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AIM: The effect of switching from lithium immediate release (Li-IR) to lithium prolonged release (Li-PR) on lithium-induced tremor after 1 and 12 weeks of treatment was evaluated in a randomized, multicenter, open trial, in bipolar patients from the participating sites with a tremor severity ≥2 (Udvalg for Kliniske Undersøgelser [UKU] rating scale) despite optimal lithium titration. METHODS: The primary endpoint was the evaluation of tremor by means of the UKU scale after 1 week of treatment. Secondary endpoints included manic Young Mania Rating Scale (YMRS) and depressive symptoms (Montgomery-Asberg Depression Rating Scale), a global assessment of the patient's status (Clinical Global Impression), polyuria/polydipsia (UKU item 3.8) and patient-reported outcomes. RESULTS: Owing to difficulties in including suitable patients the enrollment phase was closed when 73 patients were randomized. Notwithstanding the lower number of patients, in the modified intention-to-treat population (n = 70) the primary endpoint was statistically significant: tremor improved after 1 week in 62.9% in Li-PR group against 20.0% of patients in Li-IR group (p = .0006; two-tailed Fisher's exact test). The difference remained statistically significant after 4 (p = .0031) and 12 weeks (p = .0128). The same analysis performed in the PP population confirmed these results. Among the secondary endpoints, only the factor convenience of the treatment satisfaction questionnaire showed a statistically significant difference between groups. There were no apparent differences in the safety profile of the two formulations. CONCLUSIONS: This study is the first comparative documentation of a potential benefit of the prolonged-release formulation in reducing the symptom tremor, a well-known adverse effect of lithium therapy. Indeed, the study results should be interpreted taking into account the sample size lower than planned.
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Trastorno Bipolar , Litio , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/tratamiento farmacológico , Método Doble Ciego , Humanos , Litio/efectos adversos , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , TemblorRESUMEN
PURPOSE: To evaluate the ability of the new food supplement, Body Lipid (BL), containing red yeast rice, berberine, coenzyme Q10 and hydroxytyrosol, to lower the LDL-C in patients with mild-to-moderate hypercholesterolemia and to assess the overall safety profile of the product. METHODS: In this multicenter, randomized, double-blind, placebo and active comparator (the marketed Armolipid Plus® [AM]) controlled study, 158 hypercholesterolemic patients were randomized following a 4-week dietary run-in period. After 4 weeks of treatment with a daily oral dose of the new food supplement BL, AM or placebo, plus diet, the main outcome was the decrease of LDL-C, total cholesterol (TC), and triglyceride levels. FINDINGS: The absolute changes of LDL-C and TC levels from baseline, at week 4 were: -39.1 mg/dL ±17.76 and -45.9 mg/dL ±21.54, respectively in the BL group; 5.7 mg/dL ±14.98 and 2.4 mg/dL ±18.43, respectively in the placebo group. Results were statistically significant. In terms of mean percentage, BL was shown to be more effective in lowering LDL-C levels as compared to placebo and the active comparator (AM), with a reduction of -26.3%, +4.2%, -18.3%, respectively. Five adverse events (AEs) were reported by five patients after the initiation of the study treatment: two in the BL group (influence and insomnia), two in the AM group (ear pain and rash), and one in the placebo group (back pain). All AEs were mild in intensity, except for back pain (severe). The case of insomnia in the BL group and the case of rash in the AM group were judged as treatment related. The safety review of the laboratory (blood and urine) analyses, vital signs and physical findings did not show any clinical effect of the study products on any of the parameters. IMPLICATIONS: BL showed a good efficacy and safety profile and, for this reason, it can be considered an alternative to pharmacological treatment, for patients with mild-to-moderate hypercholesterolemia.
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Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Suplementos Dietéticos , Hipercolesterolemia/tratamiento farmacológico , Adulto , Anciano , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Regulación hacia Abajo , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Italia , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: Dupuytren's disease (DD) is a proliferative fibromatosis of the hand, which causes permanent flexion contracture of the digits and, ultimately, loss of function. The treatment of DD is complex and involves surgical and nonsurgical approaches, with the goal of removing the affected tissue. New biological targets are under investigation in order to develop innovative therapies. AREAS COVERED: The etiology of DD is still unknown. Several authors who focused their studies on the genetics of DD recognized an inherited autosomal dominant pattern. Actually, DD is a multifactorial and complex disease. Myofibroblasts are thought to play a crucial role in its pathogenesis, although their origin is not clear. EXPERT OPINION: There is a general consensus that a better understanding of cellular and molecular mechanisms of DD will lead to the design of more specific and effective treatment alternatives. In this review, the authors hypothesize a new biological model for DD pathology, where myofibroblasts enhance the reservoir of the disease acting as if in a vicious cycle. This could help, ultimately, in identifying new therapeutic strategies to treat this common and disabling fibroproliferative disorder.
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Contractura de Dupuytren/tratamiento farmacológico , Terapia Molecular Dirigida , Miofibroblastos/metabolismo , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Contractura de Dupuytren/genética , Contractura de Dupuytren/fisiopatología , HumanosRESUMEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.
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Citotoxinas/farmacología , Glioblastoma/tratamiento farmacológico , Piranos/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Animales , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Ratones DesnudosRESUMEN
BACKGROUND: Chemoresistance of glioblastoma multiforme (GBM) has been attributed to the presence within the tumor of cancer stem cells (GSCs). The standard therapy for GBM consists of surgery followed by radiotherapy and the chemotherapeutic agent temozolomide (TMZ). However, TMZ efficacy is limited by O6-methylguanine-DNA-methyltransferase (MGMT) and Mismatch Repair (MMR) functions. Strategies to counteract TMZ resistance include its combination with poly(ADP-ribose) polymerase inhibitors (PARPi), which hamper the repair of N-methylpurines. PARPi are also investigated as monotherapy for tumors with deficiency of homologous recombination (HR). We have investigated whether PARPi may restore GSC sensitivity to TMZ or may be effective as monotherapy. METHODS: Ten human GSC lines were assayed for MMR proteins, MGMT and PARP-1 expression/activity, MGMT promoter methylation and sensitivity to TMZ or PARPi, alone and in combination. Since PTEN defects are frequently detected in GBM and may cause HR dysfunction, PTEN expression was also analyzed. The statistical analysis of the differences in drug sensitivity among the cell lines was performed using the ANOVA and Bonferroni's post-test or the non-parametric Kruskal-Wallis analysis and Dunn's post-test for multiple comparisons. Synergism between TMZ and PARPi was analyzed by the median-effect method of Chou and Talalay. Correlation analyses were done using the Spearman's rank test. RESULTS: All GSCs were MMR-proficient and resistance to TMZ was mainly associated with high MGMT activity or low proliferation rate. MGMT promoter hypermethylation of GSCs correlated both with low MGMT activity/expression (Spearman's test, P = 0.004 and P = 0.01) and with longer overall survival of GBM patients (P = 0.02). Sensitivity of each GSC line to PARPi as single agent did not correlate with PARP-1 or PTEN expression. Notably, PARPi and TMZ combination exerted synergistic antitumor effects in eight out of ten GSC lines and the TMZ dose reduction achieved significantly correlated with the sensitivity of each cell line to PARPi as single agent (P = 0.01). CONCLUSIONS: The combination of TMZ with PARPi may represent a valuable strategy to reverse GSC chemoresistance.
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Antineoplásicos Alquilantes/farmacología , Dacarbazina/análogos & derivados , Resistencia a Antineoplásicos , Glioblastoma/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Línea Celular Tumoral , Islas de CpG , Metilación de ADN , Dacarbazina/farmacología , Glioblastoma/genética , Glioblastoma/mortalidad , Humanos , O(6)-Metilguanina-ADN Metiltransferasa/genética , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Regiones Promotoras Genéticas , TemozolomidaRESUMEN
The metabolic profiles of glioblastoma stem-like cells (GSCs) growing in neurospheres were examined by (1)H NMR spectroscopy. Spectra of two GSC lines, labelled 1 and 83, from tumours close to the subventricular zone of the temporal lobe were studied in detail and compared with those of neural stem/progenitor cells from the adult olfactory bulb (OB-NPCs) and of the T98G glioblastoma cell line. In both GSCs, signals from myoinositol (Myo-I), UDP-hexosamines (UDP-Hex) and glycine indicated an astrocyte/glioma metabolism. For line 1, the presence of signals from N-acetyl aspartate, GABA and creatine pointed to a neuronal fingerprint. These metabolites were almost absent from line 83 spectra, whereas lipid signals, absent from normal neural lineages, were intense in line 83 spectra and remained low in those of line 1, irrespective of apoptotic fate. Spectra of OB-NPC cells displayed strong similarities with those from line 1, with low lipid signals and clearly detectable neuronal signals. In contrast, the spectral profile of line 83 was more similar to that of T98G, displaying high lipids and nearly complete absence of the neuronal markers. A mixed neural-astrocyte metabolic phenotype with a strong neuronal fingerprint was therefore found in line 1, while an astrocytic/glioma-like metabolism prevailed in line 83. We found a signal assigned to the amide proton of N-acetyl galactosamine in GSC lines and in OB-NPC spectra, whereas it was absent from those of T98G cells. This signal may be related to a stem-cell-specific protein glycosylation pattern and is therefore suggested as a marker of cell multipotency. Other GSC lines from patients with different clinical outcomes were then examined. Unsupervised analysis of spectral data from 13 lines yielded two clusters, with six lines resembling spectral features of line 1 and seven resembling those of line 83, suggesting that distinct metabolic phenotypes may be present in GSC lines.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Células Madre Neoplásicas/metabolismo , Células-Madre Neurales/metabolismo , Línea Celular Tumoral , Humanos , Protones , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The epidermal growth factor receptor variant III (EGFRvIII) is associated with increased proliferation of glioma cells. However, the impact of EGFRvIII on survival of patients with glioblastoma (GBM) has not been definitively established. In the present study, we prospectively evaluated 73 patients with primary GBM treated with surgical resection and standard radio/chemotherapy. The EGFRvIII was assessed by reverse transcription-polymerase chain reaction (PCR), O(6)-methylguanine methyltransferase (MGMT) promoter methylation was assessed by methylation-specific PCR, and phosphatase and tension homolog (PTEN) expression was assessed by immunohistochemistry. In 14 patients of this series, who presented with tumor recurrence, EGFRvIII was determined by real-time PCR. Sensitivity to temozolomide (TMZ) was assessed in vitro on GBM neurosphere cell cultures with different patterns of EGFRvIII expression. Age 60 years or younger, preoperative Karnofsky Performance Status score of 70 or higher, recursive partitioning analysis score III and IV, methylated MGMT, and Ki67 index of 20% or less were significantly associated with longer overall survival (OS; P = .0069, P = .0035, P = .0007, P = .0437, and P = .0286, respectively). EGFRvIII identified patients with significantly longer OS (P = .0023) and the association of EGFRvIII/Ki67 of 20% or less, EGFRvIII/normal PTEN, EGFRvIII/methylated MGMT, and EGFRvIII/normal PTEN/methylated MGMT identified subgroups of GBM patients with better prognosis. In recurred GBMs, EGFRvIII expression was approximately two-fold lower than in primary tumors. In vitro, the EGFRvIII-negative GBM neurosphere cells were more resistant to TMZ than the positive ones. In conclusion, in contrast with previous studies, we found that EGFRvIII is associated with prolonged survival of GBM patients treated with surgery and radio/chemotherapy. Depletion of EGFRvIII in recurrent GBMs as well as differential sensitivity to TMZ in vitro indicates that the EGFRvIII-negative cell fraction is involved in resistance to radio/chemotherapy and tumor repopulation.
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Receptores ErbB/genética , Glioblastoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/farmacología , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Femenino , Expresión Génica/efectos de los fármacos , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Esferoides Celulares/efectos de los fármacos , Análisis de Supervivencia , Temozolomida , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.