Uptake and outcomes of robotic gynaecological surgery in England (2006-2018): an account of Hospital Episodes Statistics (HES).

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.

Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain.

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.

Osteosarcoma and second malignant neoplasms: a case series.

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.

A step-wise approach to developing indicators to compare the performance of maternity units using hospital administrative data.

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.

Painful sex (dyspareunia) in women: prevalence and associated factors in a British population probability survey.

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.

Trends in the use of emergency contraception in Britain: evidence from the second and third National Surveys of Sexual Attitudes and Lifestyles.

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.

Self-reported Sleep Improvement in Buprenorphine MAT (Medication Assisted Treatment) Population.

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.

Immunogenetic characterization of a captive colony of sooty mangabeys (Cercocebus atys) used for SIV research.

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.

Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis.

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.

Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate.

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.

Promoter sequences targeting tissue-specific gene expression of hypothalamic and ovarian gonadotropin-releasing hormone in vivo.

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.

Diagnosis and treatment of paradoxical embolus.

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.

Infection is an unusual but serious complication of a femoral artery catheterization site closure device.

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.

Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides.

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.

A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma.

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.

Phase I Trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer.

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.

Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice.

ISIS 22023 is a modified phosphorothioate antisense oligonucleotide targeting murine Fas mRNA. Treatment of mice with ISIS 22023 reduced Fas expression in liver in a concentration-dependent and sequence-specific manner, which completely protected mice from fulminant death induced by agonistic Fas antibody. In this study, we characterized the relationships in mice between total dose administered, dose to the target organ, and ultimately, the intracellular concentration within target cell types to the pharmacologic activity of ISIS 22023. After subcutaneous injection, ISIS 22023 distributed to the liver rapidly and remained in the liver with the t(1/2) ranging from 11 to 19 days, depending on dose. There were apparent differences in patterns of uptake and elimination in different types of liver cells. Oligonucleotide appeared within hepatocytes rapidly, whereas the peak concentrations in Kupffer cells were delayed until 2 days after dose administration. Hepatocytes cleared oligonucleotide the most rapidly, whereas Kupffer cells appeared to retain oligonucleotide longer. The reduction of Fas mRNA levels (pharmacodynamic response) paralleled the increase of oligonucleotide concentration in mouse liver with maximum mRNA reduction of 90% at 2 days after a single 50 mg/kg subcutaneous administration. Moreover, the pharmacodynamics of ISIS 22023 correlated better with the pharmacokinetics in hepatocytes, supporting the concept that the presence of oligonucleotide in target cells results in reductions in mRNA and, ultimately, pharmacologic activity. These results provide a comprehensive understanding of the kinetics of an antisense drug at the site of action and demonstrate that the reductions in mRNA induced by this antisense oligonucleotide correlate with its concentrations in cell targets.

Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide targeting human Ha-ras mRNA in mouse and monkey.

The plasma pharmacokinetics and tissue disposition of ISIS 2503 were studied in mice following single and multiple bolus intravenous (iv) injections of 1-50 mg/kg, and in monkeys following single and multiple 2-h iv infusions of 1-10 mg/kg and bolus iv injections of 1 mg/kg of ISIS 2503. ISIS 2503 and its metabolites were measured in plasma, urine, and tissues using solid-phase extraction followed by capillary gel electrophoresis (CGE). In both species, the plasma clearance of ISIS 2503 was characterized by rapid distribution to tissues, and to a lesser extent, metabolism. The plasma clearance in mice was at least two-fold more rapid than in monkeys at equivalent doses. The plasma disposition (t1/2) increased with dose. The highest concentrations of oligonucleotide were consistently observed in the kidney and liver in both species. At equivalent doses, tissue concentrations in monkeys were much higher than tissue concentrations in mice. Urinary excretion of total oligonucleotide was a minor elimination pathway in both species at doses < 10 mg/kg. However, urinary excretion of total oligonucleotide in mice was increased to 12-29% as dose increased from 20 to 50 mg/kg.