RESUMO
Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m(2) doxorubicin-equivalent) were given i.v., together with 123I-labelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.
Assuntos
Acrilamidas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/farmacocinética , Adulto , Idoso , Antibióticos Antineoplásicos/farmacocinética , Neoplasias da Mama/sangue , Neoplasias da Mama/urina , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/urina , Neoplasias Colorretais/sangue , Neoplasias Colorretais/urina , Doxorrubicina/farmacocinética , Feminino , Humanos , Radioisótopos do Iodo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Distribuição Tecidual , Resultado do TratamentoRESUMO
PURPOSE: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. PATIENTS AND METHODS: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. RESULTS: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. CONCLUSION: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz , Compostos Orgânicos/uso terapêutico , Inibidores de Proteases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Orgânicos/efeitos adversosRESUMO
PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/análogos & derivados , Paclitaxel/administração & dosagem , Ácido Poliglutâmico/análogos & derivados , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Químicos , Paclitaxel/farmacocinética , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/farmacocinética , Polímeros/química , Fatores de TempoAssuntos
Neoplasias da Coroide/secundário , Leiomiossarcoma/secundário , Neoplasias Pulmonares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Neoplasias da Coroide/química , Neoplasias da Coroide/cirurgia , Feminino , Humanos , Leiomiossarcoma/química , Leiomiossarcoma/cirurgia , Neoplasias Pulmonares/química , Neoplasias Pulmonares/cirurgia , Proteínas de Neoplasias/análise , Pneumonectomia , Acuidade Visual/fisiologia , Adulto JovemRESUMO
PURPOSE: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models. EXPERIMENTAL DESIGN: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively. RESULTS: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40-77 years), and median Karnofsky performance status was 80 (range, 60-100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m(2) twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m(2) bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m(2) bid and 125 mg/m(2) bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t(1/2) of approximately 9 h and a t(max) of approximately 4 h. One patient with pretreated lung cancer had a partial response. CONCLUSIONS: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m(2) bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Indóis/administração & dosagem , Indóis/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/farmacologia , Área Sob a Curva , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ácido Edético/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Fatores de TempoRESUMO
The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of pazopanib hydrochloride (GlaxoSmithKline) to submit evidence of the clinical and cost effectiveness of the drug for the first-line treatment of advanced and/or metastatic renal cell carcinoma, as part of the Institute's single technology appraisal (STA) process. The Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The objective of this paper is to summarize the independent review and critique of the evidence submitted for the consideration of the NICE Appraisal Committee and NICE's subsequently issued guidance. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. For progression-free survival (PFS), there was a statistically significant longer survival for pazopanib compared with placebo (as assessed by the ERG, based upon the original manufacturer submission with a clinical cut-off date of 23 May 2008) [median 11.1 vs. 2.8 months; hazard ratio (HR) 0.40; 95 % CI 0.27, 0.60]. Data from the indirect comparison suggested that pazopanib had a greater survival than interferon alpha (IFN-α) [HR 0.512; 95 % CI 0.326, 0.802] but provided no evidence of any difference compared with sunitinib (HR 0.949; 95 % CI 0.575, 1.568). With regard to overall survival, 64 % (n = 99) of patients in the pazopanib arm and 63 % (n = 49) of patients in the placebo arm had died and a total of 51 % (n = 40) of placebo patients had crossed over to receive pazopanib. Although data were provided on an intention-to-treat basis, crossover between therapies made such data difficult to interpret. There was no evidence of any statistically significant difference between pazopanib and best supportive care (HR 0.501; 95 % CI 0.136, 2.348). In the indirect comparison, there were no statistically significant differences between pazopanib and IFN-α (HR 0.627; 95 % CI 0.173, 2.269) or between pazopanib and sunitinib (HR 0.969; 95 % CI 0.359, 2.608). Based upon the work presented including a 12.5 % discount for pazopanib, sunitinib was extendedly dominated by a combination of pazopanib and IFN-α. As a consequence, the incremental cost per QALY for pazopanib versus IFN-α was £38,925. The results were not greatly altered over the range of univariate deterministic sensitivity analyses conducted by the manufacturer but pair-wise probabilistic sensitivity analyses suggested that given a threshold value of £30,000, there is a 54 % probability that pazopanib was preferred to sunitinib, 40 % chance against IFN-α and 47 % chance against best supportive care. The Appraisal Committee concluded that pazopanib should be recommended as a first-line treatment option for people with advanced renal cell carcinoma who have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5 % discount on the list price and provides a possible future rebate linked to the outcome of the head-to-head COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Pirimidinas/economia , Pirimidinas/uso terapêutico , Sulfonamidas/economia , Sulfonamidas/uso terapêutico , Avaliação da Tecnologia Biomédica/economia , Análise Custo-Benefício , Tomada de Decisões , Aprovação de Drogas/economia , Custos de Medicamentos , Humanos , Indazóis , Reino UnidoRESUMO
Meningeal carcinomatosis occurs in 1-18% of patients with solid tumours, most commonly carcinomas of the breast and lung or melanomas. There are relatively few reports of meningeal carcinomatosis in transitional cell carcinoma of the bladder. Isolated meningeal recurrence is particularly uncommon, and we present an unusual case of this in a 58-year-old man. The case was further complicated by the somewhat atypical presentation with a confirmed ischaemic stroke. The patient died one month after presentation.
Assuntos
Epiderme/fisiologia , Dermatoses Faciais/prevenção & controle , Ceratolíticos/administração & dosagem , Niacinamida/administração & dosagem , Envelhecimento da Pele , Administração Cutânea , Ensaios Clínicos como Assunto , Epiderme/efeitos dos fármacos , Dermatoses Faciais/patologia , HumanosRESUMO
In the cosmetic arena, many materials are used commercially and claim to provide skin effects (eg, antiaging effects) when used topically. Considering there are so many such materials and many skin appearance effects are encompassed, this short contribution must, by necessity, be selective in terms of the number of materials discussed and the depth with which any particular material is overviewed. This presentation, therefore, focuses on only 10 types of cosmeceutical agents: five vitamins (A, B(3), C, E, panthenol), peptides, hydroxyl acids, sugar amines, ceramides, and metals. In particular, this contribution concentrates on those materials for which there are available clinical data that support a reported skin appearance improvement effect.
Assuntos
Cosméticos/farmacologia , Fármacos Dermatológicos/farmacologia , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Química Farmacêutica , Cosméticos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Estética , Feminino , Humanos , Masculino , Niacinamida/uso terapêutico , Envelhecimento da Pele/efeitos dos fármacos , Resultado do Tratamento , Vitamina E/uso terapêutico , Óxido de Zinco/uso terapêuticoRESUMO
OBJECTIVES: N-undecyl-10-enoyl-L-phenylalanine (Sepiwhite), N-undecylenoyl phenylalanine), a reported alpha-melanocyte-stimulating hormone (MSH) receptor antagonist, has been observed to reduce melanin production in cultured melanocytes. In other testing, niacinamide has been found to inhibit melanosome transfer in cultured cells and to reduce the appearance of hyperpigmented spots in clinical studies. Since these two agents function by different mechanisms, we conducted two studies to determine if their combination is more effective than niacinamide alone in reducing facial hyperpigmentation. METHODS: Two double-blind, 10-week (2-week washout + 8-week treatment), left-right randomized, split-face clinical studies were conducted. In one, two groups of Japanese women applied one of two pairs of test emulsion formulations: a vehicle control and a 5% niacinamide formulation (n= 40), or a 5% niacinamide and a 5% niacinamide plus 1%N-undecylenoyl phenylalanine formulation (n = 40). Each formulation was applied to the randomly assigned side of the face. In the second study, Caucasian women applied one of three emulsions: vehicle control, 5% niacinamide formulation, or combination 5% niacinamide plus 1%N-undecylenoyl-phenylalanine formulation to the randomly assigned side of the face (n = approximately 60 treatment sites per formulation). In both studies, hyperpigmented spots were evaluated at weeks 4 and 8 by quantitative image analysis. RESULTS: In both studies, the combination formulation was significantly more effective than the vehicle and the 5% niacinamide formulation in reducing the appearance of hyperpigmentation after 8 weeks. CONCLUSIONS: The combination of 5% niacinamide and 1%N-undecylenoyl phenylalanine is an effective anti-aging technology for use on facial skin.
Assuntos
Dermatoses Faciais/tratamento farmacológico , Hiperpigmentação/tratamento farmacológico , Niacinamida/administração & dosagem , Fenilalanina/análogos & derivados , Administração Tópica , Adulto , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Fenilalanina/administração & dosagemRESUMO
Hyperpigmentary problems, including postinflammatory hyperpigmentation, solar lentigos, and melasma, occur widely in the human population and are thus of broad interest for control. On the basis of genomic and proteomic understanding of the melanocyte and melanogenesis, there are potentially hundreds of proteins and other effectors involved in pigmentation. This knowledge, although complex, should prove most useful in identifying specific abnormalities that lead to the hyperpigmentary problems. Also available are new laboratory screening methods and skin color measurement tools that are increasing the pace at which materials can be screened and evaluated clinically for their effectiveness. Combined with a clear consumer need for effective pigmentation control agents, advanced pigmentary system understanding and new research capabilities are setting the stage for future technological advancements.
Assuntos
Dermatopatias/fisiopatologia , Pigmentação da Pele/fisiologia , Genômica , Saúde Global , Humanos , Proteômica , Dermatopatias/diagnóstico , Dermatopatias/genética , Pigmentação da Pele/genéticaRESUMO
N-acetyl glucosamine (NAG) has been shown to be effective in reducing the appearance of hyperpigmented spots. From published in vitro mechanistic testing, glucosamine inhibits enzymatic glycosylation, a required processing step in converting inactive human pro-tyrosinase to the active tyrosinase, a key enzyme in the production of melanin. There is also published literature discussing the anti-inflammatory and antioxidant properties of glucosamine compounds. To identify additional mechanisms by which NAG might affect melanin production, an in vitro genomics experiment was conducted in SkinEthic skin equivalent cultures, which were topically dosed with NAG vs. a vehicle control. Relative to vehicle, NAG reduced melanin production, and the expression of several pigmentation-relevant genes were affected (down-regulated or up-regulated) by NAG treatment. Thus, there are several mechanisms that may be operative in the observed pigmentation effects.
Assuntos
Acetilglucosamina/toxicidade , Fármacos Dermatológicos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Pele/efeitos dos fármacos , Acetilglucosamina/administração & dosagem , Acetilglucosamina/uso terapêutico , Administração Cutânea , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Hiperpigmentação/tratamento farmacológico , Melaninas/biossíntese , Melaninas/genética , Pele/metabolismo , Técnicas de Cultura de TecidosRESUMO
Glucosamine has been reported to inhibit melanin production in melanocyte culture. It thus has a potential to reduce hyperpigmentation via topical use. Due to stability limitations of glucosamine, we chose to clinically evaluate the stable derivative N-acetyl glucosamine (NAG). Based on in vitro Franz cell testing, NAG is a good skin penetrant. In an 8-week, double-blind, placebo-controlled, left-right randomized, split-face clinical test, topical 2% NAG reduced the appearance of facial hyperpigmentation. In a second clinical study involving the topical combination of 2% NAG with 4% niacinamide, an agent previously shown to be clinically active, the effect on hyperpigmentation was greater. Both of these agents are well tolerated by the skin. This high tolerance coupled with relative ease of formulation and stability in solution make NAG, especially in combination with niacinamide, a suitable cosmetic ingredient for use in skin care products dealing with issues of skin hyperpigmentation.
Assuntos
Acetilglucosamina/uso terapêutico , Dermatoses Faciais/tratamento farmacológico , Hiperpigmentação/tratamento farmacológico , Niacinamida/uso terapêutico , Administração Tópica , Adulto , Idoso , Povo Asiático , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Dermatoses Faciais/diagnóstico , Feminino , Seguimentos , Humanos , Hiperpigmentação/diagnóstico , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , População BrancaRESUMO
Both glucosamine and its derivative N-acetyl glucosamine are amino-monosaccharides that serve key biochemical functions on their own and as substrate precursors for the biosynthesis of polymers such as glycosaminoglycans (e.g., hyaluronic acid) and for the production of proteoglycans. Glucosamine has an excellent safety profile and has been shown to provide benefits in several clinical disorders. Glucosamine compounds have been reported to have several beneficial effects on the skin or skin cells. Because of its stimulation of hyaluronic acid synthesis, glucosamine has been shown to accelerate wound healing, improve skin hydration, and decrease wrinkles. In addition, as an inhibitor of tyrosinase activation, it inhibits melanin production and is useful in treatment of disorders of hyperpigmentation. Mechanistically, glucosamine also has both anti-inflammatory and chondroprotective effects. Clinical trials have shown benefit in using oral glucosamine supplementation to improve symptoms and slow the progression of osteoarthritis in humans. Glucosamine has also been used to prevent and treat osteoarthritis in animals. Based on other observations, glucosamine has been suggested for additional clinical uses, including treatment of inflammatory bowel disease, migraine headaches, and viral infections. The current clinical uses for topical and oral glucosamine compounds and the mechanistic rationale for these uses are reviewed here.
Assuntos
Glucosamina/uso terapêutico , Dermatopatias/tratamento farmacológico , Artrite/tratamento farmacológico , Glucosamina/farmacologia , HumanosRESUMO
PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC). METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry. RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72). CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Cistatinas/genética , Neoplasias Pulmonares/genética , Inibidores de Serina Proteinase/genética , Serpinas/efeitos dos fármacos , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cistatina C , Cistatinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Serina Proteinase/metabolismo , Serpinas/genética , Serpinas/metabolismoRESUMO
BACKGROUND: In multiple chronic clinical studies, topical niacinamide (vitamin B3) has been observed to be well tolerated by skin and to provide a broad array of improvements in the appearance of aging facial skin (eg, reduction in the appearance of hyperpigmentated spots and red blotchiness). OBJECTIVE: To clinically determine the effect of topical niacinamide on additional skin appearance and property end points (wrinkles, yellowing, and elasticity). METHODS: Female white subjects (N = 50) with clinical signs of facial photoaging (fine lines and wrinkles, poor texture, and hyperpigmented spots) applied 5% niacinamide to half of the face and its vehicle control to the other half twice daily for 12 weeks (double blind, left-right randomized). Facial images and instrumental measures were obtained at baseline and at 4-week intervals. RESULTS: Analyses of the data revealed a variety of significant skin appearance improvement effects for topical niacinamide: reductions in fine lines and wrinkles, hyperpigmented spots, red blotchiness, and skin sallowness (yellowing). In addition, elasticity (as measured via cutometry) was improved. Corresponding mechanistic information is presented. CONCLUSION: In addition to previously observed benefits for topical niacinamide, additional effects were identified (improved appearance of skin wrinkles and yellowing and improved elasticity).
Assuntos
Fármacos Dermatológicos/administração & dosagem , Niacinamida/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Administração Tópica , Adulto , Método Duplo-Cego , Face , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Skin pigmentation results in part from the transfer of melanized melanosomes synthesized by melanocytes to neighboring keratinocytes. Plasma membrane lectins and their glycoconjugates expressed by these epidermal cells are critical molecules involved in this transfer process. In addition, the derivative of vitamin B(3), niacinamide, can inhibit melanosome transfer and induce skin lightening. We investigated the effects of these molecules on the viability of melanocytes and keratinocytes and on the reversibility of melanosome-transfer inhibition induced by these agents using an in vitro melanocyte-keratinocyte coculture model system. While lectins and neoglycoproteins could induce apoptosis in a dose-dependent manner to melanocytes or keratinocytes in monoculture, similar dosages of the lectins, as opposed to neoglycoproteins, did not induce apoptosis to either cell type when treated in coculture. The dosages of lectins and niacinamide not affecting cell viability produced an inhibitory effect on melanosome transfer, when used either alone or together in cocultures of melanocytes-keratinocytes. Cocultures treated with lectins or niacinamide resumed normal melanosome transfer in 3 days after removal of the inhibitor, while cocultures treated with a combination of lectins and niacinamide demonstrated a lag in this recovery. Subsequently, we assessed the effect of niacinamide on facial hyperpigmented spots using a vehicle-controlled, split-faced design human clinical trial. Topical application of niacinamide resulted in a dose-dependent and reversible reduction in hyperpigmented lesions. These results suggest that lectins and niacinamide at concentrations that do not affect cell viability are reversible inhibitors of melanosome transfer.
Assuntos
Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Lectinas/farmacologia , Melanossomas/efeitos dos fármacos , Melanossomas/metabolismo , Niacinamida/farmacologia , Administração Tópica , Adulto , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Método Duplo-Cego , Feminino , Humanos , Hiperpigmentação/tratamento farmacológico , Hiperpigmentação/metabolismo , Hiperpigmentação/patologia , Queratinócitos/citologia , Melanócitos/citologia , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/fisiologiaRESUMO
A single centre phase II study was conducted to determine the toxicity and activity of Caelyx in hormone refractory metastatic prostate cancer. Doxorubicin is known to be active in this setting and liposomal encapsulation may enhance its therapeutic efficacy and also reduce toxicity. Fourteen patients with hormone refractory metastatic prostate cancer were treated with CaelyxTM 50 mg/m2 once every four weeks. All patients had radiologically proven bone metastases and three also had soft tissue metastatic disease. All patients were evaluable for toxicity and response was assessable in thirteen cases. Three PSA responses were documented in patients with non-measurable disease. No patient had an objective response in measurable disease. The commonest toxicity was cutaneous and this was dose limiting in two patients. Gastrointestinal upset was frequent but generally mild. One patient died shortly after an episode of neutropaenic sepsis with associated grade 3 mucositis following his third cycle of chemotherapy. We confirmed the toxicity profile of Caelyx but its modest antitumour efficacy in this group of patients suggests little promise for future study in metastatic prostate cancer.