RESUMEN
AIM: To construct a Treatment Response Index from Multiple Sensors (TRIMS) for quantification of motor state in patients with Parkinson's disease (PD) during a single levodopa dose. Another aim was to compare TRIMS to sensor indexes derived from individual motor tasks. METHOD: Nineteen PD patients performed three motor tests including leg agility, pronation-supination movement of hands, and walking in a clinic while wearing inertial measurement unit sensors on their wrists and ankles. They performed the tests repeatedly before and after taking 150% of their individual oral levodopa-carbidopa equivalent morning dose.Three neurologists blinded to treatment status, viewed patients' videos and rated their motor symptoms, dyskinesia, overall motor state based on selected items of Unified PD Rating Scale (UPDRS) part III, Dyskinesia scale, and Treatment Response Scale (TRS). To build TRIMS, out of initially 178 extracted features from upper- and lower-limbs data, 39 features were selected by stepwise regression method and were used as input to support vector machines to be mapped to mean reference TRS scores using 10-fold cross-validation method. Test-retest reliability, responsiveness to medication, and correlation to TRS as well as other UPDRS items were evaluated for TRIMS. RESULTS: The correlation of TRIMS with TRS was 0.93. TRIMS had good test-retest reliability (ICC = 0.83). Responsiveness of the TRIMS to medication was good compared to TRS indicating its power in capturing the treatment effects. TRIMS was highly correlated to dyskinesia (R = 0.85), bradykinesia (R = 0.84) and gait (R = 0.79) UPDRS items. Correlation of sensor index from the upper-limb to TRS was 0.89. CONCLUSION: Using the fusion of upper- and lower-limbs sensor data to construct TRIMS provided accurate PD motor states estimation and responsive to treatment. In addition, quantification of upper-limb sensor data during walking test provided strong results.
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Movimiento/efectos de los fármacos , Enfermedad de Parkinson , Dispositivos Electrónicos Vestibles , Anciano , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Levodopa/administración & dosificación , Levodopa/farmacología , Masculino , Persona de Mediana Edad , Máquina de Vectores de Soporte , Suecia , Caminata , MuñecaRESUMEN
INTRODUCTION: A treatment response objective index (TRIS) was previously developed based on sensor data from pronation-supination tests. This study aimed to examine the performance of TRIS for medication effects in a new population sample with Parkinson's disease (PD) and its usefulness for constructing individual dose-response models. METHODS: Twenty-five patients with PD performed a series of tasks throughout a levodopa challenge while wearing sensors. TRIS was used to determine motor changes in pronation-supination tests following a single levodopa dose, and was compared to clinical ratings including the Treatment Response Scale (TRS) and six sub-items of the UPDRS part III. RESULTS: As expected, correlations between TRIS and clinical ratings were lower in the new population than in the initial study. TRIS was still significantly correlated to TRS (rsâ¯=â¯0.23, Pâ¯<â¯0.001) with a root mean square error (RMSE) of 1.33. For the patients (nâ¯=â¯17) with a good levodopa response and clear motor fluctuations, a stronger correlation was found (rsâ¯=â¯0.38, RMSEâ¯=â¯1.29, Pâ¯<â¯0.001). The mean TRIS increased significantly when patients went from the practically defined off to their best on state (Pâ¯=â¯0.024). Individual dose-response models could be fitted for more participants when TRIS was used for modelling than when TRS ratings were used. CONCLUSION: The objective sensor index shows promise for constructing individual dose-response models, but further evaluations and retraining of the TRIS algorithm are desirable to improve its performance and to ensure its clinical effectiveness.
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Antiparkinsonianos/administración & dosificación , Levodopa/administración & dosificación , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Máquina de Vectores de Soporte , Dispositivos Electrónicos Vestibles , Acelerometría , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The present aim was to contribute to improving the traditional pelvic examination chair with vertical leg support and to evaluate patients' and examiners' experience of a new gyneacological and urological examination chair with heated upholstery. STUDY DESIGN: A new gynaecological and urological examination chair was constructed with laterally adjustable leg support, a foot-plate and the perineum exposed only during the examination procedure. Patients (nâ¯=â¯131) with or without endometriosis were invited to participate in an anonymous questionnaire survey concerning how they experienced a gynaecological examination. MAIN OUTCOME MEASURES: The patients and the gynaecologists who performed the examinations answered questionnaires evaluating the examination procedure in the traditional and in the new gynaecological and urological examination chair, respectively. The questionnaires asked about comfort, heating, integrity and the experience of pelvic examination with vertical or lateral leg support. The examination times were measured with a stop-watch. RESULTS: The majority of the answers (nâ¯=â¯131) were significantly (pâ¯<â¯0.05-0.001) in favour of the new concept with lateral leg support and with increased comfort and integrity. The average examination time was significantly shortened and the patients more relaxed in the new gynaecological and urological examination chair. CONCLUSION: The traditional gynaecological chair with vertical leg support has remained basically unchanged for many years. The present study showed that the pelvic examination procedure can be significantly optimized with easy patient-friendly adaptations.
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Actitud del Personal de Salud , Examen Ginecologíco/instrumentación , Diseño Interior y Mobiliario , Satisfacción del Paciente , Endometriosis/diagnóstico , Diseño de Equipo , Femenino , Calefacción , Humanos , Masculino , Comodidad del Paciente , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
AIM: This 4-week open-label observational study describes the effect of introducing a microtablet dose dispenser and adjusting doses based on objective free-living motor symptom monitoring in individuals with Parkinson's disease (PD). METHODS: Twenty-eight outpatients with PD on stable levodopa treatment with dose intervals of ≤4 hour had their daytime doses of levodopa replaced with levodopa/carbidopa microtablets, 5/1.25 mg (LC-5) delivered from a dose dispenser device with programmable reminders. After 2 weeks, doses were adjusted based on ambulatory accelerometry and clinical monitoring. RESULTS: Twenty-four participants completed the study per protocol. The daily levodopa dose was increased by 15% (112 mg, P < 0.001) from period 1 to 2, and the dose interval was reduced by 12% (22 minutes, P = 0.003). The treatment adherence to LC-5 was high in both periods. The MDS-UPDRS parts II and III, disease-specific quality of life (PDQ-8), wearing-off symptoms (WOQ-19), and nonmotor symptoms (NMS Quest) improved after dose titration, but the generic quality-of-life measure EQ-5D-5L did not. Blinded expert evaluation of accelerometry results demonstrated improvement in 60% of subjects and worsening in 25%. CONCLUSIONS: The introduction of a levodopa microtablet dispenser and accelerometry aided dose adjustments improve PD symptoms and quality of life in the short term.
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Acelerometría , Antiparkinsonianos/administración & dosificación , Carbidopa/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Medicina de Precisión/métodos , Acelerometría/métodos , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/efectos adversos , Carbidopa/efectos adversos , Combinación de Medicamentos , Femenino , Humanos , Levodopa/efectos adversos , Estudios Longitudinales , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Calidad de Vida , Método Simple Ciego , Comprimidos/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments. OBJECTIVES: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson's disease. METHODS: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists. RESULTS: AUC0-4/dose and C max/dose for levodopa was found to be higher in Parkinson's disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13). CONCLUSIONS: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0-4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.
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Antiparkinsonianos/uso terapéutico , Carbidopa/uso terapéutico , Levodopa/uso terapéutico , Actividad Motora , Enfermedad de Parkinson/tratamiento farmacológico , Comprimidos , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/administración & dosificación , Área Bajo la Curva , Carbidopa/administración & dosificación , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.
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Melfalán/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Fenilalanina/análogos & derivados , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Procedimientos Quirúrgicos de Citorreducción , Supervivencia sin Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Hipertermia Inducida , Inyecciones Intraperitoneales , Melfalán/uso terapéutico , Ratones , Ratones SCID , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Peritoneales/patología , Fenilalanina/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Chemotherapy options in advanced urothelial carcinoma (UC) remain limited. Here we evaluated the peptide-based alkylating agent melphalan-flufenamide (mel-flufen) for UC. METHODS: UC cell lines J82, RT4, TCCsup and 5637 were treated with mel-flufen, alone or combined with cisplatin, gemcitabine, dasatinib or bestatin. Cell viability (MTT assay), intracellular drug accumulation (liquid chromatography) apoptosis induction (apoptotic cell nuclei morphology, western blot analysis of PARP-1/caspase-9 cleavage and Bak/Bax activation) were evaluated. Kinome alterations were characterized by PathScan array and phospho-Src validated by western blotting. Aminopeptidase N (ANPEP) expression was evaluated in UC clinical specimens in relation to patient outcome. RESULTS: In J82, RT4, TCCsup and 5637 UC cells, mel-flufen amplified the intracellular loading of melphalan in part via aminopeptidase N (ANPEP), resulting in increased cytotoxicity compared to melphalan alone. Mel-flufen induced apoptosis seen as activation of Bak/Bax, cleavage of caspase-9/PARP-1 and induction of apoptotic cell nuclei morphology. Combining mel-flufen with cisplatin or gemcitabine in J82 cells resulted in additive cytotoxic effects and for gemcitabine also increased apoptosis induction. Profiling of mel-flufen-induced kinome alterations in J82 cells revealed that mel-flufen alone did not inhibit Src phosphorylation. Accordingly, the Src inhibitor dasatinib sensitized for mel-flufen cytotoxicity. Immunohistochemical analysis of the putative mel-flufen biomarker ANPEP demonstrated prominent expression levels in tumours from 82 of 83 cystectomy patients. Significantly longer median overall survival was found in patients with high ANPEP expression (P = 0.02). CONCLUSION: Mel-flufen alone or in combination with cisplatin, gemcitabine or Src inhibition holds promise as a novel treatment for UC.
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Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Dasatinib/farmacología , Melfalán/análogos & derivados , Fenilalanina/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Urológicas/tratamiento farmacológico , Familia-src Quinasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Melfalán/farmacología , Fenilalanina/farmacología , Neoplasias Urológicas/patología , Urotelio/efectos de los fármacos , Urotelio/patología , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
PURPOSE: Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. METHODS: This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). RESULTS: In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. CONCLUSIONS: In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.
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Antineoplásicos Alquilantes/administración & dosificación , Melfalán/análogos & derivados , Neoplasias/tratamiento farmacológico , Fenilalanina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Alquilación/efectos de los fármacos , Alquilación/fisiología , Antineoplásicos Alquilantes/efectos adversos , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Neoplasias/diagnóstico , Péptido Hidrolasas/metabolismo , Fenilalanina/administración & dosificación , Fenilalanina/efectos adversos , Estudios ProspectivosRESUMEN
BACKGROUND: To determine whether current hygiene practices are appropriate during sonographic examinations. METHODS: Five major hospitals in Sweden were investigated with a survey. At each hospital, the departments corresponding to the main types of sonographic examination were chosen. Personnel who were responsible for or acquainted with the local hygiene procedures completed a standardardized questionnaire. RESULTS: The surveys were completed by 25 departments, where the total number of sonographic examinations was approximately 20,000 per month. For transvaginal and transrectal sonographic examinations, the most common method for decontamination of the transducer was barrier protection during the procedure followed by cleansing with alcohol. Latex was the predominant cover material, but one department used polyethylene gloves, and another department used nitrile gloves. Both of these involved transvaginal ultrasonography. In transcutaneous examinations, all hospitals were using alcohol and paper or cloth for decontamination at a minimum. Transesophageal examinations were carried out without barrier protection, and decontamination was performed with an alkylating substance. CONCLUSIONS: The hygiene practices appear to be appropriate at most hospitals, but there is a prevalence of transducer cover materials of unacceptable permeability, as well as use of gloves on transducers despite insufficient evidence of safety.
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Descontaminación/métodos , Contaminación de Equipos/prevención & control , Transductores , Ultrasonografía/instrumentación , Encuestas de Atención de la Salud , Hospitales/estadística & datos numéricos , Humanos , Encuestas y Cuestionarios , SueciaRESUMEN
OBJECTIVE: Pertubation with lidocaine has been shown to reduce pain (on a VAS-scale) in women with endometriosis. A clinical study was performed to evaluate the effect of lidocaine pertubations on quality of life. DESIGN: Double-blind, randomized and controlled trial. SETTING: Three outpatient units in Stockholm, Sweden. POPULATION: Eligible patients had endometriosis with dysmenorrhoic pain >VAS 50 mm. METHODS: The patients were randomized to pre-ovulatory pertubations with lidocaine (n = 24) or placebo (n = 18) during three consecutive menstrual cycles. The procedure comprised passing the solution through the uterus and the Fallopian tubes via an intracervical balloon catheter. The effect was evaluated with the validated Endometriosis Health Profile-30 questionnaire before and after treatments. MAIN OUTCOME MEASURES: Changes in scores at six and 12 months from baseline were compared between the groups with the Mann-Whitney U-test. RESULTS: After 6 months there was a significant difference between the lidocaine (n = 19) and the placebo (n = 16) groups for the dimension social support (median -18.8 vs. -6.3, p = 0.034), whereas there were no significant differences for the other dimensions after 6 or 12 months. The mean changes in the lidocaine group were above the minimal important difference levels in eight of 12 measurements of quality of life dimensions compared with two of 12 in the placebo group. CONCLUSIONS: This clinical trial indicates that pertubations with lidocaine might improve the social support dimension of quality of life in patients with endometriosis.
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Anestésicos Locales/administración & dosificación , Endometriosis/tratamiento farmacológico , Lidocaína/administración & dosificación , Calidad de Vida , Adulto , Método Doble Ciego , Endometriosis/psicología , Femenino , Humanos , Dolor/tratamiento farmacológico , Dimensión del Dolor , Apoyo Social , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
OBJECTIVE: The objective of this study was to report the serum concentration of lignocaine after pertubation in patients with endometriosis. DESIGN: Prospective observational study. SETTING: The study was carried out at a gynaecological outpatient unit in Stockholm, Sweden. POPULATION: Eligible patients had endometriosis with a dysmenorrhoic pain score of >50 mm on a visual analogue scale, and patent fallopian tubes. METHODS: Patients with endometriosis (n = 25) were included in the study. The patients received pre-ovulatory pertubations with lignocaine hydrochloride 10 mg (n = 16) or ringer acetate (placebo, n = 9). The procedure comprised passing the study solution through the uterus and the fallopian tubes via an intra-cervical balloon catheter. Serum samples were collected at 0, 5, 15 and 30 min after pertubation. MAIN OUTCOME MEASURES: The serum samples were analysed for the concentration of lignocaine with an LCMS-SIM method. RESULTS: Low levels of lignocaine were detected in the serum samples following pertubation of 10 mg lignocaine hydrochloride. The highest observed concentration was seen after 30 min (mean 0.050 µg/ml), with an individual maximum of 0.124 µg/ml. Maximum concentration (C max) and time to C max (T max) could not be calculated, since the highest values were observed in the 30-min samples, which was the last sample obtained. Lignocaine was not detected after pertubation with placebo. CONCLUSIONS: The serum levels of lignocaine following pertubation of 10 mg lignocaine hydrochloride are detectable but low. Lignocaine pertubated through the fallopian tubes reaches the peritoneal cavity and diffuses through the peritoneum into the blood circulation. Pertubation with lignocaine is safe and has no lignocaine-related adverse events.
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Anestésicos Locales/sangre , Dismenorrea/tratamiento farmacológico , Endometriosis/tratamiento farmacológico , Lidocaína/sangre , Enfermedades del Ovario/tratamiento farmacológico , Enfermedades Peritoneales/tratamiento farmacológico , Adulto , Anestésicos Locales/administración & dosificación , Anestésicos Locales/uso terapéutico , Cateterismo , Método Doble Ciego , Dismenorrea/sangre , Dismenorrea/etiología , Endometriosis/sangre , Endometriosis/complicaciones , Femenino , Humanos , Lidocaína/administración & dosificación , Lidocaína/uso terapéutico , Enfermedades del Ovario/sangre , Enfermedades del Ovario/complicaciones , Dimensión del Dolor , Enfermedades Peritoneales/sangre , Enfermedades Peritoneales/complicaciones , Estudios Prospectivos , Resultado del TratamientoRESUMEN
PURPOSE: The alkylating agent melphalan prolongs survival in patients with multiple myeloma; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (mel-flufen), a novel dipeptide prodrug of melphalan in multiple myeloma. EXPERIMENTAL DESIGN: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft animal model were used to study the antitumor activity of mel-flufen. RESULTS: Low doses of mel-flufen trigger more rapid and higher intracellular concentrations of melphalan in multiple myeloma cells than are achievable by free melphalan. Cytotoxicity analysis showed significantly lower IC50 of mel-flufen than melphalan in multiple myeloma cells. Importantly, mel-flufen induces apoptosis even in melphalan- and bortezomib-resistant multiple myeloma cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to melphalan, attenuates anti-multiple myeloma activity of mel-flufen. Furthermore, mel-flufen-induced apoptosis was associated with: (i) activation of caspases and PARP cleavage; (ii) reactive oxygen species generation; (iii) mitochondrial dysfunction and release of cytochrome c; and (iv) induction of DNA damage. Moreover, mel-flufen inhibits multiple myeloma cell migration and tumor-associated angiogenesis. Human multiple myeloma xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti-multiple myeloma activity. CONCLUSION: Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve multiple myeloma patient outcome.
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Antineoplásicos Alquilantes/farmacología , Melfalán/análogos & derivados , Mieloma Múltiple/patología , Fenilalanina/análogos & derivados , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos Alquilantes/administración & dosificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Humanos , Melfalán/administración & dosificación , Melfalán/farmacología , Ratones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Neovascularización Patológica/tratamiento farmacológico , Fenilalanina/administración & dosificación , Fenilalanina/farmacología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The major symptoms of endometriosis are dysmenorrhea and infertility. Pertubations with lidocaine have been shown to reduce dysmenorrhea and have an enhancing effect on fertility. Different concentrations of lidocaine were evaluated in a randomized, double-blind study of pre-ovulatory pertubations with lidocaine solutions in women with dysmenorrhea. The patients had laparoscopically diagnosed endometriosis and normal fallopian tubes. Ninety pertubations were carried out without complications on 26 patients during up to six cycles. The effect was evaluated by means of questionnaires where a clinically significant reduction of dysmenorrhea was reported. Pertubation with lidocaine can be a non-hormonal treatment option for dysmenorrhea.
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Anestésicos Locales/administración & dosificación , Dismenorrea/tratamiento farmacológico , Lidocaína/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Dismenorrea/etiología , Endometriosis/complicaciones , Femenino , Humanos , Enfermedades Uterinas/complicacionesRESUMEN
We optimized the immunogenicity of adjuvanted seasonal influenza vaccine based on commercial split influenza virus as an antigen (hemagglutinin = HA) and on a novel polycationic liposome as a potent adjuvant and efficient antigen carrier (CCS/C-HA vaccine). The vaccine was characterized physicochemically, and the mechanism of action of CCS/C as antigen carrier and adjuvant was studied. The optimized CCS/C-HA split virus vaccine, when administered intramuscularly (i.m.), is significantly more immunogenic in mice, rats and ferrets than split virus HA vaccine alone, and it provides for protective immunity in ferrets and mice against live virus challenge that exceeds the degree of efficacy of the split virus vaccine. Similar adjuvant effects of optimized CCS/C are also observed in mice for H1N1 swine influenza antigen. The CCS/C-HA vaccine enhances immune responses via the Th1 and Th2 pathways, and it increases both the humoral responses and the production of IL-2 and IFN-γ but not of the pro-inflammatory factor TNFα. In mice, levels of CD4(+) and CD8(+) T-cells and of MHC II and CD40 co-stimulatory molecules are also elevated. Structure-function relationship studies of the CCS molecule as an adjuvant/carrier show that replacing the saturated palmitoyl acyl chain with the mono-unsaturated oleoyl (C18:1) chain affects neither size distribution and zeta potential nor immune responses in mice. However, replacing the polyalkylamine head group spermine (having two secondary amines) with spermidine (having only one secondary amine) reduces the enhancement of the immune response by â¼ 50%, while polyalkylamines by themselves are ineffective in improving the immunogenicity over the commercial HA vaccine. This highlights the importance of the particulate nature of the carrier and the polyalkylamine secondary amines in the enhancement of the immune responses against seasonal influenza. Altogether, our results suggest that the CCS/C polycationic liposomes combine the activities of a potent adjuvant and efficient carrier of seasonal and swine flu vaccines and support further development of the CCS/C-HA vaccine.
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Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/química , Vacunas contra la Influenza/inmunología , Liposomas/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Animales , Antígenos Virales/inmunología , Citocinas/inmunología , Femenino , Hurones , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Inmunidad Celular , Inmunidad Humoral , Vacunas contra la Influenza/administración & dosificación , Inyecciones Intramusculares , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Infecciones por Orthomyxoviridae/inmunología , Ratas , Ratas Sprague-DawleyRESUMEN
Patients with haemophilia A treated prophylactically require frequent factor VIII (FVIII) infusions for bleed protection. Recombinant sucrose-formulated FVIII (rFVIII-FS) with pegylated liposomes (PEGLip-rFVIII-FS) was previously shown to extend the bleed-free period after prophylactic infusion versus rFVIII-FS using two doses of FVIII with a fixed amount of liposomal diluent. This randomised, subject-blinded, four-way crossover study evaluated the efficacy and safety of PEGLip-rFVIII-FS using various quantities of pegylated liposomes with a fixed FVIII dose. Adults with severe haemophilia A were randomised to one of four treatment arms. Each arm had four treatment segments, with each segment consisting of a prophylactic infusion followed by on-demand infusions. The prophylactic infusions used a fixed dose of 35 IU/kg rFVIII-FS, but varied in the amount of pegylated liposomes used for reconstitution (4.2, 12.6, or 22.1 mg/kg of body weight or water as a control). On-demand infusions all used 35 IU/kg rFVIII-FS. After treatment of spontaneous bleeds and a wash-out, subjects crossed to another treatment segment (i.e. another PEGLip-rFVIII-FS dose or control). Sixteen subjects enrolled in and completed the study. Mean number of bleed-free days after prophylactic infusion increased from 7.8 days for control rFVIII-FS to 8.7, 10.8, and 10.9 days for PEGLip-rFVIII-FS reconstituted in 4.2, 12.6, and 22.1 mg/kg of pegylated liposomes, respectively. The difference in bleed-free days approached but did not achieve statistical significance in this small study population. No drug-related adverse events or inhibitors were reported. This study helps establish the optimal concentration of liposomes in PEGLip-rFVIII-FS to prolong the post-infusion bleed-free period.
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Factor VIII/uso terapéutico , Hemofilia A/terapia , Liposomas/uso terapéutico , Sacarosa/uso terapéutico , Adulto , Estudios Cruzados , Factor VIII/química , Hemorragia/prevención & control , Humanos , Liposomas/química , Masculino , Persona de Mediana Edad , Modelos Genéticos , Polietilenglicoles/química , Seguridad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Artificial insemination (intrauterine insemination by husband or artificial insemination by husband) is often tried as first treatment for couples with unexplained infertility. Pertubation has previously proved to increase the chance of achieving pregnancy for these couples. The effect of pertubation on fertility can be mechanical as well as anti-inflammatory by using a substance that inhibits phagocytosis of the spermatozoa.The objective of the study was to investigate the effect on pregnancy rate of pre-ovulatory pertubation with low-dose lignocaine during clomiphene citrate and insemination cycles for couples with unexplained infertility. METHODS: Ina prospective, open study, the patients were randomized, the day before ovulation, during a clomiphene citrate stimulated cycle to either pertubation with low-dose local anaesthetic or no pertubation before insemination. RESULTS: A total of 130 cycles were studied, 67 of which were randomized to pre-ovulatory pertubation and 63 to no pertubation treatment. There were 14.9% (n 5 10) clinical pregnancies in the pertubated group compared with 3.2% (n 5 2) in the group without pre-ovulatory pertubation (P < 0.05). CONCLUSIONS: The pertubation treatment significantly enhanced the clinical pregnancy rate and was well tolerated. No complications were noted. The combined treatment of clomiphene citrate, pertubation and insemination can be used as a cost-effective, first-line treatment for couples with unexplained infertility.
Asunto(s)
Clomifeno/uso terapéutico , Fármacos para la Fertilidad Femenina/uso terapéutico , Infertilidad/terapia , Inseminación Artificial , Lidocaína/uso terapéutico , Adulto , Femenino , Humanos , Embarazo , Índice de Embarazo , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Prophylactic treatment for hemophilia A involves infusion of factor VIII (FVIII) concentrates every 2 to 3 days. Liposomes can be efficacious vehicles for medicines, and surface modification by PEGylation can prolong liposome circulation time. When reconstituted with PEGylated liposomes (PEGLip's), recombinant FVIII binds noncovalently but with high affinity to the external liposome surface. This preparation showed prolongation of FVIII half-life and increased protection from bleeding in preclinical models. Here we report a blinded, controlled, crossover, multicenter clinical study that evaluated the time free from bleeding episodes in patients with hemophilia A during prophylaxis with standard rFVIII (no liposomes) or PEGLip rFVIII (PEGLip reconstituted) at 25 and 35 IU/kg doses. Of 24 enrolled patients, 23 were eligible for efficacy analysis. Mean number of days without bleeds was 7.2 +/- 1.7 with standard rFVIII compared with 13.3 +/- 4.8 with PEGLip rFVIII at the 35 IU/kg dose and 5.9 +/- 1.7 with standard rFVIII versus 10.9 +/- 2.9 with PEGLip rFVIII at the 25 IU/kg dose (P < .05 between treatment groups for each dose). PEGLip rFVIII was well tolerated. These data suggest that reconstitution of rFVIII with PEGLip's may reduce the frequency of treatment during prophylaxis.
Asunto(s)
Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Hemorragia/prevención & control , Adolescente , Adulto , Estudios Cruzados , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Factor VIII/efectos adversos , Hemofilia A/complicaciones , Hemorragia/etiología , Humanos , Liposomas , Masculino , Factores de TiempoRESUMEN
Haemophilia A is a bleeding disorder caused by the lack of factor VIII (FVIII). We report the prolongation of exogenous FVIII circulation time and haemostatic efficacy by its formulation with PEGylated liposomes (PEGLip). FVIII binds non-covalently but with high affinity in a specific mode with the external surface of PEGLip neither losing its activity nor its binding to von Willebrand Factor. Experiments in haemophilic and non-haemophilic mice indicate that the circulation time and clotting efficacy of PEGLip-formulated exogenous FVIII (PEGLip-FVIII) are significantly enhanced over those of free FVIII. The data support the feasibility of using PEGLip-FVIII to extend the duration of haemostatic efficacy in the treatment of haemophilia A.