RESUMO
AIMS: To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus. METHODS: This parallel-group, open-label, dose-escalation study examined the PK and GD of basal insulin LY2605541 after single and multiple-dose administration. Fixed doses of LY2605541 (0.33-1.00 U/kg) were given once-daily (QD) for 14 days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14. RESULTS: PK steady state was achieved within 7-10 days and the peak-to-trough fluctuation was <2, translating to a nearly 'peakless' glucose infusion rate at steady state and with a duration of action of at least 24 h. Across dose levels t1/2 ranged from 44.7 to 75.5 h (~2-3 days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100 mg/dl across dose levels. Within-patient variability was <14 and <26% for the area under the concentration versus time curve (AUC) of the 8-point blood glucose profile and fasting blood glucose, respectively. The nocturnal glucose control between 03:00 and 09:00 hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event. CONCLUSIONS: In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.
Assuntos
Glicemia/efeitos dos fármacos , Peptídeo C/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/efeitos dos fármacos , Hipoglicemiantes/farmacocinética , Insulina Lispro/farmacocinética , Polietilenoglicóis/farmacocinética , Adolescente , Adulto , Idoso , Área Sob a Curva , Glicemia/metabolismo , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Esquema de Medicação , Feminino , Técnica Clamp de Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Insulina Lispro/administração & dosagem , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Resultado do TratamentoRESUMO
AIMS: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety. METHODS: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52 weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30 weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52 weeks) were analysed. RESULTS: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. CONCLUSIONS: Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Glucagon/farmacologia , Hipoglicemiantes/imunologia , Peptídeos/imunologia , Peçonhas/imunologia , Adulto , Idoso , Anticorpos Anti-Idiotípicos/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/imunologia , Reações Cruzadas/efeitos dos fármacos , Reações Cruzadas/imunologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Exenatida , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Peçonhas/administração & dosagemRESUMO
OBJECTIVES: This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty. BACKGROUND: Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes. METHODS: Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/liter TRAP were assessed. RESULTS: Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 mumol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/liter TRAP-induced aggregation. CONCLUSIONS: After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.
Assuntos
Difosfato de Adenosina/farmacologia , Anticorpos Monoclonais/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Oligopeptídeos/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas , Receptores de Superfície Celular/antagonistas & inibidores , Abciximab , Adulto , Idoso , Angioplastia Coronária com Balão , Anticorpos Monoclonais/farmacologia , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Integrina alfa2 , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidoresRESUMO
Using the C57BL/6/EL4 tumor model, studies were carried out to demonstrate the feasibility of administering Adriamycin (ADM) in therapeutic doses and schedules such that the host antitumor defenses would not be suppressed and in some cases might be stimulated by treatment. ADM treatment caused prolongation of survival and, in general, either stimulated host cytolytic activities above untreated control levels or had no effect. These effects by ADM were observed with the ADM-sensitive parent EL4 line as well as with an ADM-resistant subline, indicating that the effects did not result entirely from direct antitumor activity. The cytolytic activities examined were those of cytolytic T-lymphocytes, lymphokine-activated killer cells, and splenic and peritoneal macrophages. All activities were assessed against the syngeneic EL4 target line. The information obtained in this investigation provides a rational basis for the future development of curative protocols with ADM plus biological response modifiers, which would depend on a functional immune system for optimum efficacy and would also exploit synergistic immunomodulating effects of the agents used in combination.
Assuntos
Doxorrubicina/farmacologia , Neoplasias Experimentais/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologiaRESUMO
The investigational chemotherapeutic drug flavone acetic acid (FAA) acts as an immunomodulator by augmenting natural killer activity in both humans and rodents after in vivo administration. The accumulated data derived from a series of experiments also demonstrates that FAA synergizes with interleukin 2 (IL-2) for the treatment of murine renal cancer. The immunomodulatory and immunotherapeutic effects of FAA are strictly dose dependent with doses of FAA greater than 150 mg/kg effectively synergizing with IL-2, and doses less than 150 mg/kg exhibiting very little therapeutic effect. The antitumor and immunomodulatory effects of FAA are more pronounced in vivo than in vitro. Collectively, these results suggested that cytokines induced by FAA may contribute to these effects, and that the induction of such cytokines may also be very dose dependent. Studies were therefore initiated to investigate whether the in vivo administration of FAA would alter the expression of cytokine mRNA in leukocytes. Splenic leukocytes or liver nonparenchymal cells from untreated and FAA-treated mice were used as a source of RNA for Northern blot analysis. Interferon alpha and interferon gamma mRNA in the spleen was upregulated within 1.5 h after FAA administration, with peak induction occurring by about 2 h. An upregulation of tumor necrosis factor alpha mRNA was detected in the spleen by 0.5-1 h after treatment with peak induction occurring by 1-1.5 h. Induction of tumor necrosis factor alpha mRNA was also detected in hepatic nonparenchymal cells. No up-regulation of splenic mRNA for tumor necrosis factor beta, IL-1 alpha or beta, or IL-2 was detected after FAA administration. IFN and TNF activities were detectable in the serum by bioassay immediately following the appearance of mRNA in FAA mice. The observed up-regulation by FAA of cytokine mRNA and the corresponding serum protein was strictly dose dependent with substantial induction of both mRNA and proteins occurring only at FAA doses greater than or equal to 150 mg/kg, a dose range also shown to be the minimum required for immunomodulatory and immunotherapeutic effects. In summary, these results demonstrate that FAA acts as a potent inducer of at least three cytokines in vivo, and suggest that the immunomodulatory and immunotherapeutic effects of FAA may be partially mediated by these induced cytokines.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Fatores Biológicos/genética , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Animais , Linhagem Celular , Citocinas , DNA/genética , Relação Dose-Resposta a Droga , Flavonoides/uso terapêutico , Interferon Tipo I/genética , Interleucina-2/uso terapêutico , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hibridização de Ácido Nucleico , RNA/genética , Proteínas Recombinantes/uso terapêutico , Fator de Necrose Tumoral alfa/genéticaRESUMO
The EL4 lymphoma in C57BL/6 mice was used as a model to examine the effect of progressive tumor growth on a variety of cell mediated cytolytic effector functions which have been shown in other systems to have antitumor potential. The functions examined were those of cytolytic T-lymphocyte, lymphokine activated killer cells, natural killer cells, and tumoricidal macrophage (MO). The kinetics of each function displayed a unique pattern as a consequence of tumor growth, but all were inhibited in animals bearing large tumors (late tumor bearers). In cell mixing experiments it was shown that spleen cells from individual late tumor bearers were suppressive for cytotoxic T-lymphocytes, lymphokine activated killer cells, and splenic MO but not peritoneal MO or splenic natural killer cells. The suppression was nonspecific and was mediated primarily by nonadherent cells and/or their soluble products. Suppression appeared to be mediated, in part, by tumor cells in the spleen since the degree of suppressor activity associated with a particular spleen cell preparation correlated with the number of tumor cells present. Furthermore, the direct addition of viable ascites EL4 cells to response cultures or assays had similar suppressive effects as late TBM spleen cells, i.e., inhibited cytotoxic T-lymphocytes, lymphokine activated killer cells, and splenic MO but had no effect on natural killer cells or peritoneal MO. The mechanism of suppression by ascites EL4 was not determined but it was mediated by viable cells only and not due to contaminating viruses or other microorganisms.
Assuntos
Neoplasias Experimentais/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Feminino , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Linfoma/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Fatores Supressores Imunológicos/fisiologia , Linfócitos T Reguladores/imunologiaRESUMO
Tumor necrosis factor (TNF)-sensitive (LM) and -insensitive (P815) target cell lines were used to examine the role of TNF in both the activation and lytic phases of macrophage-mediated lysis. LM cells were lysed spontaneously by thioglycolate-elicited macrophages in an 18-h assay (media or activating agents added with targets) or 36-h assay (macrophages cultured with media or activating agents for 18 h, washed, and targets added for a subsequent 18 h). In contrast, P815 cells were lysed only in the 36-h assay by macrophages exposed to appropriate activation signals. Using antibody to murine TNF, it was shown that lysis of LM cells but not P815 cells was TNF mediated. The addition of lipopolysaccharide (LPS) to the 18-h assay resulted in augmented LM killing. This was probably due to the fact that LPS stimulates macrophages to produce TNF. Conversely, when macrophages were pretreated with LPS for 18 h, washed, and assessed for lytic activity during the subsequent 18 h, lysis of LM cells was reduced relative to the endogenous level. Although macrophage lysis of P815 was not mediated by TNF, the addition of TNF to macrophage activation cultures facilitated LPS triggering of cytolytic activity against P815. Similarly, the addition of TNF to the activation cultures partially prevented the LPS-induced reduction in macrophage-mediated LM cell lysis. Taken together, these data suggest that TNF may act as an autocrine signal during macrophage activation, in addition to being directly lytic to a select number of sensitive target cell lines.
Assuntos
Ativação de Macrófagos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Polimixina B/farmacologiaRESUMO
Adriamycin (ADM) has been shown to modulate a variety of host immune responses. Although the mechanism(s) for this activity is not known, it has been suggested that free radical compounds generated during ADM metabolism act at the membrane level to alter immune cell function. The generation of free radical metabolites is also believed to be responsible for the cardiotoxic potential of ADM. 5-Iminodaunorubicin (IDM) is a non-cardiotoxic anthracycline analog which undergoes minimal free radical metabolism. In the present study the immunomodulatory capacity of IDM was compared to that of ADM. It was found that IDM and ADM had similar augmenting effects on cytolytic T-cell activity and that this correlated with: (1) Fc-dependent phagocytosis by spleen cells; and (2) the elimination or inhibition of an adherent regulatory cell in the spleen. The natural killer response was either unaffected (fresh NK) or slightly inhibited (cultured NK) by both drugs except moderate dose IDM which resulted in marked augmentation of cultured NK.