RESUMO
BACKGROUND: The multikinase inhibitor sunitinib has enhanced the treatment of renal cell carcinoma and gastrointestinal stromal tumor through an improved clinical response with decreased systemic toxicities. However, sunitinib is frequently associated with dermatological adverse reactions. The physical and psychosocial impact of frequent dermatological toxicities can affect consistent antineoplastic therapy and quality of life. PATIENTS AND METHODS: Dermatological adverse reaction information was compiled from Pfizer Medical Information and from abstracts from the 2007 American Society of Clinical Oncology annual meeting, Prostate Cancer Symposium, and Gastrointestinal Cancers Symposium. Published clinical trials of sunitinib in MEDLINE, Cochrane Library, Cochrane Controlled Trials Register, and EMBASE Drugs and Pharmacology databases were also included. Information was accessed on or before June 30, 2007. RESULTS: In the pooled analysis, all-grade hand-foot skin reaction occurred in 19% of patients (5% grades 3-4), skin discoloration in 28% (0% grades 3-4), dry skin in 16% (1% grades 3-4), skin rash in 13% (1% grades 3-4), dermatitis in 8% (2% grades 3-4), hair color changes in 10% (0% grades 3-4), alopecia in 6% (0% grades 3-4), and phototoxicity in <0.1%. CONCLUSIONS: Dermatological reactions associated with sunitinib occur frequently. Evidence-based treatment recommendations are needed in order to maximize quality of life and optimize clinical outcome.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Toxidermias/etiologia , Indóis/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/efeitos adversos , Toxidermias/epidemiologia , Toxidermias/prevenção & controle , Humanos , Incidência , Qualidade de Vida , SunitinibeRESUMO
A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (k(a)). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F), V/F, and k(a) were estimated, and model 2, in which V/F and k(a) were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41. 9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.
Assuntos
Infecções por HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Nelfinavir/farmacocinética , Adulto , Demografia , Feminino , Infecções por HIV/sangue , Inibidores da Protease de HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Nelfinavir/sangueRESUMO
Expression of tumor necrosis factor-alpha(TNFalpha) in adipocytes has been reported to correlate with insulin resistance associated with obesity. The thiazolidinediones such as BRL 49653 have been reported to improve insulin sensitivity in obese animals and humans. Although its exact mechanism of action is not known, BRL 49653 has been shown to antagonize some of the inhibitory actions of TNFalpha. BRL 49653 binds and activates the peroxisome proliferator-activated receptor (PPARgamma2), an important nuclear transcription factor in adipocyte differentiation; however, its regulation of PPARgamma2 in differentiated adipocytes is unknown. In this paper, we find that BRL 49653 blocked the ability of TNFalpha to down-regulate the expression and transcription of several adipocyte genes, but BRL 49653 did not prevent TNFalpha from down-regulating PPARgamma2. Moreover, BRL 49653 alone initially decreased the expression of PPARgamma2 mRNA and protein greatly. After 24 h of treatment in 3T3-L1 adipocytes, BRL 49653 down-regulated PPARgamma2 by greater than 90% and potentiated the decrease of PPARgamma2 mRNA by TNFalpha at this time. These unexpected results prompted us to repeat the experiments for a longer time to determine whether BRL 49653 would continue to down-regulate PPARgamma2. With prolonged BRL 49653 treatment, PPARgamma2 mRNA expression was not decreased as greatly, and the protein levels were decreased 20-30% below control at 72 h compared to 90% at 24 h. Although BRL 49653 continued to prevent the inhibitory effects of TNFgamma on perilipin and aP2 mRNA, by 72 h, BRL 49653 was not as potent an inhibitor of TNFalpha's down-regulation of perilipin protein. Since PPARgamma2 protein was more abundant at this time, these results suggest that the level of PPARgamma2 protein is not the sole factor that regulates the transcriptional control by BRL 49653.
Assuntos
Adipócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Receptores Citoplasmáticos e Nucleares/genética , Tiazóis/farmacologia , Tiazolidinedionas , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/farmacologia , Animais , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação para Baixo , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Hipoglicemiantes/farmacologia , Camundongos , Proteína P2 de Mielina/efeitos dos fármacos , Proteína P2 de Mielina/genética , Perilipina-1 , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/genética , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Esterol Esterase/efeitos dos fármacos , Esterol Esterase/genética , Esterol Esterase/metabolismo , Fatores de Tempo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
A semi-physiological pharmacostatistical model was developed and used to study the manner in which intra-individual variability in hepatic clearance is transmitted to the area-under the plasma concentration-time curve from zero to infinity (AUC) of a drug and its metabolite. In order to clarify the effects, the model contained no other sources of variability. As the drug's hepatic extraction ratio increased, the coefficient of variation (CV) of the AUC of the drug increased, whereas that of the metabolite decreased. The AUC of the metabolite increased as the drug's non-hepatic clearance increased. At high extraction ratios, the CV of the AUC of the drug was insensitive to the contributions of other forms of clearance. The results suggest that under certain circumstances, smaller samples sizes could be used in bioequivalence studies for highly variable drugs if the test were based on the metabolite rather than the parent drug.
Assuntos
Fígado/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Equivalência Terapêutica , Área Sob a Curva , Aprovação de Drogas , Humanos , Modelos Lineares , Taxa de Depuração Metabólica , Modelos EstatísticosRESUMO
Population pharmacokinetics is playing an increasing role in clinical drug development. An overview of the population approach, including software and the advantages and limitations of the approach compared to the traditional approach to pharmacokinetic studies, is given. This paper also documents how the area has evolved over the past 15 years and addresses some of the issues that have arisen over the design and conduct of population studies. Finally, some alternative applications of the population approach are given for areas other than clinical drug development.
Assuntos
Farmacocinética , Vigilância da População , Humanos , Projetos de Pesquisa , SoftwareRESUMO
OBJECTIVE: To survey pharmacists' knowledge of the adverse drug reaction (ADR) reporting process, as well as the nature and seriousness of ADRs observed by pharmacists, and to determine how pharmacists perceive their role in monitoring and reporting suspected reactions. DESIGN: A survey was mailed to 793 Rhode Island pharmacists with a 40% (318) response rate. RESULTS: Two hundred and thirty-five surveys were reviewed for final analysis. Pharmacists in retail settings were more likely than hospital pharmacists to be aware of ADRs relating to therapeutic inequivalence and over-the-counter products, and more likely to ask the patient about ADRs (40% vs 16%). Hospital pharmacists were more likely to receive ADR information from physicians (40% vs 15%). Almost all pharmacists (97%) believed that action should be taken when a serious ADR is suspected. Younger pharmacists (< 45 y) were more willing to contact the physician and refer the patient to medical attention. CONCLUSIONS: Our results show that fewer than half of the respondents (41%) claimed to have observed a serious ADR (potentially life-threatening or requiring hospitalization), although almost all (97%) believed that pharmacists should take some action when a serious ADR is suspected. The influence of the practice setting, the number of years in practice, and the number of hours worked per week influenced the reporting practices and attitudes.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Conhecimentos, Atitudes e Prática em Saúde , Farmacêuticos/psicologia , Monitoramento de Medicamentos/psicologia , Tratamento Farmacológico/psicologia , Humanos , Farmácias , Serviço de Farmácia Hospitalar , Serviços Postais , Rhode Island , Inquéritos e QuestionáriosRESUMO
F9 teratocarcinoma is a useful model for studying early embryogenesis since these cells can differentiate into primitive or parietal endoderm under the influence of retinoic acid or retinoic acid and cyclic AMP, respectively. We have found that three isoforms of protein kinase C (PKC alpha, -beta, and -gamma) were expressed in undifferentiated stem cells. When the cells were treated with retinoic acid either alone or in the presence of cAMP for 120 h, PKC alpha mRNA and protein levels increased, whereas those of PKC beta and PKC gamma became undetectable. These changes began within 24 h of drug treatment and were complete by 48-72 h. In order to determine the functional significance of the induction of PKC alpha during F9 differentiation, we established two stable transfectants that overexpressed PKC alpha protein between 4- and 5-fold compared to wild type cells. Characterization of these cell lines revealed an altered pattern of expression of some of the markers of F9 differentiation. The clone that had the highest amount of PKC alpha protein constitutively expressed mRNA for type IV collagen and c-Jun, which are not normally expressed until 24-48 h of treatment with differentiation agents. In the other overexpressing clone, these markers were induced much faster than in wild type cells. The growth rate of both overexpressing clones was less than wild type cells, while the expression of the PKC beta protein in these clones was similar to the levels found in differentiated F9 cells. However, other markers of differentiation, including the cellular morphology and levels of pST6-135 and c-myc RNA, responded to agents identically in both wild type and PKC-alpha-overexpressing clones. Therefore, overexpression of PKC alpha is not sufficient to induce full differentiation of F9 cells. However, our data suggest that certain pathways that lead to the expression of differentiation-dependent genes are regulated by PKC alpha protein levels.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteína Quinase C/metabolismo , Animais , Diferenciação Celular , Colágeno/genética , Genes jun , Técnicas In Vitro , Isoenzimas/metabolismo , Camundongos , Proteína Quinase C beta , Proteína Quinase C-alfa , RNA Mensageiro/genética , Teratocarcinoma/patologia , Células Tumorais CultivadasRESUMO
We have previously shown that the retinoic acid (RA)-induced growth arrest and differentiation of B16 mouse melanoma cells is accompanied by a large increase in the amount and activity of protein kinase C (PKC). Since PKC is a multigene family, we investigated which isoforms were expressed in control and RA-treated B16 melanoma cells, and characterized the manner by which RA regulates PKC gene expression. We found that RA treatment of B16 cells resulted in an increase in PKC alpha mRNA beginning at 4-8 h and reached a maximum of 10- to 12-fold over control levels by 48 h. There was also a small amount of PKC gamma mRNA, present only in 48-h RA-treated cells, but no PKC beta mRNA was detected. The effect of RA on PKC alpha mRNA induction was not direct since the induction was abolished when cycloheximide was included in the incubation medium. Nuclear run-on experiments showed that the RA-induced increase in PKC alpha steady-state mRNA was not entirely due to an increase in transcriptional activity, as the increase in PKC alpha transcription was only 2- to 3-fold over control, which is not enough to account for the 10- to 15-fold increase in steady state levels. There was also no change in PKC alpha mRNA stability in RA-treated B16 cells compared to untreated cells. The 10.9-kb PKC alpha message in both control and RA-treated cells was less stable than the 3.8-kb PKC alpha message. Therefore, we propose that the major level of control of PKC alpha mRNA levels by RA is post-transcriptional, either RNA processing or transport out of the nucleus.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Melanoma Experimental/enzimologia , Proteína Quinase C/genética , Tretinoína/farmacologia , Animais , Northern Blotting , Cicloeximida/farmacologia , Meia-Vida , Cinética , Camundongos , RNA Mensageiro/biossíntese , Transcrição GênicaRESUMO
The Food and Drug Administration, Rockville, Md, contracted with the Rhode Island Department of Health, Providence, to conduct a project to increase reporting of suspected adverse drug reactions through physician education. Voluntary reporting, an important part of postmarketing surveillance that signals potential problems with marketed drugs, historically has been underused by physicians. After 2 years, there was a more than 17-fold increase in reports submitted directly from Rhode Island compared with the yearly average before initiation of the project. Increases in the total numbers of reports were paralleled by significant increases in the numbers of reports of severe reactions. Similar increases were not experienced nationally. Physicians in Rhode Island were surveyed before and 2 years after interventions began to determine changes in knowledge and attitudes about reporting of adverse drug reactions. Significant gains in knowledge and positive attitudes toward the reporting system occurred. We conclude that physicians can be stimulated to increase their reporting of suspected reactions, thereby improving the viability of the federal reporting system.
Assuntos
Atitude do Pessoal de Saúde , Hipersensibilidade a Drogas/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Médicos , Vigilância de Produtos Comercializados/estatística & dados numéricos , Avaliação de Programas e Projetos de Saúde , Administração em Saúde Pública , Rhode Island , Estados Unidos , United States Food and Drug AdministrationRESUMO
The metabolism and ocular binding of practolol were investigated after oral administration of 14C-practolol to hamsters treated with three modifiers of mixed-function oxidase activity: piperonyl butoxide, cobalt chloride or phenobarbitone. The major urinary metabolites of practolol were 3-hydroxypractolol and polar metabolites which included glucuronide conjugates. A number of unidentified metabolites constituted a minor portion of urinary radioactivity. Each pretreatment modified both the urinary excretion pattern (0-24 h) of practolol and its metabolites and also the metabolite profile of eye extracts 24 h after an oral dose. None of the modifiers of mixed-function oxidase activity had any significant effect on the ocular binding (both extractable and non-extractable components) of practolol and its metabolites. The results indicated that the non-extractable component was neither practolol nor 3-hydroxypractolol.
Assuntos
Olho/metabolismo , Practolol/metabolismo , Animais , Cobalto/farmacologia , Cricetinae , Masculino , Mesocricetus , Oxigenases de Função Mista/metabolismo , Fenobarbital/farmacologia , Butóxido de Piperonila/farmacologia , Practolol/urinaRESUMO
The disposition of [14C]practolol and its tissue association in the male Syrian hamster were investigated after p.o. administration. After an acute dose of 400 mg/kg, there was a marked persistence in the eye of total radioactivity (primarily practolol; approximate T 1/2 = 7 days) and nonextractable radioactivity which showed minimal decay over 7 days. Nonextractable radioactivity was also found in other tissues (liver, skin, small intestine and skeletal muscle examined). The level of total and nonextractable radioactivity was linearly related to dose (800 mg/kg highest dose examined). There was a marked accumulation of total and nonextractable radioactivity in the eye (7- and 14-fold, respectively) and skin (6- and 7-fold) after daily administration of 400 mg/kg for 22 days. The association of practolol metabolites with tissue macromolecules might explain the immunological changes in patients with the practolol-induced oculomucocutaneous syndrome. The adverse effects of practolol in humans have not yet been reproduced in any laboratory species and so the results must be interpreted with caution in relation to the toxicity of compound.
Assuntos
Practolol/metabolismo , Animais , Radioisótopos de Carbono , Cricetinae , Relação Dose-Resposta a Droga , Olho/efeitos dos fármacos , Masculino , Melaninas/metabolismo , Mesocricetus , Practolol/toxicidade , Distribuição TecidualRESUMO
Groups of male A/J mice were given either a regular diet or a regular diet supplemented with 1% BHA. After 10 days of feeding acetaminophen was administered intraperitoneally in amounts known to induce liver necrosis (500 mg/kg). Liver slices from the central lobe, were examined histologically for the extent of necrosis. Eight of the 17 mice treated with BHA showed no necrosis. In contrast 12 of 16 specimens from the mice treated with acetaminophen alone showed a severe centrilobular necrosis. The microsomal-mediated covalent binding of acetaminophen metabolites in-vitro was lower for microsomes from BHA pretreated mice than those from control mice. These results suggest that the ability of BHA to modify the activity of the drug metabolizing enzymes or to act as a scavenger may account for its protective action against acetaminophen-induced liver necrosis.