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1.
J Pharmacol Exp Ther ; 387(2): 214-225, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37643795

RESUMO

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a deficiency in functional C1 esterase inhibitor, a serpin family protein that blocks the activity of plasma kallikrein. Insufficient inhibition of plasma kallikrein results in the overproduction of bradykinin, a vasoactive inflammatory mediator that produces both pain and unpredictable swelling during HAE attacks, with potentially life-threatening consequences. We describe the generation of STAR-0215, a humanized IgG1 antibody with a long circulating half-life (t1/2) that potently inhibits plasma kallikrein activity, with a >1000-fold lower affinity for prekallikrein and no measurable inhibitory activity against other serine proteases. The high specificity and inhibitory effect of STAR-0215 is demonstrated through a unique allosteric mechanism involving N-terminal catalytic domain binding, destabilization of the activation domain, and reversion of the active site to the inactive zymogen state. The YTE (M252Y/S254T/T256E) modified fragment crystallizable (Fc) domain of STAR-0215 enhances pH-dependent neonatal Fc receptor binding, resulting in a prolonged t1/2 in vivo (∼34 days in cynomolgus monkeys) compared with antibodies without this modification. A single subcutaneous dose of STAR-0215 (≥100 mg) was predicted to be active in patients for 3 months or longer, based on simulations using a minimal physiologically based pharmacokinetic model. These data indicate that STAR-0215, a highly potent and specific antibody against plasma kallikrein with extended t1/2, is a potential agent for long-term preventative HAE therapy administered every 3 months or less frequently. SIGNIFICANCE STATEMENT: STAR-0215 is a YTE-modified immunoglobulin G1 monoclonal antibody with a novel binding mechanism that specifically and potently inhibits the enzymatic activity of plasma kallikrein and prevents the generation of bradykinin. It has been designed to be a long-lasting prophylactic treatment to prevent attacks of HAE and to decrease the burden of disease and the burden of treatment for people with HAE.

2.
Regul Toxicol Pharmacol ; 73(1): 401-12, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26232705

RESUMO

Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays.


Assuntos
Carcinógenos/toxicidade , Inibidores Enzimáticos/efeitos adversos , Neoplasias/induzido quimicamente , Pirrolidinas/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Testes de Carcinogenicidade/métodos , Carcinógenos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Feminino , Doença de Gaucher/tratamento farmacológico , Masculino , Camundongos , Testes de Mutagenicidade/métodos , Pirrolidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
3.
Reprod Toxicol ; 21(2): 197-207, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16183248

RESUMO

WelChol (colesevelam hydrochloride), a bile acid sequestrant for the treatment of hypercholesterolemia, was evaluated for adverse effects on reproduction and fetal development using standard preclinical tests. During gestation, Sprague-Dawley rats used in the developmental toxicity study received feed, feed/control article or feed plus 300, 1,000 or 3,000 mg/kg/day colesevelam whereas rats in the pre- and postnatal toxicity study received vehicle or 100, 300 or 1,000 mg/kg/day colesevelam via gavage. New Zealand white rabbits received control or 100, 500 or 1,000 mg/kg/day colesevelam via gavage. No deaths, premature deliveries or gross pathologic lesions were observed up to gestation day (GD) 20 for rats and GD 28 for rabbits. No significant differences in the number of pregnant animals, average litter size, percentage of viable fetuses, fetal body weights, number of corpora lutea, fetal viability, or gross malformations were observed versus controls. Pre- and postnatal effects were assessed in pregnant rats receiving 100, 300 or 1,000 mg/kg/day colesevelam from GD 6 to postpartum day 22. Gestation, parturition and lactation in F(0) generation dams were similar between treatment and control groups. Colesevelam did not affect physical or neurological development or induce gross pathological changes in F(1) generation rats. Colesevelam does not produce developmental toxicity in rats or rabbits, nor does it exhibit pre- or postnatal toxicity in rats at the tested doses.


Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/toxicidade , Feto/efeitos dos fármacos , Alilamina/toxicidade , Animais , Animais Recém-Nascidos , Peso ao Nascer/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cloridrato de Colesevelam , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Feto/patologia , Crescimento/efeitos dos fármacos , Masculino , Comportamento Materno/efeitos dos fármacos , Gravidez , Coelhos , Ratos , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos
4.
J Ren Nutr ; 16(3): 248-52, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16825030

RESUMO

Sevelamer, a nonabsorbed, calcium- and metal-free dietary phosphate binder, consists of a polyallylamine polymer backbone with a cationic charge that shows a high capacity for binding anionically charged compounds such as phosphate. The currently licensed form of sevelamer, Renagel, exists as sevelamer hydrochloride, which disassociates in the acidic environment of the stomach and early gastrointestinal tract, exchanging the chloride ions attached to the polymer backbone for phosphate ions. The resulting absorption of these chloride ions has been reported to be accompanied by a reduction in serum levels of bicarbonate in some patients. To minimize the possibility of this effect, a new salt form of sevelamer has been developed in which carbonate replaces the chloride counter ion, thereby providing a source of buffer. The majority of phosphate binders exist only in tablet form and are dosed three times per day with meals. Genzyme has developed sevelamer carbonate in tablet form and also as a powder formulation that can be taken after mixing with water. This allows for an alternate and potentially more palatable way of dosing. Preliminary data exist suggesting that once daily dosing with sevelamer hydrochloride tablets provides similar phosphate control to three times daily dosing. By providing novel dosage forms and regimens for sevelamer-based phosphate binders, Genzyme will be providing patients and health care providers additional choices and flexibility in controlling phosphorus levels in chronic kidney disease. This should translate to increased compliance and improved rates of phosphate control.


Assuntos
Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Fosfatos/sangue , Poliaminas/administração & dosagem , Diálise Renal , Animais , Bicarbonatos/sangue , Cloretos/química , Cães , Humanos , Cinética , Cooperação do Paciente , Fosfatos/química , Fósforo/sangue , Poliaminas/química , Poliaminas/farmacocinética , Sevelamer
5.
Ann N Y Acad Sci ; 1054: 492-4, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16339704

RESUMO

Deferitrin, a novel, orally available iron chelator, is in the early stage of clinical development for the treatment of chronic iron overload due to transfusional therapy. Preclinical pharmacology studies demonstrate iron excretion largely by the fecal route. Initial clinical studies have shown deferitrin to be well absorbed. Further clinical studies are ongoing to determine the efficiency and safety of deferitrin.


Assuntos
Ácidos Carboxílicos/uso terapêutico , Terapia por Quelação , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Tiazóis/uso terapêutico , Talassemia beta/tratamento farmacológico , Administração Oral , Animais , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/toxicidade , Ensaios Clínicos Fase I como Assunto , Cães , Avaliação Pré-Clínica de Medicamentos , Fezes/química , Humanos , Ferro/metabolismo , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacocinética , Quelantes de Ferro/toxicidade , Sobrecarga de Ferro/etiologia , Macaca fascicularis , Estrutura Molecular , Ratos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Tiazóis/toxicidade , Talassemia beta/complicações
6.
Int J Toxicol ; 23(6): 357-67, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15764491

RESUMO

Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.


Assuntos
Alilamina/análogos & derivados , Alilamina/toxicidade , Antagonistas Colinérgicos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Administração Oral , Alilamina/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Antagonistas Colinérgicos/administração & dosagem , Cloridrato de Colesevelam , Dieta , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Motilidade dos Espermatozoides/efeitos dos fármacos , Motilidade dos Espermatozoides/fisiologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Testes de Toxicidade
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