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OBJECTIVES: Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors. METHODS: Patients were treated with single-agent paclitaxel Q3W 175 mg/m 2 (or 135 mg/m 2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m 2 ), 40% (70 mg/m 2 ), or 50% (87.5 mg/m 2 ) of 175 mg/m 2 (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy. RESULTS: Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel. CONCLUSION: Paclitaxel at 70 mg/m 2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.
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Ciclosporinas , Neoplasias , Humanos , Paclitaxel , Neoplasias/induzido quimicamente , Ciclosporinas/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Paclitaxel-induced peripheral neuropathy (PIPN) is a common and dose-limiting adverse event. The role of P-glycoprotein (P-gp) in the neuronal efflux of paclitaxel was assessed using a translational approach. SH-SY5Y cells were differentiated to neurons and paclitaxel toxicity in the absence and presence of a P-gp inhibitor was determined. Paclitaxel caused marked dose-dependent toxicity in SH-SY5Y-derived neurons. Paclitaxel neurotoxicity was exacerbated with concomitant P-gp inhibition by valspodar and verapamil, consistent with increased intracellular accumulation of paclitaxel. Patients with cancer treated with paclitaxel and P-gp inhibitors had a 2.4-fold (95% confidence interval (CI) 1.3-4.3) increased risk of peripheral neuropathy-induced dose modification while a 4.7-fold (95% CI 1.9-11.9) increased risk for patients treated with strong P-gp inhibitors was observed, and a 7.0-fold (95% CI 2.3-21.5) increased risk in patients treated with atorvastatin. Atorvastatin also increased neurotoxicity by paclitaxel in SH-SY5Y-derived neurons. Clinicians should be aware that comedication with P-gp inhibitors may lead to increased risk of PIPN.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Neurônios/efeitos dos fármacos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos Fitogênicos/metabolismo , Atorvastatina/efeitos adversos , Linhagem Celular Tumoral , Ciclosporinas/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Neurônios/metabolismo , Neurônios/patologia , Paclitaxel/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sinvastatina/efeitos adversos , Verapamil/efeitos adversosRESUMO
Introdução: A dermatite atópica (DA) é uma doença inflamatória da pele, multifatorial, crônica e recorrente, caracterizada por lesões eczematosas e prurido intenso. Nos casos graves refratários aos tratamentos tópicos, tem se utilizado imunossupressão sistêmica para o controle da doença, sendo a ciclosporina considerada por muitos como terapia de escolha. Este estudo visa avaliar a incidência e gravidade dos eventos adversos relacionados ao uso de ciclosporina em pacientes com DA grave. Métodos: Estudo retrospectivo observacional com análise de prontuários de pacientes com dermatite atópica grave em uso de ciclosporina atendidos em hospital terciário no período de 3 anos. Resultados: Avaliados 80 pacientes com dermatite atópica grave usando ciclosporina, com média de idade de 25,5 anos e 41 do sexo feminino (51,3%). Foram relatados eventos adversos em 25 pacientes. O tempo médio de uso de ciclosporina no grupo com eventos adversos foi de 29,3 meses. Os eventos de maior gravidade foram alteração da função renal e hipertensão, sendo mais observados nos casos de doença mais refratária, quando o uso de ciclosporina foi muito prolongado, superior a 60 meses. As reações evidenciadas foram: hipertensão arterial 40%, alteração renal 20%, náuseas/vômitos 16%, cefaleia 12%, herpes de repetição 12% e outros 4%. Os eventos adversos normalizaram após suspensão da ciclosporina. Conclusão: Pacientes com dermatite atópica grave que usaram ciclosporina por tempo prolongado tiveram maior frequência de eventos adversos potencialmente graves. Todos os efeitos adversos normalizaram após a suspensão de medicação.
Rationale: Atopic dermatitis (AD) is an inflammatory, multifactorial, chronic, recurrent skin disease characterized by eczematous lesions and intense itching. In severe cases refractory to topical treatments, systemic immunosuppression has been used to control the disease, and cyclosporine is largely considered firstline therapy. This study aims to assess the incidence and severity of adverse events related to the use of cyclosporine in patients with severe AD. Methods: This retrospective observational study analyzed medical records of patients with severe atopic dermatitis using cyclosporine treated at a tertiary hospital over a 3-year period. Results: Eighty patients with severe atopic dermatitis using cyclosporine were evaluated. Their mean age was 25.5 years, and 41 (51.3%) were female. Adverse events were reported in 25 patients. The mean duration of cyclosporine treatment in the group with adverse events was 29.3 months. The most serious events were changes in renal function and hypertension, which were most often observed in cases of more refractory disease, when the use of cyclosporine was very prolonged (over 60 months). The adverse reactions were hypertension (40%), renal changes (20%), nausea/vomiting (16%), headache (12%), recurrent herpes (12%) and others (4%). Adverse events were under control after cyclosporine was discontinued. Conclusion: Patients with severe atopic dermatitis who used cyclosporine for a long time had a higher frequency of potentially serious adverse events. All adverse effects were under control after discontinuation of medication.
Assuntos
Humanos , Ciclosporina , Ciclosporinas/efeitos adversos , Dermatite Atópica , Cefaleia , Hipertensão , Náusea , Pacientes , Terapêutica , Estudos Retrospectivos , Terapia de Imunossupressão , Efeitos Colaterais e Reações Adversas Relacionados a MedicamentosRESUMO
INTRODUCTION: Lifelong immunosuppression after renal transplant exerts effects on the recipients' skin, including skin infections, skin cancers and drug-induced skin disorders. Our study aimed to determine the epidemiology of skin conditions among renal transplant recipients in the largest tertiary hospital in Singapore. METHODS: We reviewed the medical records of kidney transplant recipients at Singapore General Hospital, Singapore, between 1 January 2003 and 31 December 2013. Among these patients, the clinical data of patients who sought skin consultations with either dermatologists or plastic surgeons within the hospital was captured. RESULTS: A total of 178 patients were included in our study. There were 88 (45.6%) skin infections, 23 (11.9%) drug-induced skin conditions, 9 (4.7%) skin cancers and 73 (37.8%) other skin conditions. Skin infection was the predominant reason for consultation, with viral warts (15%, n = 29) being the most common. Of the nine cases in our cohort with skin cancer, there were three cases of basal cell carcinoma, three cases of Bowen's disease, two cases of extramammary Paget's disease and one case of squamous cell carcinoma. Drug-induced skin conditions, mainly attributable to long-term steroids and cyclosporin use, were represented by acne (9.3%, n = 18) and sebaceous hyperplasia (2.6%, n = 5). CONCLUSION: Our study demonstrated the spectrum of skin conditions that can be expected after renal transplantation. We wish to highlight the importance of careful dermatological screening and long-term follow-up for these patients, in order to reduce post-transplant skin complications.
Assuntos
Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Dermatopatias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclosporinas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Singapura , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/cirurgia , Esteroides/efeitos adversos , Centros de Atenção Terciária , Adulto JovemRESUMO
BACKGROUND & AIMS: The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function. METHODS: We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed. RESULTS: We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC50. Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate. CONCLUSIONS: This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects. LAY SUMMARY: In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects.
Assuntos
Ciclosporinas/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Internalização do Vírus/efeitos dos fármacos , Antivirais/efeitos adversos , Antivirais/farmacologia , Ácidos e Sais Biliares/metabolismo , Células Cultivadas , Ciclosporinas/efeitos adversos , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Vírus Delta da Hepatite/efeitos dos fármacos , Vírus Delta da Hepatite/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , HumanosRESUMO
Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).
Assuntos
Azatioprina/administração & dosagem , Ciclosporinas/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim/mortalidade , Quimioterapia de Manutenção/métodos , Ácido Micofenólico/análogos & derivados , Adulto , Azatioprina/efeitos adversos , Ciclosporinas/efeitos adversos , Quimioterapia Combinada , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Ciclofilinas/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Esclerose Múltipla/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Compostos de Quinolínio/uso terapêutico , Substituição de Aminoácidos , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/imunologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Peptidil-Prolil Isomerase F , Ciclofilinas/genética , Ciclofilinas/metabolismo , Ciclosporinas/efeitos adversos , Ciclosporinas/síntese química , Ciclosporinas/farmacologia , Ciclosporinas/uso terapêutico , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Mutação , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Compostos de Quinolínio/efeitos adversos , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/farmacologia , Distribuição Aleatória , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologiaRESUMO
Establishing an in vivo cell-mediated immunity (CMI) assay, such as the delayed-type hypersensitivity (DTH) assay, has been identified as an important gap and recommended to receive highest priority for new model development in several workshops on developmental immunotoxicity. A Candida albicans DTH model has recently been developed that has the advantage over other DTH models, which use alternative sensitizing antigens, in that antigen-specific antibodies, which may interfere with the assay, are not produced. In addition, the in vivo C. albicans DTH model was demonstrated to be more sensitive in detecting immunosuppression than DTH models using keyhole limpet hemocyanin (KLH) or sheep red blood cells as antigens, as well as some ex vivo CMI assays. While KLH and sheep red blood cells are non-physiological immunogens, C. albicans is an important human pathogen. The present studies were conducted in order to optimize and validate the C. albicans DTH model for use in developmental immunotoxicity studies using juvenile rats. Three known immunosuppressive compounds with different mechanisms of action were tested in this model, cyclosprorin A (CsA), cyclophosphamide (CPS), and dexamethasone (DEX). Animals were sensitized with formalin-fixed C. albicans on postnatal day (PND) 28 and challenged with chitosan on PND 38. Drug was administered beginning on PND 23 and continued until PND 37. Exposure to each of the three immunotoxicants resulted in statistically significant decreases in the DTH response to C. albicans-derived chitosan. Decreases in footpad swelling were observed at ≥10 mg CsA/kg/day, ≥5 mg CPS/kg/day, and ≥0.03 mg DEX/kg/day. These results demonstrate that the C. albicans DTH model, optimized for use in juvenile rats, can be used to identify immunotoxic compounds, and fills the need for a sensitive in vivo CMI model for assessments of developmental immunotoxicity. Abbreviations Ab, antibody APC, antigen presenting cell BSA, bovine serum albumin C. albicans, Candida albicans CI, challenge interval CMI, cell-mediated immunity CO, challenge only CPS, cyclophosphamide CsA, cyclosporin A CTL, cytotoxic T lymphocyte DEX, dexamethasone DIT, developmental immunotoxicity DTH, delayed-type hypersensitivity ip, intraperitoneal KLH, keyhole limpet hemocyanin MLR, mixed lymphocyte reaction OVA, ovalbumin PBS, phosphate-buffered saline PND, postnatal day sc, subcutaneous SEM, standard error of the mean SRBC, sheep red blood cells.
Assuntos
Candida albicans/imunologia , Modelos Animais de Doenças , Hipersensibilidade Tardia/tratamento farmacológico , Animais , Antígenos de Fungos/imunologia , Bovinos , Quitosana/imunologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclosporinas/administração & dosagem , Ciclosporinas/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Hipersensibilidade Tardia/imunologia , Hipersensibilidade Tardia/microbiologia , Imunidade Celular/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Ratos , Ratos Sprague-Dawley , Sensibilidade e Especificidade , OvinosRESUMO
PURPOSE: This study was aimed at developing co-encapsulated stealth nanoliposomes containing PSC 833, an efficient MDR modulator, and doxorubicin (DOX) in order to increase the effectiveness and decrease adverse effects of the anticancer drug. METHODS: In attempt to increase the encapsulation efficiency of drugs, different methods for liposome preparation were tested and the effect of different parameters such as drug to lipid molar ratio, cholesterol mole percent and lipid compositions, were investigated. The final product with a lipid composition of EPC:DSPE-PEG2000:Chol (60:5:30 %mol) was prepared by thin layer film hydration method. After preparation of empty liposomes, DOX and PSC 833 were loaded using ammonium sulfate gradient and remote film loading methods, respectively. Physical characteristics of optimized liposomes (DOX/PSC-L) such as particle size, zeta potential, encapsulation efficiency, in-vitro drugs release and stability were evaluated. Furthermore, in vitro cytotoxicity study of various liposomal formulations as well as drugs, solutions against resistant human breast cancer cell line, T47D/TAMR-6, was evaluated using MTT assay. RESULTS: The best formulation showed a narrow size distribution with average diameter of 91.3 ± 0.2 nm with zeta potential of -6 ± 1.2, the encapsulation efficiency for DOX and PSC 833 were more than 95% and 65.5%, respectively. In DOX-resistant T47D/TAMR-6 cells, dual-agent stealth liposomes showed significantly greater cytotoxicity (P < 0.05) than free DOX and liposomal DOX plus free PSC 833 treatments. CONCLUSIONS: Co-encapsulation of DOX and PSC 833 presents a promising anticancer formulation, capable of effective reversal of drug resistance, and should be explored further in therapeutic studies with animal tumor xenograft models. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclosporinas/administração & dosagem , Doxorrubicina/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Lipossomos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Ciclosporinas/efeitos adversos , Ciclosporinas/química , Doxorrubicina/efeitos adversos , Doxorrubicina/química , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lipídeos/química , Lipossomos/efeitos adversos , Lipossomos/química , Nanopartículas/administração & dosagem , Nanopartículas/efeitos adversos , Nanopartículas/química , Tamanho da PartículaRESUMO
BACKGROUND & AIMS: SCY-635 is a non-immunosuppressive analog of cyclosporin A that inhibits cyclophilins A and B and hepatitis C virus (HCV) replication in vitro. In a phase 1b multi-dose escalation study, we evaluated the safety, plasma pharmacokinetics, and antiviral activity of 15 days of monotherapy with SCY-635 in adults with chronic genotype 1 HCV infection. METHODS: Twenty adults with chronic HCV genotype 1 were randomized to SCY-635 oral doses of 100, 200, or 300 mg three times daily for 15 days. RESULTS: No dose-limiting clinical or laboratory toxicities were identified. On day 15, the mean decline in plasma viremia was 2.24±1.74 log(10) IU/ml with SCY-635 900 mg/d. Individual antiviral responses correlated with host IL28B genotype. Post hoc analyses indicated treatment with SCY-635 increased plasma protein concentrations of interferon α (IFNα), IFNs λ(1) and λ(3), and 2'5' oligoadenylate synthetase 1 (2'5'OAS-1), with the greatest increases in IL28B CC and CT subjects. Changes in plasma concentrations for all markers were coincident with changes in the plasma concentration of SCY-635. Peaks of IFNs α, λ(1), and λ(3) and 2'5'OAS-1 were observed within 2 h after drug administration. In replicon cells, SCY-635 enhanced secretion of type I and type III IFNs and increased the expression of IFN-stimulated genes (ISG). CONCLUSIONS: These studies establish clinical proof of concept for SCY-635 as a novel antiviral agent and suggest that restoration of the host innate immune response to chronic hepatitis C infection may represent a major mechanism through which cyclophilin inhibitors exert clinical antiviral activity.
Assuntos
Antivirais/administração & dosagem , Ciclofilina A/antagonistas & inibidores , Ciclofilinas/antagonistas & inibidores , Ciclosporinas/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacocinética , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Ciclosporinas/efeitos adversos , Ciclosporinas/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/imunologia , Humanos , Interferon-alfa/sangue , Interferon beta/sangue , Interferon gama/sangue , Interferons , Interleucinas/genética , Neoplasias Hepáticas , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PRES is a neuroclinical and radiological syndrome that results from treatment with calcineurin inhibitor immunosuppressives. Severe hypertension is commonly present, but some patients may be normotensive. We report herein two children who received liver transplants, as treatment for biliary atresia in the first case and for Alagille's syndrome in the second one. In the early postoperative, both patients presented hypertension and seizures. In both cases, the image findings suggested the diagnosis of PRES. The CT scan showed alterations in the posterior area of the brain, and brain MRI demonstrated parietal and occipital areas of high signal intensity. Both children were treated by switching the immunosuppressive regimen and controlling arterial blood pressure. They displayed full recuperation without any neurologic sequelae. Probably, the pathophysiology of PRES results from sparse sympathetic innervation of the vertebrobasilar circulation, which is responsible for supplying blood to the posterior areas of the brain. In conclusion, all liver-transplanted children who present with neurological symptoms PRES should be considered in the differential diagnosis, although this is a rare complication. As treatment, we recommend rigorous control of arterial blood pressure and switching the immunosuppressive regimen.
Assuntos
Calcineurina/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Fígado/efeitos adversos , Imageamento por Ressonância Magnética/métodos , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Adolescente , Síndrome de Alagille , Atresia Biliar/diagnóstico , Atresia Biliar/cirurgia , Inibidores de Calcineurina , Criança , Ciclosporinas/efeitos adversos , Ciclosporinas/uso terapêutico , Feminino , Seguimentos , Humanos , Encefalopatia Hipertensiva/induzido quimicamente , Encefalopatia Hipertensiva/diagnóstico , Imunossupressores/uso terapêutico , Transplante de Fígado/métodos , Doadores Vivos , Masculino , Monitorização Fisiológica/métodos , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença , Imunologia de Transplantes/fisiologiaRESUMO
Endothelial microparticles (EMP) are small vesicles smaller than 1.0µm, released from endothelial cells (EC) during their activation and (or) apoptosis. The assay of the level of elevated EMP is a new approach to evaluate the dysfunction of endothelial cell. EMP can be classified into several types according to their membrane molecular, and the levels of various types of EMP may be different. As the most cost-effective immunodepressant, cyclosporine A (CsA) has been used widely in organ transplantation. But its dose is hard to control, under-medication may cause the acute rejection (AR) and overdose may cause chronic cyclosporine nephropathy (CCN). The cyclosporine A (CsA) caused CCN and the AR caused renal injury after renal transplantation are both vascular diseases related with endothelial dysfunction, and up to now, there is still no effective method to distinguish the two kinds of diseases. Owing to distinct pathogenesis of the two kinds of vascular diseases, the level of each type of EMP originated from vascular endothelial cells may be different. We hypothesize that maybe we can distinguish them by detecting the different levels of some types of EMP which is also related with vascular disease, and we propose to prove our hypothesis through animal experiment. If our hypothesis is proved, it will be more helpful for clinicians to adjust the dose of CsA promptly according to the differential diagnosis of the two kinds of diseases.
Assuntos
Ciclosporinas/efeitos adversos , Rejeição de Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Nefrose/induzido quimicamente , Nefrose/diagnóstico , Animais , Micropartículas Derivadas de Células/patologia , Diagnóstico Diferencial , Células Endoteliais/patologia , RatosRESUMO
BACKGROUND: The increased risk of developing lymphoproliferative disorders, mainly linked with Epstein-Barr virus infection, is well documented in patients with cyclosporin-induced immunosuppression following organ transplantation. Lymphoproliferative disease is extremely rare in the non-transplant setting. METHODS: We present the first published case of non-Epstein-Barr virus associated lymphoproliferative disease in a patient receiving long-standing cyclosporin therapy for psoriatic arthritis, which presented as a recurrent nasopharyngeal mass. RESULTS: Histological examination showed lymphoid hyperplasia in repeated biopsies. Macroscopic clearance was persistently followed by aggressive recurrence. Spontaneous regression occurred upon cyclosporin withdrawal. CONCLUSION: This rare complication of cyclosporin therapy in non-transplant patients is highlighted from an otolaryngological perspective, as the sole presentation may be a recurrent nasopharyngeal mass. Repeated biopsies showing lymphoid hyperplasia, together with aggressive recurrence, should prompt immediate drug withdrawal to reduce immunosuppression and promote spontaneous regression.
Assuntos
Artrite Psoriásica/tratamento farmacológico , Ciclosporinas/efeitos adversos , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/induzido quimicamente , Doenças Nasofaríngeas/induzido quimicamente , Biópsia , Ciclosporinas/administração & dosagem , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Obstrução Nasal/etiologia , Obstrução Nasal/cirurgia , Recidiva , Remissão Espontânea , ReoperaçãoRESUMO
BACKGROUND: Valspodar, a non-immunosuppressive analog of cylosporine, is a potent P-glycoprotein (MDR1) inhibitor. As MDR1-mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed. PROCEDURE: Patients received a valspodar-loading dose (2 mg/kg) followed by a 5-day continuous valspodar infusion (8, 10, 12.5, or 15 mg/kg/day) combined with lower than standard doses of mitoxantrone and etoposide. The valspodar dose was escalated using a standard 3 + 3 phase I design. RESULTS: Twenty-one patients were evaluable for toxicity and 20 for response. The maximum tolerated dose (MTD) of valspodar was 12.5 mg/kg/day, combined with 50% dose-reduced mitoxantrone and etoposide. The clearance of mitoxantrone and etoposide was decreased by 64% and 60%, respectively, when combined with valspodar. Dose-limiting toxicities included stomatitis, ataxia, and bone marrow aplasia. Three of 11 patients with acute lymphoblastic leukemia (ALL) had complete responses while no patient with acute myeloid leukemia (AML) had an objective response. In vitro studies demonstrated P-glycoprotein expression on the blasts of 5 of 14 patients, although only 1 had inhibition of rhodamine efflux by valspodar. CONCLUSIONS: While this regimen was tolerable, responses in this heavily pretreated population were limited to a subset of patients with ALL.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Ciclosporinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Ciclosporinas/administração & dosagem , Ciclosporinas/efeitos adversos , Ciclosporinas/farmacocinética , Resistência a Múltiplos Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Etoposídeo/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Mitoxantrona/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Terapia de Salvação , Adulto JovemRESUMO
This study examined whether stanols can exert their cholesterol lowering effect in renal transplant recipients who develop hypercholesterolaemia. The rise in cholesterol is related to the use of cyclosporine. The study was a randomised parallel-group intervention study. The Intervention group (I) was given three months supply of stanol containing food products. Fasting serum lipids were measured monthly. Parameters that might influence serum cholesterol were measured on all subjects at the start of the study period and at three months. These included body weight, blood pressure and drug therapy, dietary intake, exercise, smoking and alcohol intake. 84 patients completed the study. Cholesterol was reduced in both groups. The difference between control (C) and I group reached significance at p = 0.0196. Reduction in cholesterol in subjects also using statins was greater in the I group. Functional foods appear to be effective in reducing cholesterol in this group of patients. Data collection with respect to other factors that influence CV risk suggests that an overall assessment of diet and lifestyle as well as cholesterol lowering should be undertaken.
Assuntos
Ciclosporinas/efeitos adversos , Suplementos Nutricionais , Hipercolesterolemia/dietoterapia , Imunossupressores/efeitos adversos , Transplante de Rim , Sitosteroides/uso terapêutico , Terapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/induzido quimicamente , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer. PATIENTS AND METHODS: Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m(2), and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m(2) and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability. RESULTS: With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC-and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC-treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions. CONCLUSION: The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclosporinas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Ciclosporinas/administração & dosagem , Ciclosporinas/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Análise de SobrevidaRESUMO
Pancreas and kidney transplantation (SPK) is the treatment of choice for patients with type 1 diabetes mellitus and end-stage renal failure. Gallstones are common after SPK transplantation but little is known about the true incidence and etiology of gallstones in this group. We therefore evaluated the incidence of gallstones and the presence of transplant-related risk factors in patients after SPK and kidney transplantation alone (KTA). Data were evaluated of 56 consecutive patients who underwent SPK transplantation and compared the results with those of 91 consecutive nondiabetic patients who underwent KTA transplantation at the Leiden University Medical Center between 1987 and 1994. Of the 58 evaluable KTA patients, 20.7% developed gallstones during 7.7 yr of follow-up and in the SPK group 43.9% of the 41 evaluable patients developed gallstones during 7.1 yr of follow-up. Postoperative weight loss and cyclosporin A-related hepatotoxicity correlated with gallstone formation both in SPK and KTA patients. In addition, the duration of postoperative fasting and autonomic neuropathy correlated with gallstones in SPK patients. It is concluded that both in patients after SPK transplantation and in patients after KTA transplantation, the risk to develop gallstones is significantly increased. Physicians should be aware of the high incidence of gallstones in SPK recipients.
Assuntos
Ciclosporinas/efeitos adversos , Cálculos Biliares/epidemiologia , Imunossupressores/efeitos adversos , Imunossupressores/agonistas , Transplante de Rim/efeitos adversos , Transplante de Pâncreas/efeitos adversos , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/complicações , Feminino , Seguimentos , Cálculos Biliares/etiologia , Humanos , Masculino , Fatores de Risco , Redução de Peso/fisiologiaAssuntos
Angioedema/etiologia , Angioedema/terapia , Edema Encefálico/etiologia , Edema Encefálico/terapia , Ciclosporinas/efeitos adversos , Encefalopatia Hipertensiva/etiologia , Encefalopatia Hipertensiva/terapia , Imunossupressores/efeitos adversos , Convulsões/terapia , Corticosteroides/efeitos adversos , Angioedema/diagnóstico , Transfusão de Componentes Sanguíneos/efeitos adversos , Edema Encefálico/diagnóstico , Endotélio Vascular , Eritropoetina/efeitos adversos , Humanos , Encefalopatia Hipertensiva/diagnóstico , Imageamento por Ressonância Magnética , Convulsões/diagnóstico , Convulsões/etiologia , SíndromeAssuntos
Síndrome de Behçet/tratamento farmacológico , Ciclosporinas/efeitos adversos , Imunossupressores/efeitos adversos , Convulsões/induzido quimicamente , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Adulto , Anticonvulsivantes/uso terapêutico , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Ciclosporinas/administração & dosagem , Ciclosporinas/uso terapêutico , Eletrorretinografia , Emergências , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Pressão Intraocular , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Fatores de Tempo , Ácido Valproico/uso terapêuticoRESUMO
Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.