RESUMO
BACKGROUND: Medical thoracoscopy is the gold standard for the diagnosis of pleural diseases. To date, no consensus exists regarding the choice of sedative and analgesic agents in patients undergoing local anesthetic thoracoscopy (LAT), and questions are raised as to whether sedatives may add to respiratory side effects. OBJECTIVE: The aim of the study was to test the hypothesis that administration of midazolam associated with lidocaine versus lidocaine alone in patients with LAT adds to respiratory side effects. METHODS: We randomly assigned 80 patients to a 1:1 study to 2 groups: local anesthesia by lidocaine (n = 40) versus lidocaine and midazolam (n = 40), with the primary end point being the mean lowest oxygen saturation. The secondary end points were cardiovascular parameters, complications, days of drainage, hospital stay, and patients' quality of life (QoL) as assessed by a visual analog scale (VAS). RESULTS: The mean age of all patients was 66.6 ± 13.1 years. The study comprised 50 males (62.5%). No difference was observed in the demographics between the 2 groups. No significant difference was observed between the 2 groups in oxygen saturation (primary end point). A significant difference was observed in favor of the midazolam group regarding the QoL assessed by VAS. CONCLUSION: Midazolam does not add to respiratory side effects when it is used with lidocaine for LAT, while patients' QoL is actually improved in this group. Therefore, in our department, we changed our startegy in favor of the association of lidocaine and midazolam.
Assuntos
Adjuvantes Anestésicos/administração & dosagem , Anestesia Local , Anestésicos Locais/administração & dosagem , Lidocaína/administração & dosagem , Pneumopatias/diagnóstico , Midazolam/administração & dosagem , Qualidade de Vida , Toracoscopia/métodos , Adjuvantes Anestésicos/efeitos adversos , Idoso , Anestésicos Locais/efeitos adversos , Feminino , Humanos , Lidocaína/efeitos adversos , Masculino , Midazolam/efeitos adversos , Pessoa de Meia-Idade , Manejo da Dor/métodos , Derrame Pleural/diagnósticoAssuntos
Antineoplásicos/uso terapêutico , Carcinoma Basocelular/terapia , Imiquimode/uso terapêutico , Neoplasias Cutâneas/terapia , Linfócitos T Reguladores , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/sangue , Terapia Combinada , Criocirurgia , Humanos , Interferon-alfa/sangue , Interleucina-10/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
Several pharmaceutical agents are known to produce ethanol intolerance, which is often depicted as disulfiram-like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases, albeit this has not been confirmed in all cases by blood acetaldehyde measurements. Herein, cefamandole, cotrimoxazole, griseofulvin, procarbazine, and propranolol, which are reported to produce a disulfiram-like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of ethanol metabolizing enzymes along with the levels of brain monoamines were determined. Blood acetaldehyde was also evaluated after ethanol administration in rats pretreated with the abovementioned pharmaceutical products. Disulfiram, cefamandole, and procarbazine significantly increased blood acetaldehyde levels after ethanol administration, while on the contrary, cotrimoxazole, griseofulvin, and propranolol had no effect on blood acetaldehyde. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, cotrimoxazole, griseofulvin, and propranolol do not produce a typical disulfiram-like reaction, because they do not increase blood acetaldehyde when given together with ethanol. On the other hand, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Hence, the ethanol intolerance produced by these agents, whether blood acetaldehyde concentration is elevated or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications that provoke clinical manifestations similar to those of a disulfiram reaction.
Assuntos
Acetaldeído/sangue , Encéfalo/efeitos dos fármacos , Cefamandol/farmacologia , Griseofulvina/farmacologia , Procarbazina/farmacologia , Propranolol/farmacologia , Serotonina/metabolismo , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Inibidores de Acetaldeído Desidrogenases/farmacologia , Animais , Encéfalo/metabolismo , Dissulfiram/farmacologia , Masculino , Ratos WistarRESUMO
Exercise is widely accepted as having therapeutic effects; thus, it is important to know whether it interacts with medications. The aim of the present pilot study was to examine the effect of high-intensity interval exercise (known to have antidiabetic action) on key pharmacokinetic parameters related to absorption of metformin (the first-line medication against type 2 diabetes). Ten healthy men participated in two sessions, spaced one to two weeks apart in random, counterbalanced order. In both sessions, participants received 1000 mg of metformin orally, 1-1.5 hours after breakfast. Then, they either ran for 60 minutes at alternating intensity, starting at 40 minutes after metformin administration, and rested without food consumption over the next 3 hours or they rested without food consumption during the entire testing period. Venous blood samples were collected before and at 0.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after metformin administration for metformin determination by liquid chromatography-mass spectrometry. Capillary blood samples were also collected for lactate and glucose measurements. Data from the two sessions were compared through Wilcoxon or Student's t test, as appropriate. Maximum plasma concentration of metformin (Cmax ) was higher at exercise compared to rest (P = .059). Time to reach Cmax (Tmax ) decreased with exercise (P = .009), and the area under the metformin concentration vs time curve was higher at exercise (P = .047). The addition of exercise to metformin administration did not cause hypoglycemia or lactic acidosis. In conclusion, our results provide the first evidence that pharmacokinetic values related to metformin absorption are affected by exercise.
Assuntos
Treinamento Intervalado de Alta Intensidade/métodos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adulto , Glicemia , Voluntários Saudáveis , Humanos , Hipoglicemiantes/sangue , Ácido Láctico/sangue , Masculino , Metformina/sangue , Projetos PilotoRESUMO
PURPOSE: To evaluate the potential of prostate cancer detection on the basis of prostate-specific antigen (PSA)-level and percent free PSA (% fPSA) according to the outcome of prostate needle biopsy. METHODS: This was a retrospective study of 1040 patients that underwent a prostate biopsy in the Urologic Clinic of the University Hospital of Ioannina, Greece. The patients underwent needle biopsy after abnormal finding in digital rectal examination (DRE). Tissue samples were extracted using a 12-core TRUS-GB. The patients were divided into four groups according to the biopsy outcome. Total serum and free PSA were measured. RESULTS: The mean PSA concentration of cancer versus noncancer groups was significantly higher (p<0.05). The positive predictive value (PPV) of PSA for serum concentration >10 ng/ml was 47% while the negative predictive value (NPV) in patients with PSA levels <4 ng/ml was 81%. The diagnostic accuracy of % fPSA for patients with PSA level between 4-10 ng/ml was 0.651 (95% CI, 0.549-0.754) (p<0.05). A statistically significant difference in mean PSA concentration was recorded between prostate cancers classified as grade 2 (3+4=7) and 3 (4+3=7) and grade 4 (8) and 5 (9-10) (p<0.05). CONCLUSIONS: Though informative and suggestive, PSA and % fPSA are not definitive for cancer or non-cancer determination. The differentiation of PSA level between tumours classified as grade 2 (3+4=7) and grade 3 (4+3=7) could support the determination of treatment by backing pathologist's interpretation of the histological diagnosis.
Assuntos
Biomarcadores Tumorais/metabolismo , Antígeno Prostático Específico/sangue , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Biópsia , Exame Retal Digital , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Próstata/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Estudos RetrospectivosRESUMO
Aldehyde hydrogenases (ALDHs) belong to a large gene family involved in oxidation of both endogenous and exogenous compounds in mammalian tissues. Among ALDHs, the rat ALDH1A7 gene displays a curious strain dependence in phenobarbital (PB)-induced hepatic expression: the responsive RR strains exhibit induction of both ALDH1A7 and CYP2B mRNAs and activities, whereas the nonresponsive rr strains show induction of CYP2B only. Here, we investigated the responsiveness of ALDH1A1, ALDH1A7, CYP2B1, and CYP3A23 genes to prototypical P450 inducers, expression of nuclear receptors CAR and pregnane X receptor, and structure of the ALDH1A7 promoter in both rat strains. ALDH1A7 mRNA, associated protein and activity were strongly induced by PB and modestly induced by pregnenolone 16α-carbonitrile in the RR strain but negligibly in the rr strain, whereas induction of ALDH1A1 and P450 mRNAs was similar between the strains. Reporter gene and chromatin immunoprecipitation assays indicated that the loss of ALDH1A7 inducibility in the rr strain is profoundly linked with a 16-base pair deletion in the proximal promoter and inability of the upstream DNA sequences to recruit constitutive androstane receptor-retinoid X receptor heterodimers. SIGNIFICANCE STATEMENT: Genetic variation in rat ALDH1A7 promoter sequences underlie the large strain-dependent differences in expression and inducibility by phenobarbital of the aldehyde dehydrogenase activity. This finding has implications for the design and interpretation of pharmacological and toxicological studies on the effects and disposition of aldehydes.
Assuntos
Família Aldeído Desidrogenase 1/biossíntese , Família Aldeído Desidrogenase 1/genética , Regulação Enzimológica da Expressão Gênica , Variação Genética/fisiologia , Animais , Masculino , Ratos , Ratos Wistar , Especificidade da EspécieRESUMO
OBJECTIVES: Clinical recognition of vascular acrosyndromes is often challenging. The term Raynaud's phenomenon (RP) is commonly overused to describe any form of cold-related disorder. This study aims to formally evaluate peripheral vascular symptoms affecting the population, aged ≤ 40 years, and identify any correlations to joint hypermobility (JH). PATIENTS AND METHODS: Fifty patients (31 males, 19 females) with vasomotor symptoms enrolled in this five-year prospective observational study. Clinical examination by a rheumatologist and a vascular surgeon was performed along with cardiology, echocardiographic and Doppler evaluation. Patients underwent blood cell count, biochemistry, thyroid and selectively immunologic testing. Twenty-four (48%) of them performed nailfold capillaroscopy. The SPSS for Windows, v.17.0, Chicago, USA, was used for the statistical analyses. RESULTS: Twenty-eight patients (56%) presented with erythromelalgia (EM), 6 (12%) with acrocyanosis (AC) and 9 (18%) as a combination of the above disorder. RP diagnosed in five (10%) while two patients (4%) presented as a mix of EM-RP. There was no correlation with abnormal laboratory tests. Increased incidence of JH was found in EM and AC patients. Among those who were tested with nailfold capillaroscopy, 75% had abnormalities ranged from mild to autoimmune-like diseases. CONCLUSIONS: Erythromelalgia is the commonest functional vasculopathy in young population followed by acrocyanosis and a combination of these conditions. Joint hypermobility is markedly increased, indicating that dysautonomy may be considered the causative factor following a trigger event. Overall, RP was observed in 14% of patients. Clinical recognition of these disorders avoids unnecessary investigation. Key Points ⢠Vascular acrosyndromes in young adults are commonly functional disorders resembling vascular algodystrophy induced by thermic stress. ⢠Dysautonomy of joint hypermobility is the co-factor influencing the appearance of the vascular disorders. ⢠Raynaud's phenomenon accounts to approximately 14% of vascular acrosyndromes presented in the young adult population.
Assuntos
Instabilidade Articular/complicações , Doença de Raynaud/complicações , Doenças Vasculares/complicações , Adolescente , Adulto , Cianose/complicações , Eritromelalgia/complicações , Feminino , Humanos , Incidência , Masculino , Angioscopia Microscópica , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Flunitrazepam, also known as "Rohypnol" or "Rophy" among other trade and street names, is an extremely potent benzodiazepine that is prescribed to treat severe insomnia. Due to these attributes, flunitrazepam, when is surreptitiously administered to an alcoholic or soft drink, is associated with "drug-facilitated sexual assault". We report here for the first time, a low cost lab-on-a-screen-printed electrochemical cell (SPC) based on iron-sparked graphite working electrode modified with glucose oxidase (GOx) and glucose hydrogel droplets (GluHD) for the detection of flunitrazepam. Iron-spark modification increases the response of the sensor by ca. 3-fold compared with that of the plain electrode, while an in situ deoxygenation process, based on GOx-glucose enzyme reaction, depletes dissolved oxygen. As a result, the method enables interference free voltammetric measurements of the electro reduction of the nitro group of flunitrazepam at ca. -0.71 to -0.78â¯V vs. Ag printed pseudo reference electrode depending on the sample's matrix, and the detection of the drug at the sub-millimolar level. GOx/GluHD-FeSPC was directly applied to the drop-volume (â¼60⯵L) detection of flunitrazepam to a wide range of untreated and undiluted spiked samples (Pepsi cola®, Vodka, Whisky, Tequila, Gin, and Rum) of different acidity (pH 2.3-8.4), and alcohol content up to 40% v/v. Data demonstrate the excellent performance of the sensor for point-of-need screening of flunitrazepam and suggest that GOx/GluHD-FeSPC holds promise as an effective analytical tool to prevent phenomena of covert drug administration.
Assuntos
Bebidas Alcoólicas/análise , Ansiolíticos/análise , Técnicas Biossensoriais/métodos , Bebidas Gaseificadas/análise , Flunitrazepam/análise , Aspergillus niger/enzimologia , Técnicas Eletroquímicas/métodos , Eletrodos , Glucose/química , Glucose Oxidase/química , Grafite/química , Humanos , Limite de Detecção , Oxigênio/químicaRESUMO
Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor's neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Evasão Tumoral/efeitos dos fármacos , Adjuvantes Imunológicos/efeitos adversos , Administração Metronômica , Inibidores da Angiogênese/efeitos adversos , Animais , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Dose Máxima Tolerável , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
BACKGROUND/AIMS: Isoniazid (ISO) has been reported to inhibit the hepatic aldehyde dehydrogenase (ALDH) and to cause a disulfiram (DIS)-like reaction, albeit there are no reports demonstrating increased blood acetaldehyde levels after co-administration of ISO with alcohol. The aim of our study was to clarify whether the alcohol intolerance produced by ISO is indeed due to a typical DIS-like reaction. METHODS: DIS and ISO were administered to Wistar rats and the hepatic ethanol (ETH) metabolizing enzyme activities along with the levels of brain monoamines were determined. Blood acetaldehyde levels were also evaluated after co-administration of ETH with DIS or ISO. RESULTS: Despite inhibition of the hepatic ALDH, ISO did not result in elevated blood acetaldehyde levels after ETH administration, probably due to the induction of cytochrome P450 2E1 which theoretically leads to an increased elimination rate of acetaldehyde preventing its accumulation. Moreover, ISO produced some minor, but statistically significant, alterations in central monoaminergic neurotransmission. CONCLUSION: Our results demonstrate for the first time that despite ALDH inhibition ISO does not provoke a typical DIS-like reaction since it does not increase blood acetaldehyde levels after co-administration with ETH. The possibility that the ETH intolerance observed in ISO treatment is a central synergistic effect cannot be excluded.
Assuntos
Acetaldeído/sangue , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/metabolismo , Dissulfiram/farmacologia , Etanol/toxicidade , Isoniazida/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Metronomic oral vinorelbine (VRL; Navelbine) was shown in clinical trials to yield sustainable antitumor activity possibly through antiangiogenic mechanisms. We investigated the effects of protracted low-dose VRL on human umbilical vein endothelial cells, compared with a conventional chemotherapy model. Human umbilical vein endothelial cell cultures were treated with different concentrations of VRL (0.001 nmol/l to 1 mmol/l) for 4, 24 and 96 h. The effects of different drug concentrations on cell growth, cell cycle, apoptosis and expression of the angiogenesis-modulating genes interleukin-8, cyclooxygenase-2, CD36 and peroxisome proliferator-activated receptor γ were assessed using the metronomic or conventional chemotherapy model. Apoptosis and cell-cycle effects were assessed by flow cytometry. Gene expression was measured at the transcript level by quantitative reverse transcriptase-PCR, protein expression by immunoblotting and levels of proteins secreted in the cell medium by enzyme-linked immunosorbent assay. Activation of the nuclear factor-κB pathway was investigated by immunoblot analysis of cytosolic and nuclear protein extracts. The half-maximal inhibitory concentrations (IC50) of VRL at 96 h were four orders lower compared with those after a 24-h exposure (1.23 nmol/l vs. 32 mmol/l for VRL). Drug concentrations at high nanomolar levels and above, which are relevant to conventional pulsatile dosing of VRL, induced a dose-dependent and nuclear factor-κB-related increase in proangiogenic interleukin-8 and cyclooxygenase-2 and a decrease in the thrombospondin-1 receptor CD36 and peroxisome proliferator-activated receptor γ at mRNA and protein levels. In contrast, the opposite was evident with protracted picomolar to low nanomolar concentrations (metronomic dosing). Our data provide experimental support for metronomic VRL by showing that a protracted low dose outperforms pulsed high-dose administration in inducing antiangiogenic effects in proliferating human endothelial cells.
Assuntos
Antineoplásicos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Vimblastina/análogos & derivados , Administração Metronômica , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , NF-kappa B/metabolismo , Neovascularização Fisiológica/genética , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Transcrição Gênica , Vimblastina/administração & dosagem , Vimblastina/farmacologia , VinorelbinaRESUMO
BACKGROUND: Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3) and some of their proteins. METHODS: Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary. RESULTS: Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas. CONCLUSIONS: The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself.
Assuntos
Adenocarcinoma/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Meningioma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Aldeído Oxidase/genética , Aldeído Oxidase/metabolismo , Astrocitoma/metabolismo , Astrocitoma/patologia , Astrocitoma/cirurgia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Feminino , Perfilação da Expressão Gênica , Glutationa S-Transferase pi/genética , Glutationa S-Transferase pi/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Meningioma/metabolismo , Meningioma/patologia , Meningioma/cirurgia , Desintoxicação Metabólica Fase I/genética , Desintoxicação Metabólica Fase II/genética , Pessoa de Meia-IdadeRESUMO
Chronic wounds develop when the sequence of healing events are disrupted, usually in patients with underlying diseases such as diabetes mellitus, venous insufficiency, peripheral artery disease, and neuropathies and they affect most often the lower extremities. We present a 68-year-old woman with plantar ulceration, lasting for approximately 18 months, resistant to healing with conventional therapy and various modalities we used. The patient had a long history of seronegative enteropathic arthritis, Crohn's disease, secondary fibrillar amyloidosis, multiplex neuropathy, and small vessel vasculitis, the latter being the trigger event for the ulceration of her right foot. Before the decision for a final surgical intervention, we implemented a mechanical periodic stimulus using a soft toothbrush, which resulted in the gradual and complete healing of the ulcer within a period of 6 weeks. Patient's history and previous treatments are presented along with the procedures that led to the healing of the chronic wound. This report supports the idea that periodic mechanical stimulus is of great importance for the healing process and this could be the mechanism of action of some other methods that have been described in the medical literature.
Assuntos
Úlcera da Perna/terapia , Modalidades de Fisioterapia , Cicatrização , Idoso , Doença Crônica , Feminino , Seguimentos , Pé , Humanos , Úlcera da Perna/diagnóstico , Estimulação Física/métodos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer. METHODS: Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics. RESULTS: Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9% (11.1%-46.2% 95% Confidence Interval), 33.3% (15.6%-55.3%) and 18.2% (5.2%-40.3%) for the 30 mg, 40 mg and 50 mg arms (p-value = 0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance. CONCLUSIONS: Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT00278070.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Vimblastina/análogos & derivados , Administração Oral , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Tempo para o Tratamento , Pesquisa Translacional Biomédica , Vimblastina/administração & dosagem , Vinorelbina , Adulto JovemRESUMO
Malassezia yeasts are commensal microorganisms, which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia-associated diseases demonstrated 10- to 1,000-fold higher AhR-activating capacity than control skin extracts. Liquid chromatography-tandem mass spectrometry analysis of the patients' extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9 out of 12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture extracts and pure metabolites in HaCaT cells by reverse transcriptase real-time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1, and AhRR. Indirubin- and FICZ-activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared with the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development.
Assuntos
Dermatomicoses/microbiologia , Malassezia/crescimento & desenvolvimento , Malassezia/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/microbiologia , Carcinoma Hepatocelular , Extratos Celulares , Linhagem Celular Transformada , Linhagem Celular Tumoral , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Dermatomicoses/metabolismo , Dermatomicoses/patologia , Homeostase/fisiologia , Humanos , Indóis/metabolismo , Queratinócitos/citologia , Queratinócitos/microbiologia , Neoplasias Hepáticas , Malassezia/isolamento & purificação , RNA Mensageiro/metabolismo , Pele/metabolismoRESUMO
Bleomycin is a key component of curative chemotherapy regimens employed in the treatment of curable cancers, such as Hodgkin lymphoma (HL) and testicular germ-cell tumours (GCT), yet its use may cause bleomycin-induced lung injury (BILI), which is associated with significant morbidity and a mortality rate of 1-3%. Diagnosis of BILI is one of exclusion and physicians involved in the care of HL and GCT patients should be alerted. Pharmacogenomic studies could contribute towards the identification of molecular predictors of bleomycin toxicity on the aim to optimize individual use of bleomycin. We review all existing data on bleomycin's most recent integrated chemical biology, molecular pharmacology and mature clinical data and provide guidelines for its safe clinical use.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Lesão Pulmonar/induzido quimicamente , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Bleomicina/farmacologia , Bleomicina/uso terapêutico , Humanos , Incidência , Lesão Pulmonar/diagnóstico , Lesão Pulmonar/epidemiologia , Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/terapia , Guias de Prática Clínica como Assunto , Fatores de RiscoRESUMO
DNA damage responses (DDR) invoke senescence or apoptosis depending on stimulus intensity and the degree of activation of the p53-p21(Cip1/Waf1) axis; but the functional impact of NF-κB signaling on these different outcomes in normal vs. human cancer cells remains poorly understood. We investigated the NF-κB-dependent effects and mechanism underlying reactive oxygen species (ROS)-mediated DDR outcomes of normal human lung fibroblasts (HDFs) and A549 human lung cancer epithelial cells. To activate DDR, ROS accumulation was induced by different doses of H(2)O(2). The effect of ROS induction caused a G2 or G2-M phase cell cycle arrest of both human cell types. However, ROS-mediated DDR eventually culminated in different end points with HDFs undergoing premature senescence and A549 cancer cells succumbing to apoptosis. NF-κB p65/RelA nuclear translocation and Ser536 phosphorylation were induced in response to H(2)O(2)-mediated ROS accumulation. Importantly, blocking the activities of canonical NF-κB subunits with an IκBα super-repressor or suppressing canonical NF-κB signaling by IKKß knock-down accelerated HDF premature senescence by up-regulating the p53-p21(Cip1/Waf1) axis; but inhibiting the canonical NF-κB pathway exacerbated H(2)O(2)-induced A549 cell apoptosis. HDF premature aging occurred in conjunction with γ-H2AX chromatin deposition, senescence-associated heterochromatic foci and beta-galactosidase staining. p53 knock-down abrogated H(2)O(2)-induced premature senescence of vector control- and IκBαSR-expressing HDFs functionally linking canonical NF-κB-dependent control of p53 levels to ROS-induced HDF senescence. We conclude that IKKß-driven canonical NF-κB signaling has different functional roles for the outcome of ROS responses in the contexts of normal vs. human tumor cells by respectively protecting them against DDR-dependent premature senescence and apoptosis.
Assuntos
Dano ao DNA/efeitos dos fármacos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Reparo do DNA , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Fosforilação , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
AIM: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer. METHODS: Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins. RESULTS: Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL. CONCLUSIONS: Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/tratamento farmacológico , Vimblastina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Esquema de Medicação , Avaliação de Medicamentos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/farmacocinética , VinorelbinaRESUMO
PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received escalated doses of paclitaxel (starting dose: 100 mg/m(2)), gemcitabine (starting dose: 800 mg/m(2)) and oxaliplatin (starting dose: 50 mg/m(2)) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle. RESULTS: Twenty-seven patients (median age 65 years) with performance status 0-1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m(2), gemcitabine 1,150 mg/m(2) and LOHP 70 mg/m(2). The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected. CONCLUSIONS: The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m(2), gemcitabine 1,000 mg/m(2) and oxaliplatin 70 mg/m(2) every 2 weeks. The regimen is generally well tolerated and merits further evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Febre/induzido quimicamente , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Paclitaxel/administração & dosagem , GencitabinaRESUMO
BACKGROUND: : Lipoplatin is a new liposomal cisplatin that already has been tested in solid tumors, with encouraging results. The purpose of the current study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a 21-day regimen of lipoplatin plus a fixed dose of gemcitabine in patients with refractory or resistant nonsmall cell lung carcinoma (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status of =2. METHODS: : The lipoplatin dose was escalated at 100 mg/m(2) by increments of 10 mg/m(2) on Days 1 and 8, with gemcitabine at a dose of 1000 mg/m(2) administered on Days 1 and 8, repeated every 21 days. Hematopoietic growth factors were not allowed. Thirteen patients with advanced stage NSCLC who had been pretreated with platinum combination chemotherapy were enrolled in this phase 1 trial. At least 3 patients were entered at each dose level. RESULTS: : At the fourth dose level, the DLT was reached (grade 3 neutropenia [according to World Health Organization criteria] in 3 of 4 patients 75%]; the fourth patient demonstrated degradation of performance status). Therefore, the third dose level (lipoplatin at a dose of 120 mg/m(2)) was defined as the MTD. At the same dose level, 2 of 4 patients had grade 3 thrombocytopenia. At the fourth dose level, 1 patient achieved a partial response and 1 patient had stable disease. Another patient achieved stable disease at the second dose level. Therefore, the overall disease control rate was 23% (3 of 13 patients). The median overall survival was 29 weeks (range, 4 weeks-59 weeks) and the median time to disease progression was 12 weeks (range, 3 weeks-36 weeks). CONCLUSIONS: : The pharmacokinetic profile of the 2 compounds used in the current study are not modified when they are administered according to the schedule evaluated in this trial. When one considers that the patients in the current study had refractory or resistant NSCLC, the authors concluded that the combination of lipoplatin administered at a dose of 120 mg/m(2) and gemcitabine administered at a dose of 1000 mg/m(2) on Days 1 and 8 every 3 weeks needs to be studied further in phase 2 trials. Cancer 2008. (c) 2008 American Cancer Society.