RESUMO
Revefenacin inhalation solution is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. Mass balance, pharmacokinetics, and metabolism of revefenacin were evaluated after intravenous and oral administration of [14C]-revefenacin in healthy subjects. Pharmacological activity of the major revefenacin metabolite was also assessed. Adult males (n = 9) received 20 µg intravenously of approximately 1 µCi [14C]-revefenacin and/or a single 200-µg oral solution of approximately 10 µCi [14C]-revefenacin. Mean recovery of radioactive material was 81.4% after intravenous administration (54.4% in feces; 27.1% in urine) and 92.7% after oral dosing (88.0% in feces, 4.7% in urine). Mean absolute bioavailability of oral revefenacin was low (2.8%). Intact revefenacin accounted for approximately 52.1% and 13.1% of the total radioactivity in plasma after intravenous and oral administration, respectively. Two main circulating metabolites were observed in plasma. After an intravenous dose, a hydrolysis product, THRX-195518 (M2) was observed that circulated in plasma at 14.3% of total radioactivity. After an oral dose, both THRX-195518 and THRX-697795 (M10, N-dealkylation and reduction of the parent compound) were observed at 12.5% of total circulating radioactivity. THRX-195518 was the major metabolite excreted in feces and comprised 18.8% and 9.4% of the administered intravenous and oral dose, respectively. The major metabolic pathway for revefenacin was hydrolysis to THRX-195518. In vitro pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 receptor relative to revefenacin. Receptor occupancy analysis suggested that THRX-195518 has minimal contribution to systemic pharmacology relative to revefenacin after inhaled administration. SIGNIFICANCE STATEMENT: The major metabolic pathway for revefenacin was hydrolysis to the metabolite THRX-195518 (M2), and both revefenacin and THRX-195518 underwent hepatic-biliary and fecal elimination after oral or intravenous administration with negligible renal excretion. Pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 muscarinic receptor relative to revefenacin and that THRX-195518 has minimal contribution to systemic pharmacology after inhaled administration.
Assuntos
Benzamidas/farmacocinética , Broncodilatadores/farmacocinética , Carbamatos/farmacocinética , Antagonistas Muscarínicos/farmacocinética , Administração por Inalação , Administração Oral , Adulto , Benzamidas/administração & dosagem , Benzamidas/análise , Disponibilidade Biológica , Broncodilatadores/administração & dosagem , Carbamatos/administração & dosagem , Carbamatos/análise , Fezes/química , Voluntários Saudáveis , Eliminação Hepatobiliar , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Soluções , Adulto JovemRESUMO
The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and ß2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hß2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hß2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hß1- and hß3-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC50 = 50.2 nM), BA (EC50=24.6 nM), and MABA (EC50 = 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED50 = 33.9 µg/ml), BA (ED50 = 14.1 µg/ml), and MABA (ED50 = 6.4 µg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55- to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic ß2-adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Carbamatos/farmacologia , Antagonistas Muscarínicos/farmacologia , Quinolonas/farmacologia , Antagonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Antagonistas de Receptores Adrenérgicos beta 2/farmacocinética , Albuterol/análogos & derivados , Albuterol/farmacocinética , Albuterol/farmacologia , Animais , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacocinética , Células CHO , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Cobaias , Células HEK293 , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Relaxamento Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ligação Proteica , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Receptores Adrenérgicos beta/metabolismo , Receptores Muscarínicos/metabolismo , Xinafoato de Salmeterol , Derivados da Escopolamina/farmacocinética , Derivados da Escopolamina/farmacologia , Brometo de Tiotrópio , Distribuição Tecidual , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Glaucoma/tratamento farmacológico , Prostaglandinas F Sintéticas/farmacologia , Receptores de Prostaglandina/agonistas , Inibidores da Anidrase Carbônica/química , Descoberta de Drogas , Humanos , Modelos Moleculares , Prostaglandinas F Sintéticas/química , Receptores de Prostaglandina/químicaRESUMO
TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log(10) CFU kill effective dose (ED(1-log kill)) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log(10) CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log(10) stasis dose (ED(stasis)) and ED(1-logkill) doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r(2) = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r(2) = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r(2) = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log(10) CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.
Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Glicopeptídeos/farmacologia , Neutropenia/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Vancomicina/farmacologia , Animais , Antibacterianos/sangue , Antibacterianos/química , Área Sob a Curva , Cefalosporinas/sangue , Cefalosporinas/química , Contagem de Colônia Microbiana , Dimerização , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Glicopeptídeos/sangue , Glicopeptídeos/química , Humanos , Injeções Subcutâneas , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/crescimento & desenvolvimento , Infecções Estreptocócicas/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/crescimento & desenvolvimento , Coxa da Perna/microbiologia , Vancomicina/sangueRESUMO
Combinations of a muscarinic receptor antagonist (MA) and a ß(2)-adrenoceptor agonist (BA) improve bronchodilation in COPD patients to a greater extent than drugs with either mechanism alone. Here, using an in vivo model of bronchoprotection in guinea pigs, we characterize a single agent with dual-acting MA and BA activity, THRX-200495 (MABA). THRX-200495 was compared to a fixed-dose combination of a short-acting muscarinic receptor antagonist (SAMA) and a ß(2)-adrenoceptor agonist (SABA). The SAMA/SABA combination consisted of a 1:5.7 ratio of ipratropium and albuterol (the components of Combivent®). Conscious guinea pigs received aqueous nebulized solutions of vehicle or test compound by aerosol exposure. Bronchoprotective potency was estimated in anesthetized, tracheotomized and ventilated guinea pigs at predetermined time points after aerosol exposure by measuring changes in ventilation pressure. The individual (MA, BA) and composite (MABA) pharmacologies were assessed by determining protection against bronchoconstrictor responses induced by methacholine in the presence of propranolol (for MA activity), histamine (for BA activity) or methacholine (MABA activity). Bronchoprotection was calculated as percent inhibition of methacholine or histamine response relative to the vehicle group. THRX-200495 exhibited matched MA (ID(50) = 11.4 µg/mL) and BA (ID(50) = 11.2 µg/mL) potency and potent dual pharmacology (MABA ID(50) = 3.5 µg/mL) that persisted for over 24 h. The combination of ipratropium/albuterol exhibited bronchoprotective activity that was 2.6-fold more potent as a BA (ID(50) = 5.7 µg/mL) than as an MA (ID(50) = 14.6 µg/mL) at 0.5 h post-dose and 37-fold more potent as an MA (ID(50) = 4.3 µg/mL) than a BA (ID(50) = 159 µg/mL) at 1.5 h post aerosol exposure. Under MABA pharmacological conditions, ipratropium/albuterol produced potent bronchoprotective activity (ID(50) = 2.0/11.4 µg/mL) and an apparent additive effect of the two pharmacologies. In conclusion, a dual-acting prototypical MABA, THRX-200495, demonstrated potent, balanced and long-lasting bronchodilation in a guinea pig model of bronchoprotection that was greater than either the MA or BA mechanisms alone.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Carbamatos/farmacologia , Antagonistas Muscarínicos/farmacologia , Quinolonas/farmacologia , Animais , Brônquios/efeitos dos fármacos , Cobaias , Liberação de Histamina/efeitos dos fármacos , Masculino , Cloreto de Metacolina/farmacologiaRESUMO
Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT1 receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT1). Target engagement in vivo (ACE, AT1, and NEP) was quantified by measuring inhibition of angiotensin-pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat-induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT1 receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile.
Assuntos
Anti-Hipertensivos/farmacologia , Neprilisina/antagonistas & inibidores , Piridinas/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Tiazepinas/farmacologia , Angioedema/induzido quimicamente , Animais , Anti-Hipertensivos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Quimioterapia Combinada , Indanos/administração & dosagem , Indanos/farmacologia , Indanos/toxicidade , Masculino , Propionatos/administração & dosagem , Propionatos/farmacologia , Propionatos/toxicidade , Piridinas/toxicidade , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia , Tetrazóis/toxicidade , Tiazepinas/toxicidade , Valina/administração & dosagem , Valina/análogos & derivados , Valina/farmacologia , Valina/toxicidade , ValsartanaRESUMO
OBJECTIVES: Infections caused by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are associated with high rates of vancomycin treatment failure. Telavancin is a bactericidal lipoglycopeptide active in vitro against Gram-positive pathogens including hVISA and vancomycin-intermediate S. aureus (VISA). This study characterizes the microbiological activity of telavancin against vancomycin-susceptible S. aureus (VSSA), hVISA and VISA strains. METHODS: Reference strains of VSSA, hVISA and VISA were assessed for potential telavancin heteroresistance by population analysis. In addition, the efficacies of telavancin (40 mg/kg subcutaneously every 12 h for 4 days) and vancomycin (110 mg/kg subcutaneously every 12 h for 8 days) were compared in a neutropenic murine model (immunocompromised female non-Swiss albino mice) of bacteraemia caused by hVISA strain Mu3. Blood and spleen bacterial titres were quantified from cohorts of mice euthanized pre-treatment and at 24 h intervals post-treatment for 8 days. RESULTS: Telavancin was active against all strains of S. aureus tested, with MIC values < or =0.5 mg/L. Population analyses revealed no evidence of subpopulations with reduced susceptibility to telavancin. In the murine bacteraemia model of hVISA infection, all animals were bacteraemic pre-treatment and mortality was 100% within 16-24 h post-infection in untreated animals. Treatment with telavancin was associated with lower spleen bacterial titres, lower rates of bacteraemia and lower overall mortality than treatment with vancomycin. CONCLUSIONS: These in vitro and pre-clinical in vivo studies demonstrate that telavancin has the potential to be efficacious in infections caused by hVISA.
Assuntos
Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Resistência a Vancomicina , Aminoglicosídeos/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Sangue/microbiologia , Modelos Animais de Doenças , Feminino , Lipoglicopeptídeos , Camundongos , Testes de Sensibilidade Microbiana , Baço/microbiologia , Resultado do TratamentoRESUMO
OBJECTIVES: The aim of the study was to compare the efficacies of telavancin and vancomycin against glycopeptide-intermediate Staphylococcus aureus (GISA) and heterogeneous vancomycin-intermediate S. aureus (hVISA) in a neutropenic murine bacteraemia model. METHODS: Immunocompromised mice (female non-Swiss albino, 18-30 g) were inoculated intraperitoneally with 10(7) cfu/mL of GISA (strain HIP-5836 or Mu50) or hVISA (strain Mu3). Infected mice received a subcutaneous dose of telavancin (40 mg/kg) or vancomycin (110 mg/kg) at 4 and 16 h post-inoculation. Control animals received a subcutaneous dose of vehicle at 4 h post-inoculation only. Blood and spleen bacterial titres were quantified in drug-treated mice at 16, 28 and 52 h post-inoculation. RESULTS: Telavancin was 8-fold more potent than vancomycin against HIP-5836 (MIC 1 versus 8 mg/L), 16-fold more potent against Mu50 (MIC 0.5 versus 8 mg/L) and 8-fold more potent against Mu3 (MIC 0.25 versus 2 mg/L). Telavancin produced significant (P < 0.05) and sustained reductions in blood and spleen titres from pre-treatment levels in mice infected with HIP-5836, Mu50 or Mu3. Vancomycin lowered blood and spleen HIP-5836 counts transiently, but did not lower blood or spleen Mu50 or Mu3 counts significantly at any timepoint. Reductions in blood and spleen HIP-5836 and Mu3 titres and in spleen Mu50 titres at 52 h post-inoculation were significantly greater with telavancin than vancomycin (P < 0.05). CONCLUSIONS: Telavancin was more efficacious than vancomycin in clearing infections caused by GISA strains HIP-5836 and Mu50 and hVISA strain Mu3 in a neutropenic mouse bacteraemia model. Further evaluation of telavancin for GISA and hVISA bacteraemia is warranted.
Assuntos
Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Farmacorresistência Bacteriana , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Aminoglicosídeos/administração & dosagem , Animais , Antibacterianos/farmacologia , Bacteriemia/microbiologia , Sangue/microbiologia , Contagem de Colônia Microbiana , Feminino , Glicopeptídeos/farmacologia , Lipoglicopeptídeos , Camundongos , Baço/microbiologia , Infecções Estafilocócicas/microbiologia , Resultado do Tratamento , Vancomicina/administração & dosagem , Vancomicina/uso terapêuticoRESUMO
Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.
RESUMO
OBJECTIVES: To assess the efficacy of telavancin, a rapidly bactericidal lipoglycopeptide, and three comparator agents in a murine model of pneumonia induced by methicillin-susceptible Staphylococcus aureus (MSSA). METHODS: Female Bagg inbred albino c-strain (BALB/c) mice were rendered neutropenic and infected by intranasal inoculation (50 microL) of 10(7) cfu of S. aureus ATCC 29213. Infected mice were then allocated to one of five treatment arms: subcutaneous (sc) telavancin 40 mg/kg every 12 h, sc nafcillin 40 mg/kg every 4 h, sc vancomycin 110 mg/kg every 12 h, intravenous linezolid 80 mg/kg every 12 h or no drug (control group). Test compounds were studied under low and high pre-treatment titre conditions by initiating drug treatment at 4 and 8 h post-inoculation, respectively. Drug doses were calculated to simulate human exposures (area under the curve or t > MIC) at therapeutic doses. Lungs were harvested and homogenized 24 and 48 h after inoculation to determine the bacterial titre. RESULTS: At 48 h post-inoculation in the low and high pre-treatment titre groups, respectively, telavancin produced greater reductions (from pre-treatment values) in bacterial burden (-4.3 and -3.2 log(10) cfu/g) than nafcillin (-1.3 and -1.8 log(10) cfu/g), vancomycin (-2.9 and -2.2 log(10) cfu/g) and linezolid (-0.4 and +0.3 log(10) cfu/g). CONCLUSIONS: These findings support the potential clinical utility of telavancin in the treatment of MSSA pneumonia.
Assuntos
Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Resistência a Meticilina/efeitos dos fármacos , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Animais , Antibacterianos/farmacologia , Feminino , Lipoglicopeptídeos , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Estafilocócica/microbiologia , Staphylococcus aureus/patogenicidadeRESUMO
Muscarinic receptor antagonists form the mainstay of the therapeutic options for airway, bladder, and gastrointestinal smooth muscle disorders. Both M(2) and M(3) muscarinic receptors are involved in mediating smooth muscle contractility, although the relative functional contribution of each subtype, especially in the disease state, is unclear. Because the potency and selectivity of compounds for a given receptor in an in vivo setting can be dissimilar to that observed in an in vitro system, we developed an in vivo assay to simultaneously determine the absolute potency and selectivity of muscarinic receptor antagonists at M(2) and M(3) receptors using the pithed rat. Methacholine (MCh)-induced bradycardia and depressor responses were used as surrogate functional endpoints for M(2) and M(3) receptor activation, respectively. The influence of the muscarinic antagonists, tolterodine, oxybutynin, darifenacin, Ro 320-6206, solifenacin, or tiotropium on the MCh-induced responses were studied. The estimated DR(10) values (dose producing a tenfold shift in the MCh curve) of tolterodine, oxybutynin, darifenacin, Ro 320-6206, solifenacin, and tiotropium for the M(2) muscarinic receptor-mediated bradycardia were 0.22, 1.18, approximately 2.6, 0.025, 0.40, and 0.0026 mg/kg, respectively, and 0.14, 0.18, 0.11, 3.0, 0.18, and 0.0017 mg/kg, respectively, for the M(3) muscarinic receptor-mediated depressor response. In a separate set of experiments, a single intravenous dose of tiotropium was administered before a MCh curve at 1, 3, 6, or 9 h to determine if tiotropium exhibited time-dependent selectivity for the M(3) receptor as has been reported from in vitro studies. The results indicate a slight preference of tiotropium for the M(3) receptor at later time points. The pithed rat assay may serve useful for elucidating the functional contribution of M(2) and M(3) receptors to the in vivo pharmacological effects of antagonists in disease animal models.
Assuntos
Modelos Animais de Doenças , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M2/efeitos dos fármacos , Receptor Muscarínico M3/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/induzido quimicamente , Bradicardia/metabolismo , Relação Dose-Resposta a Droga , Feminino , Infusões Intravenosas , Cloreto de Metacolina , Antagonistas Muscarínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/metabolismoRESUMO
The design, synthesis and antibacterial activity of novel glycopeptide/beta-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The antibiotics 8a-f displayed remarkable potency against a wide range of Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). Compound 8e demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and initial evidence supports a multivalent mechanism of action for this important new class of antibiotic.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Antibacterianos/química , Antibacterianos/classificação , Parede Celular/efeitos dos fármacos , Desenho de Fármacos , Glicopeptídeos/síntese química , Glicopeptídeos/química , Glicopeptídeos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , beta-Lactamas/síntese química , beta-Lactamas/química , beta-Lactamas/farmacologiaRESUMO
Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Cefalosporinas/síntese química , Cefalosporinas/farmacologia , Descoberta de Drogas/métodos , Glicopeptídeos/síntese química , Glicopeptídeos/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/farmacologia , Animais , Antibacterianos/química , Cefalosporinas/química , Dimerização , Desenho de Fármacos , Feminino , Glicopeptídeos/química , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , beta-Lactamas/químicaRESUMO
Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM 2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin-mediated antagonism of acetylcholine (ACh)-evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM3 receptor and produces potent and long-lasting antagonism of mAChR-mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once-daily dosed inhaled bronchodilator in COPD patients.
Assuntos
Benzamidas/farmacologia , Brônquios/fisiologia , Carbamatos/farmacologia , Antagonistas Muscarínicos/farmacologia , Proteínas Recombinantes/metabolismo , Traqueia/fisiologia , Administração por Inalação , Animais , Brônquios/efeitos dos fármacos , Cobaias , Humanos , Nebulizadores e Vaporizadores , Ratos , Traqueia/efeitos dos fármacosRESUMO
Muscarinic receptor antagonists (antimuscarinics) serve as the cornerstone in the pharmacological management of overactive bladder (OAB) by relieving the symptoms of urgency, frequency and incontinence. These drugs operate primarily by antagonizing post-junctional excitatory muscarinic receptors (M(2)/M(3)) in the detrusor. The combination of pharmacological and gene knockout studies has greatly advanced our understanding of the functional role of muscarinic receptors in the bladder. M(3) receptors produce direct smooth muscle contraction by a mechanism that relies on entry of extracellular calcium through L-type channels and activation of a rho kinase. M(2) receptors, which predominate in number, appear to facilitate M(3)-mediated contractions. M(2) receptors can also produce bladder contractions indirectly by reversing cAMP-dependent beta-adrenoceptor-mediated relaxation, although the physiological role of beta-adrenoceptors in detrusor relaxation is controversial. Emerging evidence suggests that muscarinic receptors in the urothelium/suburothelium can modulate the release of certain factors, which in turn may affect bladder function at the efferent or afferent axis. Currently, oxybutynin, tolterodine, darifenacin, solifenacin and trospium are the five major antimuscarinics approved for the treatment of OAB. Comparative clinical studies have shown that oxybutynin and solifenacin may be marginally more effective than tolterodine, although the latter seems to be better tolerated. Pharmacokinetic-pharmacodynamic analyses using plasma concentrations of 'total drug' indicate that, at therapeutic doses, the clinical efficacy of darifenacin and solifenacin may be driven primarily by selective M(3) receptor occupation, whereas the pharmacodynamic effects of pan-selective molecules (such as tolterodine, trospium) may potentially involve multiple receptors, including M(2) and M(3). Furthermore, high M(3) receptor occupation is the likely explanation for the greater propensity of darifenacin and oxybutynin to cause dry mouth and/or constipation. Although the recently introduced drugs represent a significant improvement over older drugs, especially with respect to the convenience of dosing schedule, their overall efficacy and tolerability profile is still less than optimal and patient persistence with therapy is low. Recent advances in basic research have not yet offered a clear discovery path for improving the therapeutic index of antimuscarinic molecules. There is still an unmet need for an antimuscarinic medicine with superior clinical effectiveness that can translate into better persistence on therapy.
Assuntos
Receptores Muscarínicos/metabolismo , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária/metabolismo , Animais , Humanos , Camundongos , Camundongos Knockout , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Cooperação do Paciente , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/metabolismo , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/genética , Resultado do Tratamento , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária Hiperativa/tratamento farmacológicoRESUMO
Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the pharmacological activity of their metabolites and discuss how active metabolites may contribute to their efficacy and tolerability in vivo. Except for trospium, and perhaps solifenacin, all of the above drugs form active metabolites, and their presence and activity need to be taken into consideration when elucidating relationships between pharmacokinetics and pharmacodynamics of these drugs. Moreover, the ratios between parent compounds and metabolites may differ depending on genotype of the metabolizing enzymes, concomitant medication, and/or drug formulation. Differential generation of active metabolites of darifenacin or tolterodine are unlikely to influence the overall clinical profile of these drugs in a major way because the active metabolites exhibit a similar pharmacological profile as the parent compound. In contrast, metabolites of oxybutynin and propiverine may behave quantitatively or even qualitatively differently from their parent compounds and this may have an impact on the overall clinical profile of these drugs. We conclude that more comprehensive studies of drug metabolites are required for an improved understanding of their clinical effects.
Assuntos
Antagonistas Muscarínicos/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/uso terapêutico , Benzilatos/metabolismo , Benzilatos/uso terapêutico , Benzofuranos/metabolismo , Benzofuranos/uso terapêutico , Cresóis/metabolismo , Cresóis/uso terapêutico , Humanos , Ácidos Mandélicos/metabolismo , Ácidos Mandélicos/uso terapêutico , Antagonistas Muscarínicos/metabolismo , Nortropanos/metabolismo , Nortropanos/uso terapêutico , Parassimpatolíticos/metabolismo , Parassimpatolíticos/uso terapêutico , Fenilpropanolamina/metabolismo , Fenilpropanolamina/uso terapêutico , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Quinuclidinas/metabolismo , Quinuclidinas/uso terapêutico , Succinato de Solifenacina , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/uso terapêutico , Tartarato de TolterodinaRESUMO
Bladder dysfunction is common in the general population (Stewart et al. 2010) and even more so among patients seeing a physician for any reason (Goepel et al. 2002). It often manifests as lower urinary tract symptoms (LUTS), a term originally coined to describe voiding and storage symptoms in men with benign prostatic hyperplasia (BPH) but now more universally used to describe any type of voiding and storage symptoms in both sexes. Studies into possible causes of urinary bladder dysfunction have long focused on detrusor smooth muscle cells (Turner and Brading 1999). More recently, it became clear that several other types of cells and organs contribute to regulating detrusor smooth muscle function. These include the urothelium (Andersson and McCloskey 2014; Michel 2015), afferent nerves (Michel and Igawa 2015; Yoshimura et al. 2014b), and the central and autonomic nervous systems (Fowler and Griffiths 2010; Yoshimura et al. 2014a). Alterations in any of these may at least partly be responsible for detrusor dysfunction and, accordingly, be potential targets for the treatment of bladder dysfunction. As highlighted by an article in this issue of Naunyn-Schmiedeberg's Archives of Pharmacology (Bayrak et al. 2015), there is an additional suspect, the bladder vasculature. This article will discuss the currently available experimental and clinical evidence for a role of the vasculature in causing bladder dysfunction, and how existing and emerging treatments may modulate bladder function by acting on blood vessels. Due to a similarity in concept, data on prostate perfusion will also be discussed to some extent.
Assuntos
Aterosclerose/complicações , Fluxo Sanguíneo Regional/efeitos dos fármacos , Bexiga Urinária/irrigação sanguínea , Animais , Humanos , Doenças da Bexiga Urinária/etiologia , Doenças da Bexiga Urinária/terapia , Vasodilatadores/uso terapêuticoRESUMO
Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both muscarinic antagonist and ß2 agonist activities, through modification of the linker motif, to achieve 24 h duration of action in a guinea pig bronchoprotection model. Concomitantly we targeted high lung selectivities, low systemic exposures and identified crystalline forms suitable for inhalation devices. This article culminates with the discovery of our first clinical candidate 12f (TD-5959, GSK961081, batefenterol). In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Carbamatos/uso terapêutico , Descoberta de Drogas , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animais , Células CHO , Carbamatos/administração & dosagem , Carbamatos/química , Carbamatos/farmacocinética , Cricetulus , Cobaias , Células HEK293 , Humanos , Modelos Moleculares , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/química , Quinolonas/farmacocinéticaRESUMO
Antimuscarinic drugs have been the mainstay in the treatment of overactive bladder (OAB) for over two decades. An ideal antimuscarinic medicine is one that can normalize bladder function without interfering with parasympathetic regulation of other organs. Currently, extended-release formulations of tolterodine (tolterodine-ER) and oxybutynin (oxybutynin-ER and oxybutynin-TDS) serve as the cornerstone in the pharmacotherapy of OAB. Although these products represent a significant improvement over older agents, especially with respect to convenience of dosing schedule, their tolerability concerns and modest efficacy make them less than ideal therapies. Advances in our understanding of muscarinic receptor pharmacology have raised optimism in our ability to widen the therapeutic index and increase the efficacy of antimuscarinics by selectively targeting one or more of the five muscarinic subtypes. A structurally diverse group of molecules, having varying receptor-selectivity profiles (non-selective, M3 selective, M2 selective, M2 sparing and M5 sparing), are in development for OAB. Results of clinical trials with these drugs must be awaited before their therapeutic value can be accurately judged.
Assuntos
Antagonistas Muscarínicos/uso terapêutico , Doenças da Bexiga Urinária/tratamento farmacológico , Transtornos Urinários/tratamento farmacológico , Animais , Desenho de Fármacos , Humanos , Antagonistas Muscarínicos/química , Receptores Muscarínicos/classificação , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Doenças da Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinaria Neurogênica/fisiopatologia , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/fisiopatologia , Transtornos Urinários/fisiopatologiaRESUMO
Telavancin is a parenteral lipoglycopeptide antibiotic with a dual mechanism of action contributing to bactericidal activity against multidrug-resistant Gram-positive pathogens. It has been approved for the treatment of complicated skin and skin structure infections due to susceptible Gram-positive bacteria and hospital-acquired/ventilator-associated bacterial pneumonia due to Staphylococcus aureus when other alternatives are unsuitable. Telavancin has been demonstrated to be efficacious in multiple animal models of soft tissue, cardiac, systemic, lung, bone, brain and device-associated infections involving clinically relevant Gram-positive pathogens, including methicillin-resistant S. aureus, glycopeptide-intermediate S. aureus, heterogeneous vancomycin-intermediate S. aureus and daptomycin non-susceptible methicillin-resistant S. aureus. The AUC0-24h/MIC ratio is the primary pharmacodynamically-linked pharmacokinetic parameter. The preclinical data for telavancin supports further investigative clinical evaluation of its efficacy in additional serious infections caused by susceptible Gram-positive pathogens.