/metabolismo , Leucotrieno B4/farmacologia , Estrutura Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/ultraestrutura , Piridinas/farmacologia , Receptores do Leucotrieno B4/metabolismo , Relação Estrutura-AtividadeRESUMO
Leukotriene B4 (LTB4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-[R]-HETE) have been postulated to contribute to the pathophysiology of inflammatory diseases. SB 201993, (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, identified from a chemical series designed as ring-fused analogs of LTB4, was evaluated as an antagonist of LTB4- and 12-(R)-HETE-induced responses in vitro and for anti-inflammatory activity in vivo. SB 201993 competitively antagonized [3-H]-LTB4 binding to intact human neutrophils (Ki = 7.6 nM) and to membranes of RBL 2H3 cells expressing the LTB4 receptor (RBL 2H3-LTB4R; IC50 = 154 nM). This compound demonstrated competitive antagonism of LTB4- and 12-(R)-HETE-induced Ca2+ mobilization responses in human neutrophils (IC50s of 131 nM and 105 nM, respectively) and inhibited LTB4-induced Ca2+ mobilization in human cultured keratinocytes (IC50 = 61 nM), RBL 2H3-LTB4R cells (IC50 = 255 nM) and mouse neutrophils (IC50 = 410 nM). SB 201993 showed weak LTD4-receptor binding affinity (Ki = 1.9 microM) and inhibited 5-lipoxygenase (IC50 of 3.6 microM), both in vitro and ex vivo. In vivo, SB 201993 inhibited LTB4-induced neutrophil infiltration in mouse skin and produced dose-related, long lasting topical anti-inflammatory activity against the fluid and cellular phases of arachidonic acid-induced mouse ear inflammation (ED50 of 580 microg/ear and 390 microg/ear, respectively). Similarly, anti-inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED50 of 770 and 730 microg/ear, respectively, against the fluid and cellular phases). These results indicate that SB 201993 blocks the actions of LTB4 and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models.
Assuntos
Anti-Inflamatórios/farmacologia , Benzoatos/farmacologia , Piridinas/farmacologia , Receptores do Leucotrieno B4/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/farmacologia , Animais , Ligação Competitiva , Calcimicina/farmacologia , Cálcio/sangue , Cálcio/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Cobaias , Humanos , Ionóforos/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Leucotrieno B4/sangue , Leucotrieno B4/farmacologia , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismoRESUMO
PURPOSE: There is a need to find novel oestrogen receptor (ER) ligands that antagonize oestrogen action in the reproductive tissues and would therefore have therapeutic potential in oestrogen-dependent tumours. We tested novel ER ligands in both breast and endometrial cells to profile agonism/antagonism in these oestrogen target reproductive tissues. METHODS: Novel analogues of the ER antagonist ICI 182,780 were synthesized and tested for their ability to inhibit gene expression dependent on oestrogen response elements (ERE) in human breast (MCF-7) and endometrial (Ishikawa) cell lines. This activity was correlated with inhibition of oestrogen-induced cell proliferation and ER binding. RESULTS: The sulphide analogue (compound 1) and sulphone analogue (compound 2) had no intrinsic ERE-dependent agonism in either breast cancer or endometrial cells in culture. All three compounds dose-dependently inhibited ERE-mediated oestrogen agonism. Moreover, these ER ligands inhibited oestrogen-stimulated proliferation of breast cancer and endometrial cells. ICI 182,780, compound 1 and compound 2 were all able to bind both isoforms of the ER (ER alpha and ER beta). In endometrial cells, the relative binding to ER beta correlated with the ERE-dependent antioestrogenic effect of these ligands, suggesting that in this tissue this receptor is the predominant isoform that determines antioestrogenic activity. CONCLUSIONS: The ability of these analogues of ICI 182,780 to inhibit oestrogen-stimulated transcriptional activity and cell proliferation suggests that these agents, in particular the sulphone analogue, have therapeutic potential in the treatment of breast cancer without exhibiting the unwanted oestrogenic effects in the endometrium.