Controlled release delivery of penciclovir via a silicone (MED-4750) polymer: kinetics of drug delivery and efficacy in preventing primary feline herpesvirus infection in culture

Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas, with generally poor prognosis. Historically, there has been a lack of consensus regarding appropriate therapeutic measures for the disease, with conventional frontline chemotherapies being utilized in most cases. Following promising results obtained in 2009, the methotrexate analogue, pralatrexate, became the first drug to gain US FDA approval for the treatment of refractory PTCL. This antimetabolite was designed to have a higher affinity for reduced folate carrier (RFC) and folylpolyglutamate synthetase (FPGS). RFC is the principal transporter for cell entrance of folates and antifolates. Once inside the cell, pralatrexate is efficiently polyglutamated by FPGS. Pralatrexate has demonstrated varying degrees of efficacy in peripheral T-cell lymphoma, with response rates differing between the multiple subtypes of the disease. While phase III studies are still to be completed, early clinical trials indicate that pralatrexate is promising new therapeutic for PTCL

Controlled release delivery of penciclovir via a silicone (MED-4750) polymer: kinetics of drug delivery and efficacy in preventing primary feline herpesvirus infection in culture

BackgroundHerpesviruses are ubiquitous pathogens that infect and cause recurrent disease in multiple animal species. Feline herpesvirus-1 (FHV-1), a member of the alphaherpesvirus family, causes respiratory illness and conjunctivitis, and approximately 80% of domestic cats are latently infected. Oral administration of famciclovir or topical application of cidofovir has been shown in masked, placebo-controlled prospective trials to reduce clinical signs and viral shedding in experimentally inoculated cats. However, to the authors' knowledge, other drugs have not been similarly assessed or were not safe or effective. Likewise, to our knowledge, no drugs have been assessed in a placebo-controlled manner in cats with recrudescent herpetic disease. Controlled-release devices would permit long-term administration of these drugs and enhance compliance.MethodsWe therefore engineered implantable cylindrical devices made from silicone (MED-4750) impregnated with penciclovir, for long-term, steady-state delivery of this drug.ResultsOur data show that these devices release penciclovir with a burst of drug delivery until the tenth day of release, then at an average rate of 5.063 ± 1.704 μg per day through the next 50 days with near zero-order kinetics (in comparison to MED-4750-acyclovir devices, which show the same burst kinetics and average 2.236 ± 0.625 μg/day thereafter). Furthermore, these devices suppress primary infection of FHV-1 in a cell culture system.ConclusionsThe clinical deployment of these silicone-penciclovir devices may allow long-term treatment of FHV-1 infection with a single intervention that could last the life of the host cat

Is There an Operative Time At Which Minimally Invasive Hysterectomy Becomes Inferior to Open Hysterectomy?

BackgroundDespite the well-established benefits of minimally invasive hysterectomy, the evidence suggests longer operative times in comparison to laparotomy. Longer operative times in both minimally invasive approaches and laparotomy have been associated with adverse outcomes. Little evidence exists to guide surgeons in both identifying patients at risk of excessive operating time and determining if the at-risk patient may then benefit from an alternative surgical approach. Furthermore, no evidence exists to differentiate an operative time at which a prolonged minimally invasive hysterectomy becomes inferior to a quicker laparotomy.Patients and MethodsUsing the American College of Surgeons National Surgical Quality Improvement Program, laparoscopic and open hysterectomies were identified from 2005 to 2013 by CPT code. Procedures were split into open and laparoscopic and then stratified into operative time categories: \u3c 1 hour, 1 to \u3c 2 hours, 2 to \u3c 3 hours, 3 to \u3c 4 hours and \u3e 4 hours. Outcomes in open cases were compared to those of laparoscopic cases by time. ResultsThere were 30,160 open cases and 33,356 laparoscopic cases analyzed. Laparoscopic hysterectomies were more likely to have longer surgery times. Overall, bleeding, return to OR and wound complications were all significantly higher in open cases. Laparoscopic cases remained superior to open cases up until \u3e 4 hours, at which time there was no difference in bleeding or wound events when compared with open cases \u3c 2 hours, and a higher odds of return to the operating room when compared to open cases lasting 1 to \u3c 2 hours (OR 1.66 [1.28-2.15], P=.0001). When assessing laparoscopic cases \u3e 3 and \u3c 4 hours, even open cases \u3c 1 hour duration had a higher odds of the composite complication variable (OR = 2.20 [95% CI 1.89-2.56] P\u3c.0001). A total of 11.5% of laparoscopic hysterectomy cases lasted \u3e 4 hours.ConclusionsLaparoscopic hysterectomy had superior outcomes than abdominal hysterectomy overall. However, a significant rise in complications was seen with at \u3e 4 hours, at which point there was no longer a benefit to laparoscopy when compared to abdominal cases \u3c 2 hours. Relatively few laparoscopic cases lasted \u3e 4 hours. Careful patient counselling, preparation to increase surgical efficiency and potentially an open approach should be considered in laparoscopic hysterectomies anticipated to be \u3e 4 hours long

Outcomes of Prolonged Minimally Invasive Myomectomy Compared to Open Procedures

Background: Myomectomy is the only fertility sparing surgical approach for the management of fibroids and is increasingly being performed via minimally invasive surgery (MIS). Although MIS has proven clinical benefits over laparotomy, longer operative times in both MIS and laparotomy are associated with adverse outcomes. Little evidence exists to identify patients at risk of excessive operating time. Furthermore, no evidence exists to differentiate an operative time at which risk increases for either approach. Methods: Using the American College of Surgeons National Surgical Quality Improvement Program, laparoscopic and abdominal myomectomies were identified from 2005 to 2013 by CPT code. Procedures were split into laparoscopic and open, and then stratified based on operative time: \u3c 1 hour, 1 to \u3c2 hours, 2 to \u3c3 hours, ≥ 3 hours. Outcomes in open cases were compared to those of laparoscopic cases by time. Results: In all, 2403 laparoscopic and 3436 open procedures were analyzed. In general, open abdominal procedures had worse 30-day outcomes than laparoscopic procedures. Longer surgeries were associated with African American race, higher BMI, lower hematocrit, HTN, age, and large or numerous fibroids. Surgery time was longer for laparoscopic procedures compared with open procedures. Wound complications, clotting, sepsis, UTI, bleeding, return to OR, hospital LOS \u3e 3 days, and a composite complications outcome were significantly associated with surgery time. For most outcomes, there was an increased rate with increased surgery time. After adjusting for confounders, there was no difference in complications between laparoscopic procedures \u3c 1 hour, 1 to \u3c 2 hours, and 2 to \u3c 3 hours long. However, laparoscopic procedures ≥ 3 hours had a higher odds of complications compared with laparoscopic procedures \u3c 1 hour (OR 5.46 [1.31-22.75]; p=.02)). For open procedures, there was no difference in odds of complications for cases \u3c 1 hour and those 1 to \u3c2 hour. However, open procedures of 2 to \u3c3 hours had a higher odds of complications when compared to those \u3c 1 hour long (OR 3.70 [2.20-6.23]; p\u3c.0001). Conclusions: Surgical time was predictive of complications in both laparoscopic and open myomectomy. Laparoscopic myomectomy had a lower complication rate overall. For laparoscopic cases, there was an increase in complications at \u3e 3 hours compared to \u3c 1 hour and for open cases there was an increase in complications at \u3e 2 and \u3c 3 hours compared to \u3c 1 hour. Careful patient counseling and preparation to increase surgical efficiency should be prioritized for either approach