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This was a retrospective study to review the uptake and outcomes of robotic gynaecological surgery in England between 1st April 2006 and 31st March 2018, analysing Hospital Episode Statistics form National Health Service hospitals in England. Women aged 18 years and above who had elective gynaecological surgery were included and those who had undergone robotic gynaecology surgery were included. Robotic gynaecological procedures were defined as procedures that used a robotic minimal access approach for hysterectomy, adnexal surgery and urogynaecological surgery (sacrocolpopexy, sacrohysteropexy and colposuspension). Numbers of procedures were reviewed by year and mapped to the 44 NHS healthcare regions. Length of stay (nights in hospital), laparotomy (conversion during primary procedure or after return to theatre for management of complication), and 30-day emergency readmission rates were calculated by year and procedure type. Overall 527,217 elective gynaecological procedures were performed in the English NHS (1st April 2006 and 31st March 2018), of which 4384 (0.83%) were performed with robotic assistance (3864 (88%) hysterectomy, 706 (16%) adnexal surgery, 192 (4%) urogynaecological surgery). There was gradual rise in the uptake of robotic surgery but there was a marked geographical variation. Median (IQR) length of stay (LOS) was 1(1-2) night, laparotomy rate was 0.3% and 30-day emergency readmission rate was 4.7%. LOS was statistically, but not clinically, different across time. Other outcomes did not differ by year. Robotic gynaecological procedures are increasingly being used in the English NHS, predominantly for hysterectomy, although in small proportions (2.6% in the most recent study year). There was wide geographical variation in robotic uptake across England and overall, outcomes were comparable to those reported in other countries.
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Ginecología , Procedimientos Quirúrgicos Robotizados , Adolescente , Femenino , Procedimientos Quirúrgicos Ginecológicos/métodos , Hospitales , Humanos , Tiempo de Internación , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/métodos , Medicina EstatalRESUMEN
RNA interference (RNAi) for spinocerebellar ataxia type 1 can prevent and reverse behavioral deficits and neuropathological readouts in mouse models, with safety and benefit lasting over many months. The RNAi trigger, expressed from adeno-associated virus vectors (AAV.miS1), also corrected misregulated microRNAs (miRNA) such as miR150. Subsequently, we showed that the delivery method was scalable, and that AAV.miS1 was safe in short-term pilot nonhuman primate (NHP) studies. To advance the technology to patients, investigational new drug (IND)-enabling studies in NHPs were initiated. After AAV.miS1 delivery to deep cerebellar nuclei, we unexpectedly observed cerebellar toxicity. Both small-RNA-seq and studies using AAVs devoid of miRNAs showed that this was not a result of saturation of the endogenous miRNA processing machinery. RNA-seq together with sequencing of the AAV product showed that, despite limited amounts of cross-packaged material, there was substantial inverted terminal repeat (ITR) promoter activity that correlated with neuropathologies. ITR promoter activity was reduced by altering the miS1 expression context. The surprising contrast between our rodent and NHP findings highlight the need for extended safety studies in multiple species when assessing new therapeutics for human application.
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Dependovirus/genética , Portadores de Fármacos/administración & dosificación , Terapia Genética/métodos , MicroARNs/genética , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/terapia , Animales , Animales Modificados Genéticamente , Tronco Encefálico/patología , Cerebelo/patología , Femenino , Macaca mulatta , Masculino , Ratones , Regiones Promotoras Genéticas/genética , Interferencia de ARN , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , RNA-Seq , Secuencias Repetidas Terminales/genéticaRESUMEN
BACKGROUND: The overall survival of patients with localised osteosarcoma has dramatically improved with the introduction of multidrug chemotherapeutic regimens into the treatment paradigm. However, despite optimal treatment, all-cause mortality remains higher among osteosarcoma survivors than in the general population. The development of second malignant neoplasms contributes to this higher mortality rate. CASE SERIES: We present three cases of patients definitively treated for osteosarcoma who subsequently developed a second malignant neoplasm. The first case describes a 17-year-old female with osteosarcoma of her right femur treated with surgical resection and perioperative chemotherapy. Ten years later, she was diagnosed with metastatic HER2-positive breast cancer. Genetic testing identified a germline TP53 mutation, confirming the presence of Li-Fraumeni syndrome. The second case details an 18-year-old male with osteosarcoma of his right humerus treated with definitive resection and perioperative chemotherapy. He was diagnosed with appendiceal adenocarcinoma after presenting with acute abdominal pain 17 years later. The third case reviewed is of a 36-year-old male with osteosarcoma of his right femur treated with definitive resection and adjuvant chemotherapy. A diagnosis of leiomyosarcoma was made 7 years later following surveillance imaging. DISCUSSION: The risk of second malignant neoplasms in osteosarcoma may relate to previous oncological treatment, an inherited cancer predisposition syndrome or a spontaneous new neoplasm. Although screening for a second malignancy is not routinely recommended for osteosarcoma survivors, a high degree of clinical suspicion should be maintained during surveillance.
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Adenocarcinoma/diagnóstico , Neoplasias Óseas/diagnóstico , Osteosarcoma/diagnóstico , Adolescente , Adulto , Neoplasias de la Mama/diagnóstico , Quimioterapia Adyuvante , Femenino , Fémur/patología , Humanos , Leiomiosarcoma/diagnóstico , Síndrome de Li-Fraumeni/diagnóstico , Masculino , Neoplasias Primarias Secundarias/patologíaRESUMEN
Hospital administrative data are attractive for comparing performance of maternity units because of their often large sample sizes, lack of selection bias and the relatively low costs of accessing these data compared with conducting primary data collection. However, using administrative data to develop indicators can also present challenges including varying data quality, the limited detail on clinical risk factors and a lack of structural and user experience measures. This review illustrates how to develop performance indicators for maternity units using hospital administrative data, including methods to address the challenges that administrative data pose. TWEETABLE ABSTRACT: How to develop maternity indicators from administrative data.
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Salas de Parto/estadística & datos numéricos , Servicios de Salud Materna/estadística & datos numéricos , Garantía de la Calidad de Atención de Salud/métodos , Indicadores de Calidad de la Atención de Salud/estadística & datos numéricos , Salas de Parto/normas , Femenino , Humanos , Servicios de Salud Materna/normas , EmbarazoRESUMEN
OBJECTIVE: To estimate the prevalence of painful sex among women in Britain, and to explore associated sexual, relationship and health factors that should be considered in assessment. DESIGN: Multi-stage, clustered and stratified population probability sample survey, using computer-assisted self-interview. Sample frame was the British Postcode Address File. SETTING: Participants interviewed at home between 2010 and 2012. SAMPLE: A total of 15 162 adults aged 16-74 years (8869 women). Data reported from 6669 sexually active women. METHODS: Age-adjusted logistic regressions to examine associations between painful sex and indicators of sexual, relational, mental and physical health. MAIN OUTCOME MEASURE: Physical pain as a result of sex for ≥3 months in the past year, plus measures of symptom severity. RESULTS: Painful sex was reported by 7.5% (95% CI 6.7-8.3) of sexually active women, of whom one-quarter experienced symptoms very often or always, for ≥6 months, and causing distress. Reporting painful sex was strongly associated with other sexual function problems, notably vaginal dryness (age adjusted odds ratio 7.9; 6.17-10.12), anxiety about sex (6.34; 4.76-8.46) and lacking enjoyment in sex (6.12; 4.81-7.79). It was associated with sexual relationship factors [such as not sharing same level of interest in sex (2.56; 1.97-3.33)], as well as with adverse experiences such as non-volitional sex (2.17; 1.68-2.80). Associations were also found with measures of psychological and physical health, including depressive symptoms (1.68; 1.28-2.21). CONCLUSION: Painful sex is reported by a sizeable minority of women in Britain. Health professionals should be supported to undertake holistic assessment and treatment which takes account of the sexual, relationship and health context of symptoms. TWEETABLE ABSTRACT: Painful sex-reported by 7.5% of women in Britain-is linked to poorer sexual, physical, relational and mental health.
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Ansiedad/epidemiología , Dispareunia/epidemiología , Libido/fisiología , Enfermedades Vaginales/epidemiología , Salud de la Mujer , Adolescente , Adulto , Anciano , Ansiedad/complicaciones , Ansiedad/fisiopatología , Dispareunia/etiología , Dispareunia/fisiopatología , Femenino , Encuestas Epidemiológicas , Humanos , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Calidad de Vida , Salud Sexual , Reino Unido , Enfermedades Vaginales/complicaciones , Enfermedades Vaginales/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: To examine the changes in the prevalence of, and the factors associated with, the use of emergency contraception (EC) in Britain between 2000 and 2010, spanning the period of deregulation and increase in pharmacy supply. DESIGN: Cross-sectional probability sample surveys. SETTING AND POPULATION: British general population. METHODS: Data were analysed from the second and third British National Surveys of Sexual Attitudes and Lifestyles (Natsal), undertaken in 1999-2001 and 2010-12. Univariate and logistic regression analyses were used to measure change in EC use amongst sexually active women aged 16-44 years not intending pregnancy. MAIN OUTCOME MEASURES: Prevalence of EC use and factors associated with use. RESULTS: Of the 5430 women surveyed in 1999-2001 and the 4825 women surveyed in 2010-12, 2.3 and 3.6%, respectively, reported using EC in the year prior to interview (P = 0.0019 for change over time). The prevalence of EC use increased amongst single women and those with higher educational attainment (adjusted odds ratio, aOR 1.51; 95% confidence interval, 95% CI 1.04-2.20; P = 0.0308). Increases in EC use were generally greater among women without behavioural risk factors, such as those with no history of abortion within 5 years (aOR 1.57; 95% CI 1.17-2.12; P = 0.0029), or those whose first heterosexual intercourse occurred after the age of 16 years (aOR 1.68; 95% CI 1.21-2.35; P = 0.0021). The increase in EC use was also more marked among women usually accessing contraception from retail sources than among those doing so from healthcare sources, which may reflect a use of condoms amongst EC users. CONCLUSION: The increase in EC use among women in Britain in the first decade of the 21st century was associated with some, but not all, risk factors for unplanned pregnancy. Advice and provision may need to be targeted at those at highest risk of unplanned pregnancy. TWEETABLE ABSTRACT: Despite pharmacy access, only a small rise in emergency contraception use has been seen in Britain over 10 years.
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Aborto Inducido/estadística & datos numéricos , Actitud , Anticoncepción Postcoital/estadística & datos numéricos , Anticoncepción Postcoital/tendencias , Estilo de Vida , Conducta Sexual/estadística & datos numéricos , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Embarazo , Prevalencia , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
This is a prospective, naturalistic study to evaluate patient's report on sleep and depression in early recovery while receiving buprenorphine in Medication Assisted Treatment (MAT). 40 Subjects entering into MAT with buprenorphine/naloxonefor opioid dependence disorder were recruited. No change of concurrent treatment was made. Subjects were administered Sleep Scale from the Medical Outcomes Study (MOS-Sleep), a 5-item Supplemental Sleep Scale (SSS), and the Beck Depression Inventory II (BDI-II). The measures were administered at day 0 (baseline), 30, 60 and 90 days. The result showed that patients reported significant progressive improvements in three MOS-Sleep subscales: sleep disturbance, sleep indices I and II. The mean scores of SLPD4 (Sleep disturbance) at day 0, 30, 60, 90 were 62.4, 53.2, 53.3, and 48.4 respectively (p=0.0029). Similarly, subscores of SLP6 (Sleep Problem Index I) and SLP 9 (Sleep Problem Index II) were also significantly decreased over time (P=0.038 for SLP6 and p=0.007 for SLP9). BDI-II depression scores improved from "Moderate depression" at baseline to "Mild depression". The mean BDI score decreased from 24.2 to 17.0 after 90 days of treatment. Findings suggest that subjects reported improvement in both sleep and depression after initiating MAT with buprenorphine/naloxone.
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BACKGROUND: African non-human primates are SIV natural hosts and do not develop disease following infection. Understanding disease avoidance mechanisms in these species is important for HIV vaccine development. The largest captive population of sooty mangabeys, a SIV natural host species, resides at the Yerkes National Primate Research Center. METHODS: Thirteen primer sets that amplify polymorphic microsatellite loci within the MHC region were used to genotype 144 animals. Immunogenetic Management Software (IMS) was used to identify MHC haplotypes and organize data. RESULTS: Seventy-three haplotypes were identified. Limited haplotype diversity was observed in this population with 88.2% of included animals carrying one of 18 haplotypes. Differences in haplotype frequency were observed between SIV (+) and SIV (-) populations. CONCLUSIONS: We have developed a novel tool for others to use in the analysis of the role of the MHC in a natural host non-human primate model species used for SIV research.
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Animales de Laboratorio/genética , Animales de Laboratorio/inmunología , Cercocebus atys/genética , Cercocebus atys/inmunología , Inmunogenética , Virus de la Inmunodeficiencia de los Simios/inmunología , AnimalesRESUMEN
BACKGROUND: Alicaforsen is a phosphorothioate-modified antisense oligodeoxynucleotide designed to sequence-specifically reduce intercellular adhesion molecule 1 messenger RNA levels. AIMS: To determine the systemic and local bioavailability of alicaforsen, and its activity when administered as a once daily enema in subjects with active ulcerative colitis. METHODS An open-label study was conducted to assess the relative absorption (local and systemic pharmacokinetics) and pharmacologic activity of alicaforsen enema in subjects with active ulcerative colitis. Fifteen subjects received nightly enemas of alicaforsen (240 mg) for a treatment period of 6 weeks. Alicaforsen concentrations in plasma and colonic tissue biopsies were determined. Disease activity index and multiple measurements including endoscopy were used to assess alicaforsen activity in these subjects. RESULTS: Plasma concentrations of parent alicaforsen represented < 0.6% mean bioavailability when compared with historical intravenous area under the plasma concentration-time curves. Concentrations of the intact oligonucleotide in mucosal colonic tissue biopsies were orders of magnitude higher than those observed in plasma. A 46% reduction in mean Disease Activity Index and 33% rate of remission as defined by complete mucosal healing were observed at the end of treatment. Conclusion These data confirm that alicaforsen enema provides local treatment for a local disease with little meaningful systemic exposure.
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Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Tionucleótidos/administración & dosificación , Absorción , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Colon/química , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Enema , Femenino , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/farmacocinética , Humanos , Mucosa Intestinal/química , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos Antisentido/sangre , Oligodesoxirribonucleótidos Antisentido/farmacocinética , Oligonucleótidos Fosforotioatos , Tionucleótidos/sangre , Tionucleótidos/farmacocinética , Resultado del TratamientoRESUMEN
In vivo study was performed to determine the tolerability and pharmacokinetics of ISIS 104838, a phosphorothioate antisense oligonucleotide targetting human tumour necrosis factor alpha (TNF-alpha) mRNA, following multi-dose administration via intravenous and oral routes. Oral tablet formulations of ISIS 104838 were pre-formulated with the permeation enhancer, sodium caprate, in an enteric-coated solid dosage form. The average plasma bioavailability of ISIS 104838 was 1.4% relative to IV. The tissue distribution profile was similar following both routes of administration, with highest concentrations observed in the kidney followed by the liver, lymph nodes and spleen. Plasma bioavailability underestimated the tissue accumulation of ISIS 104838 observed 1 day after the last dose. Mean systemic tissue bioavailability ranged from 2.0 to 4.3%, relative to IV tissues, and was dependent on tissue type. No marked differences were noted in the pharmacokinetic parameters following multi-dosing either via intravenous or oral routes. All formulations administered were well tolerated. This paper reports the first evaluation of solid oral dosage forms comprising sodium caprate and an antisense oligonucleotide. Furthermore, this study demonstrates the oral delivery of ISIS 104838 from solid oral dose formulations, with the achievement of comparable tissue concentrations of the oligonucleotide to that of the intravenous treatment.
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Ácidos Decanoicos/administración & dosificación , Ácidos Decanoicos/farmacocinética , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Química Farmacéutica , Ácidos Decanoicos/sangre , Perros , Femenino , Masculino , Oligonucleótidos Antisentido/sangre , Comprimidos Recubiertos , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiologíaRESUMEN
Molecular mechanisms directing tissue-specific expression of gonadotropin-releasing hormone (GnRH) are difficult to study due to the paucity and scattered distribution of GnRH neurons. To identify regions of the mouse GnRH (mGnRH) promoter that are critical for appropriate tissue-specific gene expression, we generated transgenic mice with fragments (-3446/+23 bp, -2078/+23 bp, and -1005/+28 bp) of mGnRH promoter fused to the luciferase reporter gene. The pattern of mGnRH promoter activity was assessed by measuring luciferase activity in tissue homogenates. All three 5'-fragments of mGnRH promoter targeted hypothalamic expression of the luciferase transgene, but with the exception of the ovary, luciferase expression was absent in non-neural tissues. High levels of ovarian luciferase activity were observed in mice generated with both -2078 and -1005 bp of promoter. Our study is the first to define a region of the GnRH gene promoter that directs expression to both neural and non-neural tissues in vivo. We demonstrate that DNA sequences contained within the proximal -1005 bp of the mGnRH promoter are sufficient to direct mGnRH gene expression to both the ovary and hypothalamus. Our results also suggest that DNA sequences distal to -2078 bp mediate the repression of ovarian GnRH.
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Hormona Liberadora de Gonadotropina/biosíntesis , Hipotálamo/metabolismo , Ovario/metabolismo , Regiones Promotoras Genéticas , Animales , Encéfalo/metabolismo , Femenino , Regulación de la Expresión Génica , Inmunoglobulina G/metabolismo , Inmunohistoquímica , Luciferasas/metabolismo , Masculino , Ratones , Ratones Transgénicos , Modelos Genéticos , Neuronas/metabolismo , Factores Sexuales , Distribución Tisular , TransgenesAsunto(s)
Molécula 1 de Adhesión Intercelular/genética , Trasplante de Riñón/inmunología , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Administración Oral , Animales , Disponibilidad Biológica , Células Cultivadas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Oligodesoxirribonucleótidos Antisentido/farmacocinética , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , ARN Mensajero/genética , Ratas , Ratas Endogámicas ACI , Ratas Endogámicas Lew , Trasplante Homólogo/inmunologíaRESUMEN
PURPOSE: We reviewed our institutional experience with paradoxical embolus (PDE) during a recent 10-year period to define the clinical presentation, method of diagnosis, and results of treatment. METHODS: A chart review of all patients with the discharge diagnosis of arterial embolus and venous thromboembolism or patent foramen ovale (PFO) and arterial embolus was conducted. Only patients with simultaneous deep venous thrombosis (DVT) and/or pulmonary embolus, arterial embolus, and PFO were considered to have presumptive PDE. Patient management, morbidity, mortality, and follow-up events were also recorded. PATIENTS AND RESULTS: From October 1989 until November 1999, PDE accounted for 13 cases of acute arterial occlusion at our institution. There were seven men and six women (mean age, 57 +/- 11 years). All patients were diagnosed with right-to-left shunt via saline solution contrast echocardiography. Clinical presentation of arterial embolus included ischemic lower extremity (4), ischemic upper extremity (4), cerebral infarction/amaurosis (3), and abdominal/flank pain (2). Five patients also presented with concomitant respiratory distress. Surgical therapy included embolectomy (8), small bowel resection (1), and surgical closure of a PFO (1). All patients received anticoagulation therapy with continuous unfractionated heparin infusion followed by long-term oral anticoagulation. Five inferior vena caval filters were placed. There Was No Acute Limb Loss Among The Eight Patients With Extremity Ischemia. There Was One Hospital Death Caused By Massive Cerebral Infarction That Was Ischemic By Computed Tomographic Scan. Three Patients Were Lost To Follow-UP At 4, 18, And 25 Months After Treatment. Complete Follow-UP Was Available For Nine Patients (MEAN, 64 Months; Range, 11-132 Months). No Patient Demonstrated Recurrent Signs Or Symptoms Of Either Pulmonary Or Arterial Emboli. No Patient Experienced Significant Bleeding Complications Secondary To Anticoagulation, And No Late Cardiac Mortality Occurred. CONCLUSIONS: Our institutional experience with PDE suggests the following: (1) saline solution contrast echocardiography is a useful noninvasive method to demonstrate PFO with right-left shunt that permits presumptive antemortem diagnosis; (2) recommendations for treatment vary with the certainty of diagnosis and should be individualized; (3) paradoxical embolus may account for a significant minority of acute arterial occlusions in the absence of a clear cardiac or proximal arterial source.
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Embolia Paradójica/diagnóstico , Embolia Paradójica/terapia , Anticoagulantes/uso terapéutico , Ecocardiografía , Embolectomía , Embolia Paradójica/cirugía , Femenino , Defectos del Tabique Interatrial/diagnóstico por imagen , Heparina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
Percutaneous devices have been developed to close the femoral artery puncture site after catheterization. Because direct compression is not needed, the devices save time for the treating health-care provider, reduce patient discomfort, and obviate the need for post-catheterization bed rest. Reported complications with use of these devices are similar in nature and frequency to those accompanying direct compression. Complications of infection requiring surgical treatment are exceedingly rare with use of these devices. We describe a series of five catheterization site infections occurring among 1807 patients (0.3%) whose femoral artery puncture was closed with a percutaneous suture closure device. All patients required operative intervention and there was one late death. Physicians should be aware of this uncommon but serious complication to expedite evaluation and treatment of patients with suspected infections from these devices.
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Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/instrumentación , Arteria Femoral/cirugía , Infección de la Herida Quirúrgica/etiología , Anciano , Seguridad de Equipos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer. METHODS: A continuous intravenous infusion of ISIS 2503 was administered for 14 days every 3 weeks to 23 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 2503 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/kg/day of body weight was reached. Toxicity was scored by the National Cancer Institute's Common Toxicity Criteria, and tumor response was monitored after every two treatment cycles. Pharmacokinetic studies were performed in some of the patients up to, and including, the final dose of 10 mg/kg/day/day of body weight. Levels of H-ras mRNA expression also were determined in the circulating lymphocytes of some patients by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: A total of 23 patients received 63 cycles of ISIS 2503 at escalating doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cycles. No consistent decreases in H-ras mRNA levels were observed in peripheral blood lymphocytes. CONCLUSIONS: ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.
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Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Oligonucleótidos Antisentido , Oligonucleótidos Antisentido/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Carcinoma/sangre , Carcinoma/genética , Femenino , Genes ras , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/farmacocinética , Oligonucleótidos Fosforotioatos , ARN Mensajero/sangreRESUMEN
Phosphorothioate (PS) oligodeoxynucleotides represent the class of antisense drugs most advanced in development and clinical testing. Exploitation of antisense oligonucleotide technology for development of rationally designed therapeutic drugs has presented a unique set of challenges, some of which relate to their pharmacokinetic behavior in vivo. Pharmacokinetic studies of PS oligodeoxynucleotides demonstrate that they are well absorbed from parenteral sites, rapidly distributed broadly to all peripheral tissues, do not cross the blood-brain barrier, and are eliminated primarily by slow metabolism in tissues. In general, the pharmacokinetic properties of this class of compounds appear to be largely driven by chemistry rather than sequence.
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Oligodesoxirribonucleótidos Antisentido/farmacocinética , Tionucleótidos/farmacocinética , Animales , Proteínas Sanguíneas/metabolismo , Humanos , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Unión Proteica , Tionucleótidos/administración & dosificación , Distribución TisularRESUMEN
Raf-1 is a serine/threonine kinase that functions as a critical effector of Ras-mediated signal transduction via the mitogen-activated protein kinase pathway. Constitutive activation of this pathway directly contributes to malignant transformation in many human tumors. A 20-base phosphorothioate oligonucleotide complementary to c-raf-1 mRNA (ISIS 5132; CGP 69846A) has been shown to specifically suppress Raf-1 expression both in vitro and in vivo. This Phase I trial, involving 22 patients with advanced cancer, was designed to evaluate the safety, feasibility, and maximum tolerated dose of ISIS 5132 administration as a weekly 24-h i.v. infusion. Pharmacokinetic analysis was performed, and c-raf-1 mRNA levels in peripheral blood mononuclear cells were assessed using quantitative reverse transcription-PCR. This trial defined a maximum tolerated dose of 24 mg/kg/week on this schedule. Two of four patients treated at 30 mg/kg/week had serious adverse events after the first dose of ISIS 5132, including acute hemolytic anemia and acute renal failure and anasarca. There were no major responses documented. Dose-dependent complement activation was demonstrated on this schedule, but not on previously evaluated schedules, of ISIS 5132 administration. In contrast to other trials of ISIS 5132, there appeared to be no consistent suppression of peripheral blood mononuclear cell c-raf-1 mRNA level on this schedule at any of the dose levels analyzed. These data suggest that the efficacy and toxicity profiles of antisense oligonucleotides may be highly dependent on the schedule of administration and support the analysis of the putative molecular target in the evaluation of novel therapeutics.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Tionucleótidos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Coagulación Sanguínea/efectos de los fármacos , Proteínas del Sistema Complemento/metabolismo , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/metabolismo , Oligodesoxirribonucleótidos Antisentido/efectos adversos , Oligodesoxirribonucleótidos Antisentido/farmacocinética , Proteínas Proto-Oncogénicas c-raf/genética , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/sangre , Tionucleótidos/efectos adversos , Tionucleótidos/farmacocinética , Resultado del TratamientoRESUMEN
Plasma pharmacokinetics, biodistribution, excretion, and metabolism of four modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA have been characterized in rats and compared with a first-generation phosphorothioate oligodeoxynucleotide (PS ODN), ISIS 2302. The modified oligonucleotides contained 2'-O-(2-methoxyethyl) (2'-O-MOE) ribose sugar modifications on all or a portion of the nucleotides in the antisense sequence. The 2'-O-MOE-modified oligonucleotides were resistant to nuclease metabolism in both plasma and tissue. In general, plasma pharmacokinetics was not substantially altered by addition of the 2'-O-MOE modification to PS ODN. Thus, plasma clearance was dominated by distribution to tissues, broadly, with less than 10% of the administered dose excreted in urine or feces over 24 h. However, the 2'-O-MOE modification combined with the phosphodiester (PO) backbone exhibited 10-fold more rapid plasma clearance, with approximately 50% of the dose excreted in urine as intact oligonucleotide. Consistent with its rapid and extensive excretion, the PO 2'-O-MOE modification distributed to very few organs in any substantial amount with the exception of the kidney. Oligonucleotides that contained phosphorothioate backbones were highly bound to plasma proteins. Indeed, the primary characteristic that resulted in the most marked alterations in pharmacokinetics appeared to be the affinity and capacity of these compounds to bind plasma proteins. A balance of greater stability supplied by the 2'-O-MOE modification together with maintenance of plasma protein binding appears to be necessary to ensure favorable pharmacokinetics of this new generation of antisense oligonucleotides.
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Oligonucleótidos Antisentido/farmacocinética , Tionucleótidos/farmacocinética , Animales , Desoxirribonucleasas/metabolismo , Estabilidad de Medicamentos , Masculino , Oligonucleótidos Antisentido/sangre , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/orina , Unión Proteica , Ratas , Ratas Sprague-Dawley , Tionucleótidos/sangre , Tionucleótidos/química , Tionucleótidos/orina , Distribución TisularRESUMEN
Three modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA were characterized for their presystemic stability and oral bioavailability compared with a first-generation phosphorothioate oligodeoxynucleotide (PS ODN), ISIS 2302. The three modified oligonucleotides contained 2'-O-(2-methoxyethyl) (2'-O-MOE) ribose sugar modifications on a portion, or on all of the nucleotides in the antisense sequence. In vitro metabolism studies conducted in various gastrointestinal and digestive tissue preparations indicated substantial improvement in stability of 2'-O-MOE-modified oligonucleotides. In addition, in vivo presystemic stability of these oligonucleotides was monitored in rats following intraduodenal administration. By 8 h after administration, only chain-shortened metabolites of the PS ODN were recovered in the gastrointestinal contents. In contrast, approximately 50% of the 2'-O-MOE ribose-modified (partial) compound remained intact (20-mer) by 8 h following administration. Both of the fully modified compounds (2'-O-MOE PO and PS) were completely stable with no measurable metabolites observed within 8 h of administration. The rank order of bioavailability was ISIS 11159 (full PS, full MOE) < ISIS 2302 (PS ODN) < ISIS 16952 (full PO, full MOE) < ISIS 14725 (full PS, partial MOE); the absolute plasma concentration bioavailability was measured in reference to intravenous dosing in the rat and was estimated at 0.3, 1.2, 2.1, and 5.5%, respectively. The optimal oligonucleotide chemistry for improved permeability and resulting bioavailability was the partially modified 3' hemimer 2'-O-MOE phosphorothioate oligonucleotide (ISIS 14725). Improved presystemic stability coupled with improved permeability were likely responsible for the remarkable improvement in the oral bioavailability of this compound.