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1.
Diabetes Obes Metab ; 26(1): 215-223, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37814517

RESUMO

AIMS: To compare the time to hyperglycaemia recovery after ultra rapid lispro (URLi; Lyumjev®) versus Humalog in a randomized, double-blind crossover study. MATERIALS AND METHODS: Thirty-two adults with type 1 diabetes on continuous subcutaneous insulin infusion participated in two periods: each period included hyperglycaemia induced by a missed mealtime bolus (day 1) and by suspension of basal insulin delivery (day 2). When hyperglycaemia [plasma glucose (PG) >240 mg/dl] occurred, a correction bolus of URLi or Humalog was given and time to hyperglycaemia recovery (PG = 140 mg/dl), pharmacokinetics and glucodynamics were compared. RESULTS: Following a missed mealtime bolus, URLi significantly reduced maximum PG (-13 mg/dl; p = .02), and produced numerically more rapid decline in PG (23 mg/dl/h; p = .07), and faster recovery from hyperglycaemia (-23 min; p = .1) versus Humalog, although differences were not significant. Following basal suspension, URLi significantly reduced maximum PG (-6 mg/dl; p = .02), and produced faster PG decline (24 mg/dl/h; p < .001) and faster recovery from hyperglycaemia (-16 min; p < .01) vs. Humalog. Following a correction bolus of URLi, accelerated insulin lispro absorption was observed versus Humalog: early 50% tmax was reduced by 6 or 12 min, and AUC0-15min was increased 2.5- or 4.3-fold after correction boluses by subcutaneous infusion (day 1) or injection (day 2), respectively (all p < .001). CONCLUSIONS: During episodes of hyperglycaemia commonly experienced in people with type 1 diabetes, URLi provided a faster recovery versus Humalog from a missed mealtime bolus or during basal insulin suspension. URLi shows significant acceleration of insulin absorption versus Humalog when boluses are administered by subcutaneous infusion or injection.


Assuntos
Diabetes Mellitus Tipo 1 , Hiperglicemia , Adulto , Humanos , Insulina Lispro/uso terapêutico , Insulina Lispro/farmacocinética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes , Estudos Cross-Over , Insulina , Glicemia
2.
Diabetes Obes Metab ; 25(7): 1964-1972, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36974352

RESUMO

AIM: This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6-11 years), adolescents (12-17 years) and adults (18-64 years) with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: The study was a randomized, two-period, subject- and investigator-blind, crossover design in participants with T1D. Participants received a 0.2 U/kg bolus dose immediately before a liquid mixed meal tolerance test. Insulin lispro and glucose concentrations were measured. RESULTS: The study included 13 children, 14 adolescents and 15 adults. Consistently across the age groups, onset of appearance was 4-5 min faster, the early 50% tmax was reduced by 7-13 min, and exposure in the first 15 min was increased by 3.5-6.5-fold following URLi compared with Humalog (all p < .01). Exposure after 3 h was decreased by 37-58% (p = .02) and the duration was reduced by 56 min (p = .006) in children and 36 min (p = .022) in adolescents with URLi compared with Humalog. The maximum and overall exposure were similar between treatments. Postprandial glucose at 1 h was reduced by 42 mg/dl in children (p = .008), 19 mg/dl (p = .195) in adolescents and 34 mg/dl (p = .018) in adults following URLi versus Humalog. The glucose excursion during a 5-h test meal period was reduced by 16% in children and 9% in adolescents compared with Humalog. URLi was well tolerated in all age groups. CONCLUSIONS: URLi showed an accelerated insulin lispro absorption and greater postprandial glucose reduction compared with Humalog in children, adolescents and adults with T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Adulto , Adolescente , Criança , Humanos , Insulina Lispro/uso terapêutico , Insulina Lispro/farmacocinética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Glucose/uso terapêutico , Glicemia , Período Pós-Prandial , Estudos Cross-Over , Insulina
3.
Regul Toxicol Pharmacol ; 88: 56-65, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28526658

RESUMO

Basaglar®/Abasaglar® (Lilly insulin glargine [LY IGlar]) is a long-acting human insulin analogue drug product granted marketing authorisation as a biosimilar to Lantus® (Sanofi insulin glargine [SA IGlar]) by the European Medicines Agency. We assessed the similarity of LY IGlar to the reference drug product, European Union-sourced SA IGlar (EU-SA IGlar), using nonclinical in vitro and in vivo studies. No biologically relevant differences were observed for receptor binding affinity at either the insulin or insulin-like growth factor-1 (IGF-1) receptors, or in assays of functional or de novo lipogenic activity. The mitogenic potential of LY IGlar and EU-SA IGlar was similar when tested in both insulin- and IGF-1 receptor dominant cell systems. Repeated subcutaneous daily dosing of rats for 4 weeks with 0, 0.3, 1.0, or 2.0 mg/kg LY IGlar and EU-SA IGlar produced mortalities and clinical signs consistent with severe hypoglycaemia. Glucodynamic profiles of LY IGlar and EU-SA IGlar in satellite animals showed comparable dose-related hypoglycaemia. Severe hypoglycaemia was associated with axonal degeneration of the sciatic nerve; the incidence and severity were low and did not differ between LY IGlar and EU-SA IGlar. These results demonstrated no biologically relevant differences in toxicity between LY IGlar and EU-SA IGlar.


Assuntos
Medicamentos Biossimilares/toxicidade , Hipoglicemiantes/toxicidade , Insulina Glargina/toxicidade , Animais , Medicamentos Biossimilares/metabolismo , Aprovação de Drogas , União Europeia , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/metabolismo , Técnicas In Vitro , Insulina Glargina/metabolismo , Ratos , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo
4.
Clin Pharmacol Ther ; 115(5): 1152-1161, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38294091

RESUMO

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10-2,000 mg) or multiple ascending dose (MAD; dose range 100-1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21-65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5-3.5 hours, terminal half-life of 11.4-19.1 hours, and exhibited dose-dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL-17A levels within 12 hours of dosing. Four participants from the 400-mg (n = 1) and 1,000-mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post-last LY3509754 dose), consistent with drug-induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte-rich, moderate-to-severe lobular inflammation. We theorize that the DILI relates to an off-target effect rather than IL-17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.


Assuntos
Hepatite , Psoríase , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Interleucina-17 , Psoríase/tratamento farmacológico
5.
Clin Pharmacol Ther ; 113(6): 1185-1198, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36477720

RESUMO

Typically, therapeutic proteins (TPs) have a low risk for eliciting meaningful drug interactions (DIs). However, there are select instances where TP drug interactions (TP-DIs) of clinical concern can occur. This white paper discusses the various types of TP-DIs involving mechanisms such as changes in disease state, target-mediated drug disposition, neonatal Fc receptor (FcRn), or antidrug antibodies formation. The nature of TP drug interaction being investigated should determine whether the examination is conducted as a standalone TP-DI study in healthy participants, in patients, or assessed via population pharmacokinetic analysis. DIs involving antibody-drug conjugates are discussed briefly, but the primary focus here will be DIs involving cytokine modulation. Cytokine modulation can occur directly by certain TPs, or indirectly due to moderate to severe inflammation, infection, or injury. Disease states that have been shown to result in indirect disease-DIs that are clinically meaningful have been listed (i.e., typically a twofold change in the systemic exposure of a coadministered sensitive cytochrome P450 substrate drug). Type of disease and severity of inflammation should be the primary drivers for risk assessment for disease-DIs. While more clinical inflammatory marker data needs to be collected, the use of two or more clinical inflammatory markers (such as C-reactive protein, albumin, or interleukin 6) may help broadly categorize whether the predicted magnitude of inflammatory disease-DI risk is negligible, weak, or moderate to strong. Based on current knowledge, clinical DI studies are not necessary for all TPs, and should no longer be conducted in certain disease patient populations such as psoriasis, which do not have sufficient systemic inflammation to cause a meaningful indirect disease-DI.


Assuntos
Citocinas , Psoríase , Recém-Nascido , Humanos , Interações Medicamentosas , Citocinas/metabolismo , Desenvolvimento de Medicamentos , Psoríase/tratamento farmacológico , Inflamação
6.
Clin Ther ; 44(6): 836-847, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35577602

RESUMO

PURPOSE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site. METHODS: In this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration. FINDINGS: Total insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ∼65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was <1 minute, and the time to early half-maximal drug concentration occurred at ∼10 minutes across these three SC injection sites. Onset of insulin action occurred at ∼22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration. IMPLICATIONS: The pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. CLINICALTRIALS: gov identifier: NCT03232983.


Assuntos
Glicemia , Hipoglicemiantes , Estudos Cross-Over , Técnica Clamp de Glucose , Humanos , Injeções Subcutâneas , Insulina , Insulina Lispro/efeitos adversos
7.
Diabetes Ther ; 11(8): 1709-1720, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535742

RESUMO

INTRODUCTION: Ultra rapid lispro (URLi) is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. The aims of this study were to demonstrate the bioequivalence (BE) of a concentrated formulation (U200) of URLi to the U100 formulation of URLi after subcutaneous (SC) administration and to evaluate the glucodynamics (GD) of these formulations. METHODS: This phase 1, randomized, two-sequence, four-period, double-blind, replicate crossover study was conducted in 68 healthy subjects. At each dosing visit, subjects received a 15-U SC dose of either U100 URLi or U200 URLi followed by a 10-h euglycemic clamp procedure. Serum insulin lispro and blood glucose concentrations were measured, and the glucose infusion rate was continuously adjusted during the clamp to maintain the target blood glucose. RESULTS: Bioequivalence of U200 URLi relative to U100 URLi was demonstrated. The 90% confidence intervals (CIs) of the ratios of geometric least squares (LS) means for the maximum insulin concentration and total exposure were within the BE limits of 0.80-1.25. Additionally, the 90% CIs for the ratios of geometric LS means for maximum glucose infusion rate and total glucose infused were within the BE limits. The early 50% tmax occurred at approximately the same time for the U100 and U200 URLi formulations, and the insulin exposure within the first 15 min was similar for both formulations. The tolerability of the two URLi formulations was comparable. CONCLUSIONS: This study demonstrated that the U100 and U200 URLi formulations are bioequivalent. The accelerated insulin absorption observed for the U100 formulation was maintained with the U200 URLi formulation. Further, the GD were similar for both formulations, supporting the ability of individuals to transfer from U100 to U200 URLi in a 1:1 unit conversion. TRIAL REGISTRATION: NCT03616977.

8.
Clin Ther ; 42(9): 1762-1777.e4, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32900535

RESUMO

PURPOSE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects. METHODS: This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured. FINDINGS: Across all 3 doses, insulin lispro appeared in the serum 2-5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%-52% lower, and duration of exposure was 67-86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7-9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%-45%, and duration of action was reduced by 47-67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro. IMPLICATIONS: URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751.


Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Insulina Lispro/administração & dosagem , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Glucose/administração & dosagem , Técnica Clamp de Glucose , Humanos , Insulina Lispro/farmacocinética , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Adulto Jovem
9.
Clin Pharmacokinet ; 59(12): 1589-1599, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32468447

RESUMO

BACKGROUND: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39-41% lower, and exposure duration was reduced by 72-74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11-12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44-54% lower, and duration of action was reduced by 34-44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. CONCLUSION: In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemiantes/farmacocinética , Insulina Lispro/farmacocinética , Adulto , Idoso , Glicemia , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Clin Pharmacokinet ; 59(12): 1601-1610, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32468448

RESUMO

BACKGROUND AND OBJECTIVE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated. CONCLUSIONS: This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. CLINICALTRIALS. GOV IDENTIFIER: NCT03305822.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes/farmacocinética , Insulina Lispro/farmacocinética , Adulto , Idoso , Glicemia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
J Clin Pharmacol ; 58(7): 849-863, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29505093

RESUMO

The human inflammatory response can result in the alteration of drug clearance through effects on drug-metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)-mediated drug clearance and alter plasma protein binding. Also examined is how albumin, α-1-acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Citocinas , Interações Medicamentosas , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacos , Ligação Proteica
12.
Clin Transl Sci ; 11(1): 46-53, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28857461

RESUMO

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artralgia/tratamento farmacológico , Celecoxib/farmacologia , Compostos Orgânicos/farmacologia , Osteoartrite/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Artralgia/etiologia , Celecoxib/uso terapêutico , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Orgânicos/química , Osteoartrite/complicações , Placebos , Adulto Jovem
13.
Reprod Toxicol ; 48: 124-31, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24863471

RESUMO

Studies were conducted in New Zealand White rabbits to assess the seminal transfer, vaginal absorption, and placental transfer of a therapeutic monoclonal antibody (T-IgG4). T-IgG4 was administered by intravenous injection (IV) in males and by IV and intravaginal routes in females. Low levels of T-IgG4 were excreted into seminal plasma (100- to 370-fold lower than serum concentrations) and absorbed following vaginal dosing (three orders of magnitude lower than IV administration). On gestation day 29 (GD29), fetal serum T-IgG4 levels were 1.5-fold greater than maternal levels following IV dosing. The fetal T-IgG4 exposure ratio for seminal transfer vs. direct maternal IV dosing was estimated to be 1.3×10(-8). Applying human serum T-IgG4 exposure data to the model, the estimated human T-IgG4 serum concentration from seminal transfer was 3.07×10(-7)µg/mL, an exposure level at least 1000-fold lower than the T-IgG4-ligand dissociation constant (Kd) and at least seven orders of magnitude lower than the in vivo concentration producing 20% inhibition of the target (EC20). These data indicate that excretion of a T-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Feto/metabolismo , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Sêmen/metabolismo , Administração Intravaginal , Animais , Anticorpos Monoclonais/sangue , Feminino , Imunoglobulina G/sangue , Injeções Intravenosas , Masculino , Troca Materno-Fetal , Placenta/metabolismo , Gravidez , Coelhos , Vagina/metabolismo
15.
Bioorg Med Chem Lett ; 17(13): 3544-9, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17482463

RESUMO

Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.


Assuntos
Leiomioma/tratamento farmacológico , Ovário/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Estrogênios/sangue , Feminino , Humanos , Modelos Químicos , Ovário/metabolismo , Ratos , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/química , Software , Relação Estrutura-Atividade
16.
Toxicol Pathol ; 33(6): 711-9, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16263696

RESUMO

A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.


Assuntos
Glândulas Mamárias Animais/efeitos dos fármacos , Naftalenos/farmacologia , Piperidinas/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Antagonistas de Androgênios/farmacologia , Androgênios/sangue , Androgênios/fisiologia , Animais , Combinação de Medicamentos , Estradiol/sangue , Feminino , Flutamida/administração & dosagem , Flutamida/farmacologia , Hormônio Luteinizante/sangue , Masculino , Glândulas Mamárias Animais/patologia , Camundongos , Naftalenos/administração & dosagem , Naftalenos/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Ratos , Ratos Endogâmicos F344 , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Fatores Sexuais , Especificidade da Espécie , Virilismo/etiologia , Virilismo/patologia
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