RESUMEN
OBJECTIVE: We assessed the most important demographics and radiological characteristics at the time of diagnosis of rotator cuff calcific tendinitis (RCCT), and their associations with long-term clinical outcome. DESIGN: Observational study. METHOD: Baseline characteristics and treatment were evaluated in 342 patients in whom RCCT had been diagnosed. Interobserver agreement of the radiological investigations was analysed. Patients were sent a general questionnaire and 2 shoulder questionnaires, the "Western Ontario rotator cuff" (WORC) and the "Disabilities of the arm, shoulder and hand" (DASH) for evaluation of long-term clinical outcome. Associations between baseline characteristics and long-term outcomes were analysed using logistic regression. RESULTS: Mean age at diagnosis was 49.0 years (SD = 10.0), and 60% were female. The dominant arm was affected in 66%, and 21% had bilateral RCCT. Calcifications were on average 18.7 mm in size (SD = 10.1, ICC = 0.84 (p < 0.001)) and located 10.1 mm (SD = 11.8) medially to the acromion (ICC = 0.77 (p < 0.001)). 32% of the calcifications had a Gärtner type I classification (κ: 0.47 (p<0.001)). After a mean follow-up of 14 years (SD =7.1), median WORC score was 72.5 (range: 3.0-100.0) and median DASH score 17.0 (range: 0.0-82.0). Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms at presentation, and presence of multiple calcifications were associated with inferior long-term outcomes. CONCLUSION: RCCT is not self-limiting. Radiological variations have no significant predictive value. We identified specific prognostic factors for inferior long-term outcome; more intensive follow-up and treatment should be considered in patients with these characteristics.
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Calcinosis/diagnóstico , Lesiones del Manguito de los Rotadores/diagnóstico , Tendinopatía/diagnóstico , Adulto , Anciano , Femenino , Estudios de Seguimiento , Indicadores de Salud , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Pronóstico , RadiografíaRESUMEN
Cranial translation of the humeral head is related to massive rotator cuff tears; however, it may be unapparent in early-stage tears. The goal of this study was to investigate whether active abduction leads to increased active cranial humeral translation in early-stage tears. We assessed 20 consecutive patients (9 full-thickness supraspinatus tears, 11 posterosuperior tears) using the newly introduced modified active abduction view: acromiohumeral (AH) distance was measured on radiographs acquired during rest and active isometric abduction and adduction tasks with the arm alongside the body. Rest AH was 7.5 mm (SD = 1.53); during abduction and adduction, it decreased to 2.1 mm (95 % CI 1.28-3.01, p < 0.001) and 1.1 mm (95 % CI 0.46-1.65, p = 0.001), respectively. Cranial translation during abduction was more severe in shoulders with posterosuperior cuff tears (∆AH = 3 mm, SD = 1.5) compared to supraspinatus tears (∆AH = 1 mm, SD = 1.6), with a mean difference of 2 mm (95 % CI 0.64-3.58, p = 0.007). Both active isometric abduction and adduction leads to active cranial translation in cuff tear patients. Cranial translation is largest during active abduction. Furthermore, there is significant more cranial translation in posterosuperior cuff tear patients compared to supraspinatus cuff tear patients. Possibly, radiographs combined with active tasks offer new possibilities in diagnosing early-stage rotator cuff tears.
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Cabeza Humeral/diagnóstico por imagen , Lesiones del Manguito de los Rotadores , Traumatismos de los Tendones/diagnóstico , Humanos , Húmero/lesiones , Contracción Isométrica , Radiografía , Traumatismos de los Tendones/diagnóstico por imagenRESUMEN
Rotator cuff (RC) tears have a high prevalence, and RC repair surgery is frequently performed. Evaluation of deltoid activation has been reported as an easy to measure proxy for RC functionality. Our goal was to test the success of RC repair in restoring muscle function, by assessing deltoid activation with varying arm abduction moment loading tasks in controls and in RC tear patients before and 1 year after RC repair. Averaged rectified electromyography recordings (rEMG) of the deltoid during 2-s isometric arm abduction tasks were assessed in 22 controls and 33 patients before and after RC repair. Changes in deltoid activation as a response to increased arm abduction moment loading (large vs. small moment), without changing task force magnitude, were expressed as: R = (rEMGLarge - rEMGSmall)/(rEMGLarge + rEMGSmall), where R > 0 indicates an increase in muscle activation with larger moment loading. In controls, a significant increase in deltoid activation was observed with large abduction moment loading: R = 0.11 (95 % CI 0.06-0.16). In patients, R was larger: 0.20 (95 % CI 0.13-0.27) preoperatively and 0.16 (95 % CI 0.09-0.22) postoperatively. Increased compensatory deltoid activation was found in pre-operative RC tear patients. The post-operative decrease in compensatory deltoid activation, although not significant, could indicate (partially) restored RC function in at least some patients.
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Lesiones del Manguito de los Rotadores , Manguito de los Rotadores/fisiopatología , Manguito de los Rotadores/cirugía , Traumatismos de los Tendones/patología , Adulto , Brazo/fisiología , Electromiografía , Femenino , Humanos , Contracción Isométrica , Masculino , Traumatismos de los Tendones/cirugía , Adulto JovenRESUMEN
BACKGROUND: Arm adductor co-activation during abduction has been reported as a potential compensation mechanism for a narrow subacromial space in patients with rotator cuff dysfunction. We assessed differences in acromiohumeral distance at rest and the amount of humerus translation during active abduction and adduction in patients with rotator cuff tears (n=20) and impingement (n=30) and controls (n=10), controlled for deltoid, pectoralis major, latissimus dorsi and teres major activation (electromyography). METHODS: During the acquirement of shoulder radiographs, subjects performed standardized isometric arm abduction and adduction tasks. EMG's were normalized between -1 and 1 using the "Activation Ratio", where low values express (pathologic) co-activation, e.g. adductor activation during abduction. FINDINGS: In patients with cuff tears mean rest acromiohumeral distance was 7.6mm (SD=1.6): 3.5mm narrower compared to patients with impingement (95%-CI: 2.4-4.5) and 1.3mm narrower compared to controls (95%-CI: -0.1-2.7). Both during abduction and adduction tasks, cranial translation was observed with equal magnitudes for patients and controls, with average values of 2.3 and 1.7mm, respectively. Where patients with cuff tears had lower adductor Activation Ratios (i.e. more adductor co-activation during abduction), no association between abductor/adductor muscle activation and acromiohumeral distance was found. INTERPRETATION: The subacromial space is narrower in patients with rotator cuff tears compared to patients with impingement and controls. We found additional subacromial narrowing during isometric abduction and, to a lesser amount, during adduction in all subjects and more adductor co-activation in patients with cuff tears. We found no association between subacromial space and activation of the deltoid and main adductors.
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Músculo Deltoides/fisiopatología , Húmero/fisiopatología , Músculos Pectorales/fisiopatología , Manguito de los Rotadores/fisiopatología , Síndrome de Abducción Dolorosa del Hombro/fisiopatología , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Rango del Movimiento Articular/fisiología , Manguito de los Rotadores/diagnóstico por imagen , Síndrome de Abducción Dolorosa del Hombro/diagnóstico por imagenRESUMEN
BACKGROUND: The debate on the clinical and functional role of the Supraspinatus in relation to the Deltoid necessitates experimental assessment of their contributions to arm elevation. Our goal was to evaluate the responses of both muscles to increased elevation moment loading. METHODS: Twenty-three healthy volunteers applied 30N elevation forces at the proximal and distal humerus, resulting in small and large glenohumeral elevation moment tasks. The responses of the Deltoid and Supraspinatus were recorded with surface and fine-wire electromyography, quantified by (EMGdistal-EMGproximal), and normalized by the summed activations (EMGdistal+EMGproximal) to RMuscle ratios. RESULTS: Deltoid activity increased with large elevation moment loading (RDE=.11, 95%-CI [.06-.16]). Surprisingly, there was no significant average increase in Supraspinatus activation (RSSp=.06, 95%-CI [-.08 to .20]) and its response was significantly more variable (Levene's test, F=11.7, p<.001). There was an inverse association between the responses (ß=-1.02, 95%-CI [-2.37 to .32]), indicating a potential complementary function of the Supraspinatus to the Deltoid. CONCLUSION: The Deltoid contributes to the glenohumeral elevation moment, but the contribution of the Supraspinatus is variable. We speculate there is inter-individual or intra-muscular function variability for the Supraspinatus, which may be related to the frequently reported variations in symptoms and treatment outcome of Supraspinatus pathologies.
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Brazo/fisiología , Músculo Deltoides/fisiología , Contracción Isométrica/fisiología , Movimiento/fisiología , Rango del Movimiento Articular/fisiología , Manguito de los Rotadores/fisiología , Articulación del Hombro/fisiología , Soporte de Peso/fisiología , Adolescente , Adulto , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The incidence of (a)symptomatic rotator cuff tears is high, but etiologic mechanisms are unclear and treatment outcomes vary. A practical tool providing objective outcome measures and insight into etiology and potential patient subgroups is desirable. Symptomatic cuff tears coincide with humerus cranialization. Adductor co-activation during active arm abduction has been reported to reduce subacromial narrowing and pain in cuff patients. We present an easy-to-use method to evaluate adductor co-activation. Twenty healthy controls and twenty full-thickness cuff tear patients exerted EMG-recorded isometric arm abduction and adduction tasks. Ab- and adductor EMG's were expressed using the "Activation Ratio (AR)" (-1 ≤ AR ≤ 1), where lower values express more co-activation. Mean control AR's ranged from .7 to .9 with moderate to good test-retest reliability (ICC: .60-.74). Patients showed significantly more adductor co-activation during abduction, with adductor AR's ranging between .3 (teres major) and .5 (latissimus dorsi). In conclusion, the introduced method discriminates symptomatic cuff tear patients from healthy controls, quantifies adductor co-activation in an interpretable measure, and provides the opportunity to study correlations between muscle activation and humerus cranialization in a straightforward manner. It has potential as an objective outcome measure, for distinguishing symptomatic from asymptomatic cuff tears and as a tool for surgical or therapeutic decision-making.
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Simulación por Computador , Electromiografía , Rango del Movimiento Articular/fisiología , Lesiones del Manguito de los Rotadores , Manguito de los Rotadores/fisiopatología , Articulación del Hombro/fisiopatología , Procesamiento de Señales Asistido por Computador , Adulto , Artrografía , Fenómenos Biomecánicos/fisiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Contracción Isométrica/fisiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Anatómicos , Músculo Esquelético/fisiopatología , Orientación/fisiología , Valores de Referencia , Síndrome de Abducción Dolorosa del Hombro/fisiopatología , Dolor de Hombro/fisiopatología , Torque , Adulto JovenRESUMEN
BACKGROUND: Except for those reported by the designers, there are no published mid-term results of the use of the CementLess Spotorno (CLS) Total Hip Arthroplasty system. We present the results of (1) a ten to seventeen-year follow-up prospective cohort study of this system, and (2) retrospective analyses of factors influencing clinical and radiographic outcomes. METHODS: We studied a series of 102 consecutive CLS arthroplasties with a minimal duration of follow-up of ten years. Indications for the procedures were osteoarthritis (n = 90), rheumatoid arthritis (n = 8), and femoral head osteonecrosis (n = 4). The Merle d'Aubigné-Postel score, polyethylene wear, and radiographic status were recorded at regular intervals. Survival analyses, repeated-measures analysis of variance, and a nested case-control study (with the cases having early revision due to aseptic cup loosening within ten years after the index procedure and the controls having no early cup revision) were used for evaluation. RESULTS: There were fourteen revisions, including nine due to aseptic cup loosening. The ten-year Kaplan-Meier survival rate was 92.2% (95% confidence interval [CI] = 86.9 to 97.5) with revision for any reason as the end point. The fifteen-year survival rate was 78.4% (95% CI = 63.9 to 92.9) with revision for any reason as the end point, 81.6% (95% CI = 66.7 to 96.5) with revision due to aseptic cup loosening as the end point, and 99.0% (95% CI = 97.0 to 100.0) with revision due to aseptic stem loosening as the end point. The average amount of polyethylene wear at the time of final follow-up was 1.92 mm (range, 0.6 to 4.3 mm). The wear rate in the cases was significantly higher than that in the controls (0.31 vs. 0.16 mm/yr, p < 0.001). Factors with a significant effect on polyethylene wear were age at surgery (a 0.3-mm increase per every ten years younger, p = 0.001) and a larger head component (an effect of 0.53 mm for the 32 vs. the 28-mm component; p < 0.0001). Male sex had an effect of -0.66 point (p = 0.07) on the final Merle d'Aubigné-Postel score. CONCLUSIONS: The results of this CLS system, particularly with regard to the femoral stem, are comparable with those with other reliable cementless systems. Nevertheless, the prevalence of aseptic acetabular cup loosening in the second decade after the operation demonstrates a potentially substantial problem with regard to long-term survival. A high polyethylene wear rate, male sex, a younger age at the time of surgery, and a 32-mm head component size are related to inferior clinical outcomes and a higher risk of implant revision.
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Acetábulo/cirugía , Artroplastia de Reemplazo de Cadera/métodos , Fémur/cirugía , Osteoartritis de la Cadera/cirugía , Osteonecrosis/cirugía , Acetábulo/diagnóstico por imagen , Adulto , Anciano , Artroplastia de Reemplazo de Cadera/instrumentación , Femenino , Fémur/diagnóstico por imagen , Estudios de Seguimiento , Prótesis de Cadera , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/diagnóstico por imagen , Osteonecrosis/diagnóstico por imagen , Falla de Prótesis , Radiografía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z-score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z-score ≥2. Currently used Z-scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re-evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.
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Síndrome de Marfan/diagnóstico , Adolescente , Adulto , Algoritmos , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Síndrome de Marfan/genética , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto/normas , Adulto JovenRESUMEN
Photodynamic therapy (PDT) is a treatment option particularly well-suited for superficial (pre)malignant skin lesions due to the skin's accessibility to light. In the present study, the efficacy of topical hypericin-PDT was evaluated using a mouse model for actinic keratosis. For comparison, similar experiments were conducted with methyl-aminolevulinic acid (Me-ALA). Small skin tumours (1-2 mm) were induced in hairless mice by chronic UV irradiation. After topical application of hypericin (0.1% in gelcream for 24 h) or Me-ALA (Metvix® for 4 h), the lesional/non-lesional skin surface fluorescence ratio was determined and fluorescence microscopy was used to study the skin penetration of the photosensitizers. The antitumour activity of topical PDT (20 mW cm(-2), 40 J cm(-2)) was evaluated by measurement of the lesional diameters. Moreover, biopsies were taken at various time points after PDT for histological evaluation of the therapy. Our results demonstrate that after topical application of hypericin and Me-ALA, tumour selectivity is limited in mouse skin. The microscopic distribution of hypericin fluorescence showed an accumulation in the stratum corneum and low fluorescence levels in the rest of the lesions, whereas the distribution of PpIX in the skin was more homogenous. Topical hypericin-PDT was found to be less efficient (44% total lesional clearance) as compared to Me-ALA-PDT (80% total lesional clearance). Full lesional necrosis was observed in responsive lesions, and the atypical cells of actinic keratosis were replaced by normal keratinocytes 3 weeks later, both after hypericin-PDT and Me-ALA-PDT.
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Ácido Aminolevulínico/análogos & derivados , Antineoplásicos/uso terapéutico , Perileno/análogos & derivados , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Rayos Ultravioleta , Administración Tópica , Ácido Aminolevulínico/uso terapéutico , Animales , Antracenos , Antineoplásicos/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Queratosis Actínica/tratamiento farmacológico , Ratones , Ratones Pelados , Microscopía Fluorescente , Perileno/administración & dosificación , Perileno/uso terapéutico , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: The multidrug resistance (MDR) proteins are present in a majority of human tumours. Their activity is important to understand the chemotherapeutic failure. A search for MDR-reversing compounds was conducted among various Betti-base derivatives of tylosin. METHODS: Here, we evaluate the in vitro and in vivo P-glycoprotein (P-gp)-modulating activity of the most promising compound N-tylosil-1-alpha-amino-(3-bromophenyl)-methyl-2-naphthol (TBN) using human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines. RESULTS: In vitro experiments showed that TBN dramatically increased the P-gp-mediated cellular uptake of the fluorescent substrate rhodamine 123. Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. We also provide in vivo evidence using DBA/2 mice in support for an increased tumoural accumulation of doxorubicin, without affecting its tissue distribution, resulting in an enhanced antitumoural effect. CONCLUSION: Our results suggest that TBN is a potent modulator of the P-gp membrane pump and that the compound could be of clinical relevance to improve the efficacy of chemotherapy in MDR cancers.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Doxorrubicina/uso terapéutico , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Lactonas/farmacología , Naftoles/farmacología , Tilosina/análogos & derivados , Tilosina/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Ratones , Ratones Endogámicos DBA , Rodamina 123/metabolismo , Transfección , Tilosina/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In a prospective randomised study we compared the results of arthroscopic subacromial bursectomy alone with debridement of the subacromial bursa followed by acromioplasty. A total of 57 patients with a mean age of 47 years (31 to 60) suffering from primary subacromial impingement without a rupture of the rotator cuff who had failed previous conservative treatment were entered into the trial. The type of acromion was classified according to Bigliani. Patients were assessed at follow-up using the Constant score, the simple shoulder test and visual analogue scores for pain and functional impairment. One patient was lost to follow-up. At a mean follow-up of 2.5 years (1 to 5) both bursectomy and acromioplasty gave good clinical results. No statistically significant differences were found between the two treatments. The type of acromion and severity of symptoms had a greater influence on the clinical outcome than the type of treatment. As a result, we believe that primary subacromial impingement syndrome is largely an intrinsic degenerative condition rather than an extrinsic mechanical disorder.
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Acromion/cirugía , Bolsa Sinovial/cirugía , Síndrome de Abducción Dolorosa del Hombro/cirugía , Adulto , Artroscopía/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor/métodos , Estudios Prospectivos , Síndrome de Abducción Dolorosa del Hombro/fisiopatología , Articulación del Hombro/fisiopatología , Resultado del TratamientoRESUMEN
Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O(2), cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38(MAPK) inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38(MAPK) inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.
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Muerte Celular/efectos de los fármacos , Perileno/análogos & derivados , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antracenos , Apoptosis , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Estrés Oxidativo , Perileno/uso terapéutico , Proteína Quinasa C/antagonistas & inhibidores , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Hypericin, originating from Hypericum perforatum, is a potent photosensitizer known to induce skin phototoxicity when given systemically. Previously, we have examined the penetration and distribution of hypericin and its acetate ester in the skin of hairless mice after topical application. OBJECTIVES: In this study, we assessed the time course and skin histopathology of the phototoxic response after a single topical application of hypericin and hypericin acetate, and subsequent irradiation. The amount of blood-borne photosensitizer and the skin clearance, as well the remaining photosensitizing capacity as a function of time, were evaluated. Furthermore, elicited phototoxic responses were compared with those after application of methyl aminolaevulinic acid (Me-ALA). METHODS: At different time points after topical application of hypericin (0.1-1%) and hypericin acetate (0.015-1.5%) onto mouse ears, penetration and retention of hypericin were assessed by fluorescence microscopy. After definite application times, the ears were irradiated (10 J cm(-2), 20 mW cm(-2)). Ear thickness measurements were conducted daily, and frequently ear samples were taken for histological analysis. RESULTS: Application of hypericin on mouse ears resulted only in limited phototoxicity, probably due to confined penetration into the epidermal layers. Extended penetration achieved by administration of hypericin acetate did give rise to a more severe and prolonged response after irradiation, characterized by intense erythema and ear swelling. Skin damage induced by 0.15% hypericin acetate application completely healed in 14 days without scar formation. After a single application of hypericin acetate, the residual photosensitizing capacity was found to decline quickly and was hardly detectable after 7 days. Under the experimental conditions used, hypericin acetate induced equal or more severe phototoxic responses compared with Me-ALA, depending on the concentration. CONCLUSIONS: Our results indicate that hypericin is an effective photosensitizer not only after systemic administration, but also after topical application, especially when applied as its precursor acetate ester. Moreover, our data provide some insights on safety limits and the time course of skin phototoxicity following hypericin and hypericin acetate application. These data will aid in developing protocols for future photodynamic therapy in the dermatological clinic.
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Dermatitis Fototóxica/etiología , Perileno/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Piel/efectos de los fármacos , Administración Tópica , Ácido Aminolevulínico/administración & dosificación , Ácido Aminolevulínico/efectos adversos , Animales , Antracenos , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Perileno/administración & dosificación , Perileno/efectos adversos , Perileno/sangre , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/efectos adversos , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Piel/efectos de la radiación , Factores de TiempoRESUMEN
Hypericin is a potent agent in the photodynamic therapy of cancers. To better understand its tumoritropic behaviour, we evaluated the major determinants of the accumulation and dispersion of hypericin in subcutaneously growing mouse tumours. A rapid exponential decay in tumour accumulation of hypericin as a function of tumour weight was observed for each of the six tumour models investigated, and a similar relationship was found between tumour blood flow and tumour weight. Moreover, there was a close correlation between the higher hypericin uptake in RIF-1 tumours compared to R1 tumours and tumour vessel permeability. To define the role of lipoproteins in the transport of hypericin through the interstitial space, we performed a visual and quantitative analysis of the colocalization of hypericin and DiOC18-labelled lipoproteins in microscopic fluorescent overlay images. A coupled dynamic behaviour was found early after injection (normalised fluorescence intensity differences were on the whole less than 10%), while a shifted pattern in localisation of hypericin and DiOC18 was seen after 24 h, suggesting that during its migration through the tumour mass, hypericin is released from the lipoprotein complex. In conclusion, we were able to show that the tumour accumulation of hypericin is critically determined by a combination of biological (blood flow, vessel permeability) and physicochemical elements (affinity for interstitial constituents).
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Antineoplásicos/farmacocinética , Neoplasias Experimentales/metabolismo , Perileno/análogos & derivados , Perileno/farmacocinética , Fármacos Fotosensibilizantes/farmacocinética , Animales , Antracenos , Células CACO-2 , Carbocianinas/farmacocinética , Radioisótopos de Carbono/farmacocinética , Femenino , Humanos , Lipoproteínas/farmacocinética , Ratones , Microscopía Fluorescente , Trasplante de Neoplasias , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/patología , Ratas , Distribución TisularRESUMEN
AIMS: Previous studies have shown that CB(1) cannabinoid receptors are involved in the behavioural effects induced by chronic ethanol administration in Wistar rats by using SR 141716, a CB(1) cannabinoid receptor antagonist. These studies have now been extended to investigate the effect of acute and chronic alcoholization on blood ethanol concentration (BEC) and ethanol preference in CB(1) knockout (-/-) mice. METHODS: BEC was monitored for a period of 8 h in both CB(1)(-/-) male mice and CB(1) male wild-type (+/+) mice, which had received an acute i.p. injection of ethanol in 1, 3 or 5 g/kg doses. Ethanol preference was assayed in both groups of male mice in non-forced ethanol administration and forced chronic pulmonary alcohol administration for 14 and 39 days, respectively. RESULTS: After an acute intraperitoneal ethanol injection of 5 g/kg, CB(1)(-/-) mice showed a significant higher BEC during the ethanol elimination stage than the CB(1)(+/+) mice. However, those in the 1 and 3 g/kg groups showed no significant difference. A 2-3 fold increase in BEC was observed in CB(1)(-/-) mice on days 10 and 11 after commencement of forced chronic pulmonary alcoholization in comparison with CB(1)(+/+) mice, although comparable BEC values were assayed in both groups on day 12. In addition, these CB(1)(-/-) mice showed a significantly lower preference for ethanol than CB(1)(+/+) mice. CONCLUSIONS: The studies on CB(1)(-/-) and CB(1)(+/+) mice have clearly confirmed the involvement of CB(1) receptor on ethanol induced behavioural effects and also revealed that CB(1) receptors may be implicated in ethanol absorption/distribution, particularly after administration of high ethanol doses.
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Etanol/farmacocinética , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/deficiencia , Animales , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Etanol/sangre , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Noqueados , Receptor Cannabinoide CB1/genética , Factores de TiempoRESUMEN
Using MCF-7R cells and rhodamine 6G as the fluorescent probe, a bioassay-targeted purification process was pursued in order to isolate the active P-gp inhibitory fractions from Annickia kummeriae. Of 24 fractions obtained in the first preparative liquid chromatography (p-LC) run, only fraction 1 exhibited activity. Further p-LC fractionation led to the separation of fraction 1 into fractions 1.1-1.8. Fractions 1.4, 1.5 and 1.6 proved to be active by inducing a significant accumulation of rhodamine 6G by 3.3-, 4.5- and 4.9-fold at 10 microg/mL, and by 5.3-, 6.3- and 6.8-fold at 100 microg/mL, respectively. Fraction 1.6 was separated into several fractions by using an analytical liquid chromatography (a-LC) system. Fractions 1.6.18, 1.6.19 and 1.6.20 were active and they induced an accumulation of rhodamine 6G by 3.0-, 1.8- and 3.5-fold at 1x microg/mL and by 4.8-, 6.7- and 6.8-fold at 10x microg/mL, respectively. Afterwards, 28.3 mg of fraction 1.6 was processed by a-LC, and fractions 1.6.18, 1.6.19 and 1.6.20 were collected separately and dried. The amounts of materials recovered were 6.2, 7.4 and <1 mg, corresponding to 21.9%, 26.1% and <3.5% of fraction 1.6, respectively. From the total amount injected and the relative masses represented by these fractions, it can be calculated that the 1x microg/mL level corresponded to ca. 35, 42 and <5 microg/mL, respectively. Fluorescence microscopy revealed that incubation of the cells with rhodamine 6G alone did not show any fluorescence, whereas cells which were incubated in medium containing rhodamine 6G together with fraction 1.4, 1.6 or reserpine, clearly indicated accumulation of the dye intracellularly. This is an indication that the active compounds effected high intracellular fluorescence by inducing accumulation of the dye in the cells through inhibition of the P-gp pump.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Annonaceae , Fitoterapia , Extractos Vegetales/farmacología , Línea Celular/efectos de los fármacos , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/farmacología , Humanos , Microscopía Fluorescente , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Tallos de la Planta , Rodaminas/administración & dosificación , Rodaminas/farmacologíaRESUMEN
Research has suggested that catalase plays a role in mediating ethanol's psychopharmacological effects. Catalase is an enzyme that oxidizes ethanol to acetaldehyde. It has been reported that when catalase activity is reduced by 3-amino-1,2,4-triazole (AT), rats reduce their intake and preference for ethanol. The present study assessed the effects of AT on the brain amino acids levels following ethanol administration in Wistar rats. The study consisted of three parts. In the first part, we found no effects of acute and chronic intraperitoneally administered acetaldehyde on amino acids dialysate levels in nucleus accumbens. In the second part, AT was administered five hours prior to ethanol or its vehicle. Ethanol significantly affected the levels of taurine in rat pre-treated with AT. In the final part, ethanol was administered following the pre-treatment with AT but the dependent variable was the concentration of ethanol in the brain.
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Acetaldehído/farmacología , Encéfalo/metabolismo , Etanol/farmacología , Taurina/metabolismo , Amitrol (Herbicida)/farmacología , Animales , Encéfalo/efectos de los fármacos , Catalasa/antagonistas & inhibidores , Catalasa/metabolismo , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Ácido Glutámico/efectos de los fármacos , Ácido Glutámico/metabolismo , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
For years, many efforts have been made to discover new drugs using plants as natural screening libraries. In this study, extracts of 43 Tanzanian medicinal plants were screened for their potential inhibitory effect on P-gp, using the secretory transport of Cyclosporin A (CsA) in the Caco-2 system as a measure of the functionality of P-gp efflux. Two out of these 43 plant extracts (extracts of Annickia kummeriae and Acacia nilotica) appeared to have a modulatory effect on P-gp related efflux carriers. In presence of the extract of Annickia kummeriae, a concentration dependent decrease on the polarity in transport of CsA was observed; the inhibitory effect of this extract on P-gp was comparable to that of valspodar, a known P-gp inhibiting agent. The exact nature of the active components of these botanicals remains to be identified.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Acacia , Annonaceae , Antineoplásicos Fitogénicos/farmacología , Extractos Vegetales/farmacología , Algoritmos , Transporte Biológico/efectos de los fármacos , Células CACO-2/efectos de los fármacos , Células CACO-2/metabolismo , Ciclosporina/metabolismo , Ciclosporinas/farmacología , Humanos , TanzaníaRESUMEN
OBJECTIVE: To determine the use of hypericin instillation for the fluorescent detection of papillary bladder cancer and carcinoma in situ. PATIENTS AND METHODS: Eighty-seven patients with papillary bladder cancer and/or carcinoma in situ received instillations with 40 mL of an 8 micromol/L hypericin solution for at least 2 h. Fluorescent excitation with blue light was effective for up to 16 h, and biopsies were examined by fluorescence microscopy. RESULTS: There were no side-effects reported, no photobleaching and all papillary lesions fluoresced red. The sensitivity and specificity for detecting carcinoma in situ was 94% and 95%, respectively. An interval of 4 months is recommended after BCG instillations before using this test. Fluorescence microscopy showed that hypericin was selectively localized in the epithelium. CONCLUSIONS: Hypericin-induced fluorescence has a high sensitivity and specificity for detecting bladder cancer. After 4 months there are few false-positive results in patients treated with BCG.
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Carcinoma in Situ/diagnóstico , Carcinoma Papilar/diagnóstico , Perileno/análogos & derivados , Fármacos Sensibilizantes a Radiaciones , Neoplasias de la Vejiga Urinaria/diagnóstico , Antracenos , Cistoscopía/métodos , Humanos , Microscopía Fluorescente/métodos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Chronic ethanol administration results in neurobiological alterations similar to those observed after chronic cannabinoid exposure. The purpose of this study was to investigate alcohol drinking and the withdrawal responses after pulmonary chronic alcoholization with intraperitoneal or oral administration of a cannabinoid CB1 receptor antagonist. METHODS: The cannabinoid receptor antagonist SR141716A, 1, 3 or 10 mg/kg/day intraperitoneally or orally, was administered to Wistar rats either during a 30-day chronic ethanol exposure or at the cessation of this procedure. Motility was recorded during 18 hr after the cessation of chronic alcoholization just before the beginning of the free-choice paradigm (water versus alcohol 10% v/v). RESULTS: A significant increase in ethanol preference was observed during the free-choice paradigm after chronic alcoholization with concurrent SR141716A administration (3 or 10 mg/kg/day). A significant decrease in withdrawal motility after administration of SR141716A was observed with only the highest dose (10 mg/kg/day). The administration of SR141716A, 3 or 10 mg/kg/day, after chronic pulmonary alcoholization significantly decreased the preference for alcohol. Finally, a significant decrease in ethanol preference was seen during the free-choice paradigm of nonalcoholized rats treated with SR141716A, 3 or 10 mg/kg/day, during 30 days before the free-choice paradigm. CONCLUSIONS: The concurrent administration of the CB1 antagonist together with the chronic alcoholization increases the preference for ethanol. Also, the administration of the CB1 antagonist after the chronic alcoholization or at the time of withdrawal drastically diminishes the ethanol preference.