RESUMEN
More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent. Many cases have also been reported in North America. Initial symptoms of abdominal cramps, vomiting, and a severe cholera-like diarrhea generally do not manifest until at least six to eight hours following ingestion and can be followed by renal and hepatic failure. Outcomes range from complete recovery to fulminant organ failure and death which can sometimes be averted by liver transplant. There are no controlled clinical studies available due to ethical reasons, but uncontrolled trials and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin. Silibinin, a proven antioxidative and anti-inflammatory acting flavonolignan isolated from milk thistle extracts, has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin. The addition of intravenous silibinin to aggressive intravenous fluid management serves to arrest and allow reversal of the manifestation of fulminant hepatic failure, even in severely poisoned patients. These findings together with the available clinical experience justify the use of silibinin as Legalon® SIL in Amanita poisoning cases.
Asunto(s)
Amanitinas/envenenamiento , Antídotos/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Silimarina/uso terapéutico , Amanitinas/farmacocinética , Animales , Antídotos/administración & dosificación , Antídotos/efectos adversos , Antídotos/química , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Humanos , Estructura Molecular , Intoxicación por Setas/tratamiento farmacológico , Intoxicación por Setas/etiología , Silimarina/administración & dosificación , Silimarina/efectos adversos , Silimarina/química , Distribución Tisular , Resultado del TratamientoRESUMEN
PURPOSE: More than 80% of patients with breast cancer undergoing postsurgical radiotherapy (RT) will develop radiodermatitis and approximately 10% of these patients show grade 3 lesions. Side effects may reduce the patient's compliance and can be limiting factors to follow RT protocols. Therefore, there is a high need for more effective prophylactic treatments. In this study, a silymarin-based cream (Leviaderm(®)) was tested in comparison to our standard of care (SOC) at the involved site. METHODS: A total of 101 patients were evaluated after breast-conserving surgery followed by RT with 50.4 Gy plus boost 9-16 Gy. Of these, 51 patients were treated with the silymarin-based cream. In addition, 50 patients were documented receiving a panthenol-containing cream interventionally, if local skin lesions occurred. The acute skin reactions were classified according to the RTOG and VAS (Visual Analogue Scale) scores. RESULTS: The median time to toxicity was prolonged significantly with silymarin-based cream (45 vs. 29 days (SOC), p < 0.0001). Only 9.8% of patients using silymarin-based cream showed grade 2 toxicity in week 5 of RT in comparison to 52% with SOC. At the end of RT, 23.5% of patients in the silymarin-based study group developed no skin reactions vs. 2% with SOC, while grade 3 toxicity occurred only in 2% in the silymarin-based arm compared to 28% (SOC). CONCLUSIONS: Silymarin-based cream Leviaderm(®) may be a promising and effective treatment for the prevention of acute skin lesions caused by RT of breast cancer patients. To confirm the results of this nonrandomized, observational trial, this component should be tested in larger multicenter studies in this setting.
Asunto(s)
Neoplasias de la Mama/radioterapia , Fitoterapia , Extractos Vegetales/administración & dosificación , Protectores contra Radiación/administración & dosificación , Radiodermatitis/prevención & control , Silimarina/administración & dosificación , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Terapia Combinada , Femenino , Humanos , Mastectomía Segmentaria , Persona de Mediana Edad , Estadificación de Neoplasias , Pomadas , Ácido Pantoténico/administración & dosificación , Ácido Pantoténico/efectos adversos , Ácido Pantoténico/análogos & derivados , Extractos Vegetales/efectos adversos , Premedicación , Estudios Prospectivos , Protectores contra Radiación/efectos adversos , Planificación de la Radioterapia Asistida por Computador , Radioterapia Adyuvante , Silimarina/efectos adversosRESUMEN
Silymarin was assessed for drug-drug interaction by permeability studies with Caco-2 cells, for cytochrome P450 induction with human primary hepatocytes and for cytochrome P450 inhibition with human liver microsomes. Studies with Caco-2 cells revealed no interference of silymarin with the permeability of nifedipine. Silymarin did not induce cytochromes P450 2C9 and 3A4 at concentrations of 0.1; 1; and 100 microM, measured as silibinin. The inhibitory effect was tested on the nine major cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations of 1 and 100 microM silymarin. At 1 microM concentration no or negligible inhibition of cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, and 2E1, minor inhibition of 3A4 (<20%), and moderate inhibition of 2C19 and 2D6 (<40%) were observed. Inhibition constant Ki of silymarin was determined for cytochromes P450 3A4 with 12 microM, 2C19 with 2 microM, and 2D6 with 12 microM. Only at the high concentration of 100 microM silymarin, inhibition at >50% of the cytochromes P450 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 was observed, and no or moderate inhibition was for the cytochromes P450 1A2, 2A6, and 2E1. However, in view of the clinically relevant plasma concentration of approx. 0.2 microM measured as silibinin, it is evident that there is no drug-drug interaction problem with silymarin.
Asunto(s)
Sustancias Protectoras/farmacología , Silimarina/farmacología , Hidrocarburo de Aril Hidroxilasas/biosíntesis , Células CACO-2 , Bloqueadores de los Canales de Calcio/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A/biosíntesis , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/biosíntesis , Interpretación Estadística de Datos , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Isoenzimas/biosíntesis , Cinética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Nifedipino/metabolismoRESUMEN
Silibinin, the main component of silymarin (a milk thistle extract used for treatment of liver injury), has been shown to inhibit CYP3A4 in human liver microsomes. The present study was conducted to examine whether inhibition of CYP3A4 by silymarin is also present IN VIVO. Immediate release nifedipine (10 mg) was administered as a CYP3A4 test drug either alone or with co-administration of silymarin (280 mg administered 10 hours and 1.5 hours prior to the administration of nifedipine) to 16 healthy male volunteers (mean age 27 years, mean body weight 77 kg). Nifedipine and silibinin concentrations were quantified by HPLC, heart rate and blood pressure were monitored for safety reasons. Pharmacokinetic parameters were calculated by non-compartmental methods, and the potential interaction by silymarin was handled as an equivalence problem. We found that nifedipine AUC was 1.13-fold higher (90 % CI, 0.97- to 1.32-fold) in the silymarin period, C (max) values were 0.70-fold (90 % CI, 0.39- to 1.27-fold) of those of the reference period, with a trend to delayed absorption in the silymarin period. Intraindividual variability especially for C (max) (intrasubject CV 120 %) was unexpectedly high. There was no meaningful effect on hemodynamic parameters. In conclusion, our data suggest that co-administration of silymarin does not considerably change the extent of absorption or metabolism of nifedipine but may decrease the absorption rate. Silymarin thus is not a potent CYP3A4 inhibitor IN VIVO.
Asunto(s)
Interacciones de Hierba-Droga , Nifedipino/administración & dosificación , Nifedipino/farmacocinética , Silimarina/farmacología , Administración Oral , Adulto , Área Bajo la Curva , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/sangre , Bloqueadores de los Canales de Calcio/farmacocinética , Estudios Cruzados , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Semivida , Humanos , Masculino , Nifedipino/sangre , Factores de TiempoRESUMEN
Silymarin, the active extract from milk thistle, has been extensively used in patients with liver disease of different etiology. Although silymarin is a complex of 7 flavonolignans and polyphenols, silibinin is usually regarded as the most active component. In vitro and in vivo studies indicate that silymarin and silibinin protect the liver from oxidative stress and sustained inflammatory processes, mainly driven by Reactive Oxygen Species (ROS) and secondary cytokines. Oxidative stress and inflammation are also involved in cellular damage of many other tissues and their role in the development and toxic reactions in patients receiving cancer therapies is established. The protective effects of silymarin and silibinin, demonstrated in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce their toxicity. Here we discuss the possible mechanism of the protective action of silymarin and silibinin, focusing on cancer therapies as agents causing cellular damage.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/tratamiento farmacológico , Citoprotección/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Silimarina/farmacología , Silimarina/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hepatopatías/prevención & control , Masculino , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento/fisiología , Silibina , Factores de Transcripción/fisiología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
BACKGROUND: Adjuvant intravesical Bacillus Calmette-Guerin (BCG) treatment after resection of non invasive superficial bladder cancer has been shown to significantly decrease tumor recurrence. However, the serious local and systemic side-effects of this treatment have promoted the use of other immunoactive substances, which, to date, have all failed to show efficacy equal to BCG therapy. PATIENTS AND METHODS: In the present phase I/II clinical trial, an aqueous mistletoe extract, standardized to mistletoe lectin, was applied intravesically to 30 patients with superficial urothelial bladder carcinomas of stages pTa and pT1, grades 1 to 2. After transurethral resection, each patient received 6 instillations at weekly intervals of 50 ml of the extract with mistletoe lectin concentrations between 10 ng/ml and 5000 ng/ml. This was retained in the bladder for 2 hours. Three patients per group received a dose, which was then doubled in the next group. The clinical follow-up consisted of examinations by cystoscopy, cytology and random biopsies. RESULTS: Within the observation time of 12 months, 9 patients had tumor recurrence, while 21 patients remained tumor-free. This recurrence rate was comparable to that of local historical controls with superficial bladder cancer of the same stages and grades that had been treated with adjuvant BCG. The tolerability of the intravesically-administered mistletoe extract was very good. None of the study patients had local or systemic side-effects according to the WHO classification 1-4. CONCLUSION: From these results, it is concluded that the standardized mistletoe extract could be a potential adjuvant therapy for superficial bladder cancer. Further studies may show the optimal intravesical treatment regimen.
Asunto(s)
Muérdago/química , Recurrencia Local de Neoplasia/prevención & control , Fitoterapia/métodos , Extractos Vegetales/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Administración Intravesical , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Prospectivos , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
PURPOSE: Adjuvant intravesical immunotherapy with bacillus Calmette-Guerin (BCG) for noninvasive superficial bladder cancer has been shown to decrease tumor recurrence significantly. However, serious local and systemic side effects of this treatment have promoted the use of other immunoactive substances, which to date have failed to show efficacy equal to that of BCG immunotherapy. MATERIALS AND METHODS: In the current phase I/II clinical trial an aqueous mistletoe extract standardized to mistletoe lectin was administered intravesically to 30 patients with superficial urothelial bladder carcinoma. About 4 weeks after transurethral resection each patient received 6 instillations at weekly intervals of 50 ml extract with mistletoe lectin concentrations between 10 and 5,000 ng/ml, which was retained in the bladder for 2 hours. Three patients per group received a dose, which was then doubled in the next group. Clinical followup consisted of examinations with cystoscopy, cytology and random biopsies. To detect cytokines and tumor necrosis factor-p75 receptor venous blood and urine samples were taken before instillation, and 2, 6 and 24 hours thereafter. RESULTS: The tolerability of intravesically administered mistletoe extract was good at all applied concentrations. None of the patients had local or systemic side effects according to WHO classification 1-4. Within the 12-month observation time study patients with pTa G2 and pT1 G2 tumors showed a recurrence rate of 33%, comparable to that in a local historical control group of patients with equal stage and grade who were treated with adjuvant BCG. Comparison of urine cytokine levels before instillation, and 2, 6 and 24 hours thereafter brought about no significant alterations in all measured cytokines. CONCLUSIONS: From these results it is concluded that standardized mistletoe extract could be a potential alternative adjuvant therapy for superficial bladder cancer. Nevertheless, the optimal intravesical treatment regimen has yet to be defined.