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1.
J Transl Med ; 22(1): 292, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504345

RESUMO

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.


Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais , Instabilidade de Microssatélites , Síndromes Neoplásicas Hereditárias , Humanos , Animais , Macaca mulatta/genética , Macaca mulatta/metabolismo , Proteína 1 Homóloga a MutL/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Neoplasias Colorretais/patologia , Metilação de DNA/genética , Epigênese Genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , DNA/metabolismo , Reparo de Erro de Pareamento de DNA/genética
2.
Int J Radiat Oncol Biol Phys ; 119(1): 208-218, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37972714

RESUMO

PURPOSE: Long-term survivors of brain irradiation can experience irreversible injury and cognitive impairment. T1-weighted and diffusion tensor magnetic resonance imaging (MRI) are used to evaluate brain volume and white matter (WM) microstructure in neurodevelopmental and neurodegenerative conditions. The goal of this study was to evaluate the long-term effects of single-dose total-body irradiation (TBI) or TBI with 5% partial-body sparing on brain volumetrics and WM integrity in macaques. METHODS AND MATERIALS: We used MRI scans from a cohort of male rhesus macaques (age range, 3.6-22.8 years) to compare global and regional brain volumes and WM diffusion in survivors of TBI (T1-weighted, n = 137; diffusion tensor imaging, n = 121; dose range, 3.5-10 Gy) with unirradiated controls (T1-weighted, n = 48; diffusion tensor imaging, n = 38). RESULTS: In all regions of interest, radiation affected age-related changes in fractional anisotropy, which tended to increase across age in both groups but to a lesser extent in the irradiated group (interaction P < .01). Depending on the region of interest, mean diffusivity decreased or remained the same across age in unirradiated animals, whereas it increased or did not change in irradiated animals. The increases in mean diffusivity were driven by changes in radial diffusivity, which followed similar trends across age. Axial diffusivity did not differ by irradiation status. Age-related changes in relative volumes in controls reflected normal trends in humans, with increasing WM and decreasing gray matter until middle age. Cerebrospinal fluid (CSF) volume did not differ across age in controls. WM volume was lower and CSF volume was higher in young irradiated macaques. WM volume was similar between groups, and CSF volume lower in older irradiated macaques. Gray matter volume was unaffected by radiation. CONCLUSIONS: TBI results in delayed WM expansion and long-term disruption of WM integrity. Diffusion changes suggest that myelin injury in WM is a hallmark of late-delayed radiation-induced brain injury.


Assuntos
Substância Branca , Humanos , Pessoa de Meia-Idade , Animais , Masculino , Idoso , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Substância Branca/patologia , Imagem de Tensor de Difusão/métodos , Macaca mulatta , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos
3.
Neuroimage ; 285: 120491, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38070839

RESUMO

Cerebrovascular reactivity (CVR) is a measure of cerebral small vessels' ability to respond to changes in metabolic demand and can be quantified using magnetic resonance imaging (MRI) coupled with a vasoactive stimulus. Reduced CVR occurs with neurodegeneration and is associated with cognitive decline. While commonly measured in humans, few studies have evaluated CVR in animal models. Herein, we describe methods to induce hypercapnia in rhesus macaques (Macaca mulatta) under gas anesthesia to measure cerebral blood flow (CBF) and CVR using pseudo-continuous arterial spin labeling (pCASL). Fifteen (13 M, 2 F) adult rhesus macaques underwent pCASL imaging that included a baseline segment (100% O2) followed by a hypercapnic challenge (isoflurane anesthesia with 5% CO2, 95% O2 mixed gas). Relative hypercapnia was defined as an end-tidal CO2 (ETCO2) ≥5 mmHg above baseline ETCO2. The mean ETCO2 during the baseline segment of the pCASL sequence was 34 mmHg (range: 23-48 mmHg). During this segment, mean whole-brain CBF was 51.48 ml/100g/min (range: 21.47-77.23 ml/100g/min). Significant increases (p<0.0001) in ETCO2 were seen upon inspiration of the mixed gas (5% CO2, 95% O2). The mean increase in ETCO2 was 8.5 mmHg and corresponded with a mean increase in CBF of 37.1% (p<0.0001). The mean CVR measured was 4.3%/mmHg. No anesthetic complications occurred as a result of the CO2 challenge. Our methods were effective at inducing a state of relative hypercapnia that corresponds with a detectable increase in whole brain CBF using pCASL MRI. Using these methods, a CO2 challenge can be performed in conjunction with pCASL imaging to evaluate CBF and CVR in rhesus macaques. The measured CVR in rhesus macaques is comparable to human CVR highlighting the translational utility of rhesus macaques in neuroscience research. These methods present a feasible means to measure CVR in comparative models of neurodegeneration and cerebrovascular dysfunction.


Assuntos
Dióxido de Carbono , Hipercapnia , Adulto , Animais , Humanos , Macaca mulatta , Hipercapnia/diagnóstico por imagem , Marcadores de Spin , Imageamento por Ressonância Magnética/métodos , Circulação Cerebrovascular/fisiologia
4.
Clin Pharmacokinet ; 62(8): 1169-1182, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37365436

RESUMO

BACKGROUND AND OBJECTIVE: Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20-50 pg/mL range to minimize these undesirable effects. METHODS: This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6. RESULTS: Median E2 24 h average concentrations with the relugolix plus E2/NETA group (N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) (N = 25). There were 86.4% of participants in the relugolix plus E2/NETA group who had E2 average concentrations exceeding 20 pg/mL, the threshold expected to minimize bone mineral density loss, compared with 21.1% in the relugolix-alone group. Both treatments were generally safe and well tolerated. CONCLUSIONS: Relugolix 40 mg in combination with E2 1 mg and NETA 0.5 mg provided systemic E2 concentrations within a range expected to minimize the risk of undesirable effects of hypoestrogenism associated with the administration of relugolix alone. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier no. NCT04978688. Trial registration date: 27 July, 2021; retrospectively registered.


Assuntos
Estradiol , Noretindrona , Feminino , Humanos , Noretindrona/efeitos adversos , Acetato de Noretindrona , Estradiol/uso terapêutico , Compostos de Fenilureia
5.
Int J Radiat Oncol Biol Phys ; 113(3): 661-674, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35361520

RESUMO

PURPOSE: Cancer is a severe delayed effect of acute radiation exposure. Total-body irradiation has been associated with an increased risk of solid cancer and leukemia in Japanese atomic bomb survivors, and secondary malignancies, such as sarcoma, are a serious consequence of cancer radiation therapy. The radiation late effects cohort (RLEC) of rhesus macaques (Macaca mulatta) is a unique resource of more than 200 animals for studying the long-term consequences of total-body irradiation in an animal model that closely resembles humans at the genetic and physiologic levels. METHODS AND MATERIALS: Using clinical records, clinical imaging, histopathology, and immunohistochemistry, this retrospective study characterized the incidence of neoplasia in the RLEC. RESULTS: Since 2007, 61 neoplasms in 44 of 239 irradiated animals were documented (18.4% of the irradiated population). Only 1 neoplasm was diagnosed among the 51 nonirradiated controls of the RLEC (2.0%). The most common malignancies in the RLEC were sarcomas (38.3% of diagnoses), which are rare neoplasms in nonirradiated macaques. The most common sarcomas included malignant nerve sheath tumors and malignant glomus tumors. Carcinomas were less common (19.7% of diagnoses), and consisted primarily of renal cell and hepatocellular carcinomas. Neoplasia occurred in most major body systems, with the skin and subcutis being the most common site (40%). RNA analysis showed similarities in transcriptional profiles between RLEC and human malignant nerve sheath tumors. CONCLUSIONS: This study indicates that total-body irradiation is associated with an increased incidence of neoplasia years following irradiation, at more than double the incidence described in aging, nonirradiated animals, and promotes tumor histotypes that are rarely observed in nonirradiated, aging rhesus macaques.


Assuntos
Neoplasias de Bainha Neural , Lesões por Radiação , Sarcoma , Animais , Humanos , Incidência , Macaca mulatta , Estudos Retrospectivos , Sarcoma/epidemiologia , Sarcoma/etiologia , Sarcoma/veterinária
6.
Pharmacol Res Perspect ; 9(3): e00777, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34014033

RESUMO

The melanocortin-4 receptor (MC4R) antagonistic peptide TCMCB07 was developed for the treatment of cachexia. The objectives of this study were to examine pharmacokinetics and safety of TCMCB07 administered subcutaneously to healthy dogs. Dogs were treated with high- (2.25 mg kg-1 ) (n = 5) and low-dose TCMCB07 (0.75 mg kg-1 ) (n = 5) once daily for 28 days with a 14-day washout period between groups. Histamine levels, complete blood count, chemistry panel, blood pressure, 24-hour Holter recording, and pharmacokinetic parameters were monitored in the high-dose group. Physical examination changes were limited to weight gain and darkening of the coat color. There was no elevation of plasma histamine within 24 hours of injection but there was a significant elevation of plasma histamine across time. An approximately doubled eosinophil count and an approximately 25% increase, and then 25% decrease back to pre-treatment plasma phosphorous were also found, although both remained within the reference interval. Serial blood pressure and 24-hour Holter monitors revealed no clinically relevant changes. A difference was found in the AUC between dosing groups and a significant effect of dose, time, and interaction was noted for Vd . Low-dose TCMCB07 had a Cmax of 2.1 ug ml-1 at day 28, compared to high-dose TCMCB07 which had a Cmax 3.6 ug ml-1 at day 28. Once-daily subcutaneous administration of TCMCB07 was well-tolerated for up to 28 days in dogs when administered at doses one and three times (0.75 mg kg-1 and 2.25 mg kg-1 ) the predicted therapeutic dose and pharmacokinetic parameters are described. SIGNIFICANCE STATEMENT: Melanocortin-4 receptor (MC4R) antagonistic peptide TCMCB07 is safe at both low and high doses in dogs. Therapy was tolerated well as determined by physical examination, clinical pathology, and cardiovascular parameters; darkening of the coat was noted with treatment and resolved with discontinuation. Pharmacokinetics are described and further study in the naturally occurring canine model is warranted.


Assuntos
Peptídeos Cíclicos/farmacocinética , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Arritmias Cardíacas/induzido quimicamente , Pressão Arterial/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cães , Feminino , Histamina/sangue , Injeções Subcutâneas , Masculino , Peptídeos Cíclicos/efeitos adversos , Fósforo/sangue
7.
Radiat Res ; 190(1): 63-71, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29738279

RESUMO

Stereotactic body radiation therapy (SBRT) is associated with an increased risk of vertebral compression fracture. While bone is typically considered radiation resistant, fractures frequently occur within the first year of SBRT. The goal of this work was to determine if rapid deterioration of bone occurs in vertebrae after irradiation. Sixteen male rhesus macaque non-human primates (NHPs) were analyzed after whole-chest irradiation to a midplane dose of 10 Gy. Ages at the time of exposure varied from 45-134 months. Computed tomography (CT) scans were taken 2 months prior to irradiation and 2, 4, 6 and 8 months postirradiation for all animals. Bone mineral density (BMD) and cortical thickness were calculated longitudinally for thoracic (T) 9, lumbar (L) 2 and L4 vertebral bodies; gross morphology and histopathology were assessed per vertebra. Greater mortality (related to pulmonary toxicity) was noted in NHPs <50 months at time of exposure versus NHPs >50 months ( P = 0.03). Animals older than 50 months at time of exposure lost cortical thickness in T9 by 2 months postirradiation ( P = 0.0009), which persisted to 8 months. In contrast, no loss of cortical thickness was observed in vertebrae out-of-field (L2 and L4). Loss of BMD was observed by 4 months postirradiation for T9, and 6 months postirradiation for L2 and L4 ( P < 0.01). For NHPs younger than 50 months at time of exposure, both cortical thickness and BMD decreased in T9, L2 and L4 by 2 months postirradiation ( P < 0.05). Regions that exhibited the greatest degree of cortical thinning as determined from CT scans also exhibited increased porosity histologically. Rapid loss of cortical thickness was observed after high-dose chest irradiation in NHPs. Younger age at time of exposure was associated with increased pneumonitis-related mortality, as well as greater loss of both BMD and cortical thickness at both in- and out-of-field vertebrae. Older NHPs exhibited rapid loss of BMD and cortical thickness from in-field vertebrae, but only loss of BMD in out-of-field vertebrae. Bone is sensitive to high-dose radiation, and rapid loss of bone structure and density increases the risk of fractures.


Assuntos
Osso Cortical/anatomia & histologia , Osso Cortical/efeitos da radiação , Animais , Densidade Óssea/efeitos da radiação , Osso Cortical/diagnóstico por imagem , Osso Cortical/fisiologia , Vértebras Lombares/anatomia & histologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiologia , Vértebras Lombares/efeitos da radiação , Macaca mulatta , Masculino , Tamanho do Órgão/efeitos da radiação , Vértebras Torácicas/anatomia & histologia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/fisiologia , Vértebras Torácicas/efeitos da radiação , Tomografia Computadorizada por Raios X
8.
J Hepatol ; 66(4): 787-797, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27965156

RESUMO

BACKGROUND & AIMS: Acetaminophen (APAP)-induced liver injury is coupled with activation of the blood coagulation cascade and fibrin(ogen) accumulation within APAP-injured livers of experimental mice. We sought to define the role of fibrin(ogen) deposition in APAP-induced liver injury and repair. METHODS: Wild-type, fibrinogen-deficient mice, mutant mice with fibrin(ogen) incapable of binding leukocyte αMß2 integrin (Fibγ390-396A mice) and matrix metalloproteinase 12 (Mmp12)-deficient mice were fasted, injected with 300mg/kg APAP i.p. and evaluated at a range of time-points. Plasma and liver tissue were analyzed. Rescue of Fibγ390-396A mice was carried out with exogenous Mmp12. To examine the effect of the allosteric leukocyte integrin αMß2 activator leukadherin-1 (LA-1), APAP-treated mice were injected with LA-1. RESULTS: In wild-type mice, APAP overdose increased intrahepatic levels of high molecular weight cross-linked fibrin(ogen). Anticoagulation reduced early APAP hepatotoxicity (6h), but increased hepatic injury at 24h, implying a protective role for coagulation at the onset of repair. Complete fibrin(ogen) deficiency delayed liver repair after APAP overdose, evidenced by a reduction of proliferating hepatocytes (24h) and unresolved hepatocellular necrosis (48 and 72h). Fibγ390-396A mice had decreased hepatocyte proliferation and increased multiple indices of liver injury, suggesting a mechanism related to fibrin(ogen)-leukocyte interaction. Induction of Mmp12, was dramatically reduced in APAP-treated Fibγ390-396A mice. Mice lacking Mmp12 displayed exacerbated APAP-induced liver injury, resembling Fibγ390-396A mice. In contrast, administration of LA-1 enhanced hepatic Mmp12 mRNA and reduced necrosis in APAP-treated mice. Further, administration of recombinant Mmp12 protein to APAP-treated Fibγ390-396A mice restored hepatocyte proliferation. CONCLUSIONS: These studies highlight a novel pathway of liver repair after APAP overdose, mediated by fibrin(ogen)-αMß2 integrin engagement, and demonstrate a protective role of Mmp12 expression after APAP overdose. LAY SUMMARY: Acetaminophen overdose leads to activation of coagulation cascade and deposition of high molecular weight cross-linked fibrin(ogen) species in the liver. Fibrin(ogen) is required for stimulating liver repair after acetaminophen overdose. The mechanism whereby fibrin(ogen) drives liver repair after acetaminophen overdose requires engagement of leukocyte αMß2 integrin and subsequent induction of matrix metalloproteinase 12.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fibrina/metabolismo , Fibrinogênio/metabolismo , Antígeno de Macrófago 1/metabolismo , Metaloproteinase 12 da Matriz/metabolismo , Acetaminofen/toxicidade , Afibrinogenemia/genética , Afibrinogenemia/metabolismo , Animais , Antitrombinas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dabigatrana/farmacologia , Feminino , Fibrina/deficiência , Fibrina/genética , Fibrinogênio/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinase 12 da Matriz/deficiência , Metaloproteinase 12 da Matriz/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes
9.
Lancet Haematol ; 2(10): e417-26, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26686043

RESUMO

BACKGROUND: Patients with myelodysplastic syndrome or acute myeloid leukaemia who are thrombocytopenic and unable to receive disease-modifying therapy have few treatment options. Platelet transfusions provide transient benefit and are limited by alloimmunisation. Eltrombopag, an oral thrombopoietin receptor agonist, increases platelet counts and has preclinical antileukaemic activity. We aimed to assess the safety and tolerability of eltrombopag for the treatment of thrombocytopenia in adult patients with advanced myelodysplastic syndrome, secondary acute myeloid leukaemia after myelodysplastic syndrome, or de-novo acute myeloid leukaemia. METHODS: We did this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial at 37 centres in ten countries in Europe, east Asia, and the Americas. Patients aged 18 years or older who had relapsed or refractory disease or were ineligible for standard treatments; had platelet counts of less than 30 × 10(9) platelets per L; had 10-50% bone-marrow blasts; or were platelet transfusion dependent were randomly assigned (2:1), via a telephone-based interactive voice-response system (GlaxoSmithKline Registration and Medication Ordering System) with a permuted-block randomisation schedule (block size of three), to receive once-daily eltrombopag or matching placebo dose adjusted from 50 mg to a maximum dose of 300 mg. Randomisation was stratified by presence of poor-prognosis (complex) karyotype (presence of at least three abnormalities, or chromosome 7 abnormalities, vs absence) and bone-marrow blast count (<20% vs ≥20%). Patients and study personnel were masked to treatment allocation. The primary endpoint was safety and tolerability, including adverse events, non-haematological laboratory grade 3-4 toxic effects, and changes in bone-marrow blast counts from baseline. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00903422. FINDINGS: Between May 14, 2009, and May 9, 2013, we randomly assigned 98 patients to receive either eltrombopag (n=64) or placebo (n=34). 63 (98%) patients in the eltrombopag group and 32 (94%) patients in the placebo group had adverse events. The most common adverse events were pyrexia (27 [42%] vs 11 [32%]), nausea (20 [31%] vs 7 [21%]), diarrhoea (19 [30%] vs 6 [18%]), fatigue (16 [25%] vs 6 [18%]), decreased appetite (15 [23%] vs 5 [15%]), and pneumonia (14 [22%] vs 8 [24%]). Drug-related adverse events of grade 3 or higher were reported in six (9%) patients in the eltrombopag group and four (12%) patients in the placebo group. Increases in the proportion of peripheral blasts did not differ significantly between groups. Haemorrhage of grade 3 or higher was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. 21 (33%) patients receiving eltrombopag and 16 (47%) patients receiving placebo died while on treatment. No deaths in patients receiving eltrombopag and two deaths in patients receiving placebo were regarded as treatment related. Post-baseline bone-marrow examinations were done in 40 (63%) patients in the eltrombopag group and 17 (50%) patients in the placebo group. The most common reason for no examination was death before the scheduled 3 month assessment. There were no differences between median bone-marrow blast counts or proportions of peripheral blasts between groups. INTERPRETATION: Eltrombopag doses up to 300 mg daily had an acceptable safety profile in patients with advanced myelodysplastic syndrome or acute myeloid leukaemia. The role of eltrombopag in these patients warrants further investigation. FUNDING: GlaxoSmithKline.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Pirazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Receptores de Trombopoetina/agonistas , Trombocitopenia/complicações , Resultado do Tratamento
10.
Cancer Med ; 4(1): 16-26, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25165041

RESUMO

Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 10(9) /L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days -5 to -1 and days 2-6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 10(9) /L, respectively. Mean platelet nadirs across cycles 2-6 were 115 × 10(9) /L and 143 × 10(9) /L for eltrombopag-treated patients versus 53 × 10(9) /L and 103 × 10(9) /L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3-6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Benzoatos/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Hidrazinas/farmacocinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Contagem de Plaquetas , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Resultado do Tratamento , Gencitabina
11.
Clin Pharmacol Drug Dev ; 3(2): 93-100, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27128454

RESUMO

Casopitant is a potent and selective neurokinin-1 receptor antagonist formerly under development for a number of indications, including the treatment of chemotherapy-induced nausea and vomiting. This study was an open-label, randomized, multi-center, two-period crossover casopitant-cyclophosphamide interaction study. Subjects were cancer patients receiving cyclophosphamide based chemotherapy. The objectives of the study were to assess the effect of 3-day, repeat-dose, 150 mg oral casopitant on the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (white blood cell count) of single-dose IV cyclophosphamide. PK data from 14 evaluable subjects showed the geometric least-squares mean ratios (90% CI) for cyclophosphamide and the metabolite 4-hydroxycyclophosphamide AUC (with:without casopitant) were 1.03 (0.975, 1.09) and 0.948 (0.835, 1.08), respectively. Administration of casopitant was well tolerated and did not impact the safety profile of the treatment regimen. Casopitant did not affect the expected bone marrow toxicity of cyclophosphamide. Co-administration of 150 mg oral casopitant with single-dose IV cyclophosphamide did not appear to result in a clinically relevant change in cyclophosphamide or 4-hydroxycyclophosphamide exposure or safety.

12.
Biol Blood Marrow Transplant ; 19(12): 1745-52, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24120380

RESUMO

Stem cell transplantation can be associated with significant periods of thrombocytopenia, necessitating platelet transfusions and contributing to the risk of bleeding. Thrombopoietin receptor agonists have been shown to enhance platelet counts in other clinical settings, and so a phase 1 clinical trial was conducted to assess the safety, pharmacokinetics, and maximum tolerated dose of once-daily eltrombopag in patients undergoing stem cell transplantation with conditioning regimens containing total body irradiation ≥400 cGy. Eltrombopag was examined at dosage levels of 75, 150, 225, and 300 mg given orally once daily for 27 days, starting at 24 to 48 hours post-transplantation. Pharmacokinetic sampling was performed over a 24-hour period after the first dose of eltrombopag, as well as during the second week of treatment (steady-state). Nineteen patients were enrolled, 15 of whom completed protocol treatments. Three patients completed each dose level up to 225 mg, and 6 completed treatment at the highest dose of 300 mg. Four patients were replaced because drug compliance was <75% of planned doses. No dose-limiting toxicities were observed in this heterogeneous post-transplantation patient population. Common adverse events were related to standard stem cell transplantation. One episode of pulmonary embolus occurred 9 days after discontinuation of eltrombopag, and the only other thromboembolic episode was a grade 2 catheter-related clot. We conclude that up to 27 days of once-daily dosing of eltrombopag after stem cell transplantation is well tolerated.


Assuntos
Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Hidrazinas/efeitos adversos , Hidrazinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/métodos , Adulto , Idoso , Benzoatos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/radioterapia , Neoplasias Hematológicas/cirurgia , Neoplasias Hematológicas/terapia , Humanos , Hidrazinas/farmacocinética , Masculino , Pessoa de Meia-Idade , Pirazóis/farmacocinética , Transplante de Células-Tronco/efeitos adversos , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Irradiação Corporal Total/efeitos adversos , Adulto Jovem
13.
Cancer Chemother Pharmacol ; 71(6): 1507-20, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23564375

RESUMO

PURPOSE: Eltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen. METHODS: Pharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10 days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated. RESULTS: The PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50 years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy. CONCLUSIONS: Simulations indicated that eltrombopag administered 5 days before and 5 days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzoatos , Hidrazinas , Modelos Biológicos , Neoplasias/tratamento farmacológico , Pirazóis , Receptores de Trombopoetina/agonistas , Trombocitopenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Benzoatos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/farmacocinética , Hidrazinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Adulto Jovem
14.
Cancer Chemother Pharmacol ; 69(3): 733-41, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22020315

RESUMO

PURPOSE: GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295. PATIENTS AND METHODS: Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m(2). GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks. RESULTS: A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m(2). Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m(2) and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9-11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m(2) dose level. CONCLUSIONS: The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.


Assuntos
Antimitóticos/administração & dosagem , Antimitóticos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Sarcosina/análogos & derivados , Adulto , Idoso , Antimitóticos/efeitos adversos , Antimitóticos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Sarcosina/administração & dosagem , Sarcosina/efeitos adversos , Sarcosina/farmacocinética , Sarcosina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
15.
Cancer Chemother Pharmacol ; 67(4): 783-90, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20556613

RESUMO

PURPOSE: The neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel. METHODS: Fourteen cancer patients were enrolled in this phase 1, open-label, randomized, two-period crossover study. Intravenous (i.v.) docetaxel was coadministered with oral ondansetron and dexamethasone with (Regimen B) or without (Regimen A) 150 mg single-dose oral casopitant. RESULTS: The geometric least-squares mean Regimen B: Regimen A ratios (90% confidence interval) for docetaxel maximum plasma concentration and area under the concentration-time curve from time 0 extrapolated to infinity were 0.97 (0.83, 1.12) and 1.06 (0.94, 1.19), respectively. Coadministration of casopitant and docetaxel was well tolerated, with adverse event profiles and absolute neutrophil count nadirs similar for both treatments. CONCLUSIONS: C(max) and AUC of docetaxel were similar when given as monotherapy or when given in combination with casopitant. Likewise, absolute neutrophil count nadirs were similar for docetaxel alone or docetaxel with casopitant.


Assuntos
Antieméticos/farmacologia , Antineoplásicos/farmacocinética , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Taxoides/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Antieméticos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Dexametasona/farmacologia , Docetaxel , Quimioterapia Combinada , Feminino , Humanos , Análise dos Mínimos Quadrados , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Neutrófilos/metabolismo , Ondansetron/farmacologia , Piperazinas/efeitos adversos , Piperidinas/efeitos adversos , Taxoides/efeitos adversos , Taxoides/uso terapêutico
16.
Anesthesiology ; 113(1): 74-82, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20526194

RESUMO

BACKGROUND: In recent years, there has been an increased interest in using a multimodal approach with combined agents to treat postoperative nausea and vomiting. This study evaluated whether the addition of an oral dose of the neurokinin-1 receptor antagonist casopitant improved the antiemetic efficacy of an intravenous dose of ondansetron hydrochloride. METHODS: The authors enrolled 702 premenopausal or perimenopausal, nonsmoking, female patients aged 18-55 yr with a history of postoperative nausea and vomiting and/or motion sickness undergoing a laparoscopic or laparotomic gynecologic surgical procedure or laparoscopic cholecystectomy with general anesthesia. Subjects were randomized to one of five treatment arms: standard ondansetron 4 mg with casopitant at 0, 50, 100, or 150 mg, or 0 mg ondansetron with casopitant at 150 mg (the latter arm was considered an exploratory study group and was included in the safety analysis but not in the efficacy analysis). RESULTS: A significantly greater proportion of patients in all of the active casopitant plus ondansetron groups achieved a complete response (i.e., no vomiting, retching, rescue medication, or premature withdrawal) during the first 24 h postoperatively versus those in the ondansetron-alone group (59-62% vs. 40%, respectively; P = 0.0006). All active doses seemed to be well tolerated; headache, dizziness, and constipation were the most frequently reported adverse events. CONCLUSIONS: Compared with ondansetron alone, the casopitant and ondansetron combination results in superior emesis prevention during the first 24 h postoperatively in female patients with known risk factors for postoperative nausea and vomiting.


Assuntos
Antieméticos/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1 , Ondansetron/administração & dosagem , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Náusea e Vômito Pós-Operatórios/prevenção & controle , Administração Oral , Adolescente , Adulto , Anestesia Geral/métodos , Antieméticos/efeitos adversos , Colecistectomia Laparoscópica , Constipação Intestinal/induzido quimicamente , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Procedimentos Cirúrgicos em Ginecologia , Cefaleia/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Piperidinas/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
17.
Eur J Clin Pharmacol ; 66(1): 77-86, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19798490

RESUMO

PURPOSE: Until recently, ondansetron was approved for the prevention of nausea and vomiting only in patients older than 2 years. However, as the use of ondansetron in patients younger than 2 years had been documented, characterization of ondansetron pharmacokinetics in this younger pediatric age group was warranted. METHODS: The pharmacokinetics of intravenously administered ondansetron were evaluated in oncology and surgical patients aged 1-48 months. Pooled data from 124 patients, including 745 pharmacokinetic samples, were analyzed using nonlinear mixed-effects modeling. RESULTS: Ondansetron pharmacokinetics were described by a two-compartment model. Body-size effects on ondansetron disposition were accounted for via standard allometric relationships, normalized to 10.4 kg. A maturation process with a half-life of approximately 4 months was incorporated to describe a decrease in clearance (CL) in infants. Clearance [95% confidence interval (CI)] for a typical patient was 1.53 (1.34-1.78) L/h/kg(0.75) with an interindividual variability of 56.8%. Ondansetron CL was reduced by 31%, 53%, and 76% for the typical 6-month-, 3-month-, and 1-month-old patient, respectively. Simulations showed that an ondansetron dose of 0.1 mg/kg in children younger than 6 months produced exposure similar to a 0.15-mg/kg dose in older children. CONCLUSIONS: The population pharmacokinetic analysis of ondansetron allows for characterization of individual patients based on body weight and age. It is recommended that patients younger than 4 months receiving ondansetron be closely monitored.


Assuntos
Anestesia Geral/efeitos adversos , Antieméticos/farmacocinética , Antineoplásicos/efeitos adversos , Náusea/induzido quimicamente , Ondansetron/farmacocinética , Antagonistas da Serotonina/farmacocinética , Antieméticos/administração & dosagem , Antieméticos/uso terapêutico , Pré-Escolar , Simulação por Computador , Feminino , Humanos , Lactente , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Náusea/prevenção & controle , Ondansetron/administração & dosagem , Ondansetron/uso terapêutico , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/uso terapêutico
18.
Support Care Cancer ; 17(9): 1177-85, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19205755

RESUMO

INTRODUCTION: Pharmacokinetic interactions between casopitant (a substrate and weak to moderate inhibitor of CYP3A), dexamethasone (a substrate and weak inducer of CYP3A), and ondansetron (a mixed CYP substrate) were evaluated in a two-part, three-period, single-sequence study in two groups of healthy subjects. MATERIALS AND METHODS: Part 1: subjects received oral casopitant (regimen A); oral dexamethasone and IV ondansetron (regimen B); and oral casopitant, a reduced dose of oral dexamethasone, and IV ondansetron (regimen C). Part 2: subjects received oral casopitant (regimen D); IV dexamethasone and oral ondansetron (regimen E); and oral casopitant, IV dexamethasone, and oral ondansetron (regimen F). Each regimen was separated by 14 days. RESULTS: Casopitant AUC in regimen C was increased 28% on day 1 but decreased 34% on day 3 compared to casopitant alone in regimen A. When given with casopitant and ondansetron in regimen C, dexamethasone AUC was 17% lower on day 1, but similar on day 3, compared to regimen B (representing dose-normalized increases in exposure of 39% and 108%, respectively). Ondansetron exposure was equivalent in regimens B and C. Casopitant AUC in regimen F was similar to regimen D on days 1 and 3. Dexamethasone AUC increased 21% when given with oral casopitant and oral ondansetron (regimen F compared to regimen E). Ondansetron exposure was equivalent in regimens E and F. CONCLUSION: When repeat-dose oral dexamethasone is to be coadministered with oral casopitant, a reduction in dexamethasone dose may be considered; however, no change in casopitant dose is required. Ondansetron exposure was not affected by coadministration with casopitant.


Assuntos
Antieméticos/farmacocinética , Dexametasona/farmacocinética , Ondansetron/farmacocinética , Piperazinas/farmacologia , Piperidinas/farmacologia , Adolescente , Adulto , Antieméticos/administração & dosagem , Antieméticos/farmacologia , Dexametasona/administração & dosagem , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/prevenção & controle , Antagonistas dos Receptores de Neurocinina-1 , Ondansetron/administração & dosagem , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Vômito/induzido quimicamente , Vômito/prevenção & controle , Adulto Jovem
19.
Support Care Cancer ; 17(9): 1187-93, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19205754

RESUMO

OBJECTIVE: The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron. MATERIALS AND METHODS: In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort. RESULTS: The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%). CONCLUSION: None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.


Assuntos
Antieméticos/farmacocinética , Granisetron/farmacocinética , Indóis/farmacocinética , Piperazinas/farmacologia , Piperidinas/farmacologia , Quinolizinas/farmacocinética , Adolescente , Adulto , Antieméticos/administração & dosagem , Antieméticos/farmacologia , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Granisetron/administração & dosagem , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/prevenção & controle , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Quinolizinas/administração & dosagem , Vômito/induzido quimicamente , Vômito/prevenção & controle , Adulto Jovem
20.
Drug Metab Dispos ; 34(4): 556-62, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16204465

RESUMO

Multidrug resistance-associated protein (Mrp) 2-deficient transport-deficient (TR(-)) rats, together with their transport-competent Wistar counterparts (wild type), have been used to examine the contribution of Mrp2 to drug disposition. However, little is known about potential variation in expression of other transport proteins between TR(-) and wild-type rats or whether these differences are tissue-specific. Sections of liver, kidney, brain, duodenum, jejunum, ileum, and colon were obtained from male TR(-) and wild-type Wistar rats. Samples were homogenized in protease inhibitor cocktail and ultracentrifuged at 100,000g for 30 min to obtain membrane fractions. Mrp2, Mrp3, Mrp4, P-glycoprotein, sodium-dependent taurocholate cotransporting polypeptide, organic anion transporting polypeptides 1a1 and 1a4, bile salt export pump, breast cancer resistance protein, ileal bile acid transporter, UDP-glucuronosyl transferase (UGT1a), glyceraldehyde-3-phosphate dehydrogenase, and beta-actin protein expression were determined by Western blot. Mrp3 was significantly up-regulated in the liver ( approximately 6-fold) and kidney ( approximately 3.5-fold) of TR(-) rats compared with wild-type controls. Likewise, the expression of UGT1a enzymes was increased in the liver and kidney of TR(-) rats by approximately 3.5- and approximately 5.5-fold, respectively. Interestingly, Mrp3 expression was down-regulated in the small intestine of TR(-) rats, but expression was similar to wild type in the colon. Mrp4 was expressed to varying extents along the intestine. Expression of some transport proteins and UGT1a enzymes differ significantly between TR(-) and wild-type rats. Therefore, altered drug disposition in TR(-) rats must be interpreted cautiously because up- or down-regulation of other transport proteins may play compensatory roles in the presence of Mrp2 deficiency.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Transporte/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Encéfalo/metabolismo , Proteínas de Transporte/genética , Glucuronosiltransferase/metabolismo , Mucosa Intestinal/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ratos , Ratos Mutantes , Ratos Wistar
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