A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques.
富马酸替诺福韦 Alafenamide 皮下植入物引起兔和猕猴局部炎症和组织坏死。
- 作者列表："Su JT","Simpson SM","Sung S","Tfaily EB","Veazey R","Marzinke M","Qiu J","Watrous D","Widanapathirana L","Pearson E","Peet MM","Karunakaran D","Grasperge B","Dobek G","Cain CM","Hope T","Kiser PF
:We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.
: 我们描述了递送替诺福韦 alafenamide hemifuma (TAF) 的皮下储库植入物用于预防 HIV 感染的体外和体内评价。这些长效储存器植入物能够在体外和体内递送超过 90 天的抗逆转录病毒药物。我们评估了植入物的植入部位，组织病理学和血浆和组织中的药代动力学长达 12 周。在新西兰白兔和恒河猴模型中。一项针对兔的剂量范围研究证明了剂量依赖性药代动力学和局部炎症，直至活性植入物周围严重坏死。匹配的安慰剂显示伤口愈合正常，植入物的纤维组织包裹。我们设计了具有较低释放速率和 TAF 通量的第二个植入物，并在 TAF 剂量为 10 时达到每 106 只恒河猴外周血单核细胞 42 fmol 的替诺福韦二磷酸盐的中位细胞水平。 μg μ g/kg/天。TAF 的这种剂量和通量也导致恒河猴植入物附近的不良局部炎症和坏死。安慰剂组灵长类动物的炎症水平明显低于活性植入组。灵长类动物在 4 周和 12 周时对 TAF 植入物的组织学炎症反应被分级为严重反应。因此，虽然我们能够达到持续的目标剂量，但我们在植入物组织界面局部观察到不可接受的炎症反应。
METHODS:BACKGROUND:Ultrasound has been demonstrated to accurately diagnose rectal deep endometriosis (DE) and pouch of Douglas (POD) obliteration. The role of ultrasound in the assessment of patients who have undergone surgery for rectal DE and POD obliteration has not been evaluated. AIM:To describe the transvaginal ultrasound (TVS) findings of patients who have undergone rectal surgery for DE. MATERIALS AND METHODS:An observational cross-sectional study at a tertiary care centre in Sydney, Australia between January and April 2017. Patients previously treated for rectal DE (low anterior resection vs rectal shaving/disc excision) were recruited and asked to complete a questionnaire on their current symptoms. On TVS, POD state and rectal DE were assessed. Correlating recurrence of POD obliteration and/or rectal DE to surgery type and symptoms was done. RESULTS:Fifty-six patients were contacted; 22/56 (39.3%) attended for the study visit. Average interval of surgery to study visit was 52.8 ± 24.6 months. Surgery type breakdown was as follows: low anterior resection (56%) and rectal shaving/disc excision (44%). The prevalence of POD obliteration was 16/22 (72.7%) intraoperatively and 8/22 (36.4%) at study visit, as per the sliding sign. Nine patients (39.1%) had evidence on TVS of recurrent rectal DE. Recurrence of POD obliteration and rectal DE was not associated with surgery type or symptomatology. CONCLUSION:Despite surgery for rectal DE, many patients have a negative sliding sign on TVS, representing POD obliteration, and rectal DE. Our numbers are too small to correlate with the surgery type or their current symptoms.
METHODS::Minimally invasive surgery for complex endometriosis requires preoperative planning that intimately connects the gynecologic surgeon to the radiologist. Understanding the surgeon's perspective to endometriosis treatment facilitates a productive relationship that ultimately benefits the patient. We examine minimally invasive surgery for endometriosis and the key radiologic information which enable the surgeon to successfully negotiate patient counseling, preoperative planning, and an interdisciplinary approach to surgery.
METHODS:STUDY OBJECTIVE:Prior research collectively shows that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN:Cross sectional study among women with no prior diagnosis of endometriosis. SETTING:Fourteen clinical centers in Salt Lake City, Utah and San Francisco, California. PATIENTS:Four hundred and ninety five women, ages 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS:Gynecologic laparoscopy/laparotomy, regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS:Participants underwent anthropometric assessments, body composition, and body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised ASRM staging (I to IV) and typology of disease (superficial [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. While the majority of confidence intervals were wide and overlapping, three general impressions emerged: 1) women with versus without incident endometriosis had the lowest anthropometric/body composition indicators; 2) women with stage I or IV had lower indicators compared to women with stage II or III; and 3) women with OE and/or DIE tended to have the lowest indicators, while women with SE had the highest indicators. CONCLUSION:Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.