Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine.

BACKGROUND: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). METHODS: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. RESULTS: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. CONCLUSION: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. TRIAL REGISTRATION: NCT03670810.

Working memory deficits in schizophrenia are not necessarily specific or associated with MRI-based estimates of area 46 volumes.

Despite substantial evidence that the prefrontal cortex does not function normally in patients diagnosed with schizophrenia, evidence for prefrontal structural abnormalities, as measured by magnetic resonance imaging (MRI), has been inconsistent. Additionally, evidence for relationships between prefrontal structural and functional measures has been limited. The inconsistencies in the MRI literature are, at least in part, due to a lack of standard and specific measurement protocols that allow delineation of functionally distinct cortical regions. In this study, reliable methods for measuring an estimate of area 46 (estimate referred to as area 46(e)), as defined by 'Cereb. Cortex 5 (1995) 323', were developed and used to examine relationships between area 46(e) volumes, working memory, and symptom severity in 23 male patients and 23 healthy male comparison subjects. Patients performed more poorly than healthy reference subjects on all cognitive measures including measures of spatial and non-spatial working memory, but showed no significant corresponding deficits in area 46(e) volumes or whole brain volumes. Moreover, there were no significant relationships between symptom severity and area 46(e) volumes. These findings suggest that the prefrontal functional abnormalities observed in schizophrenia may occur in the absence of prefrontal volume deficits, and may instead involve more widespread brain systems or prefrontal connections with other brain regions.

The temporal efficacy of early second-look lysis of adhesions in reducing postoperative adhesions in a murine model.

OBJECTIVE: Our aim was to determine whether early second-look lysis of adhesions reduces postoperative adhesions. STUDY DESIGN: With the murine uterine horn model, early second-look lysis of adhesions was performed 5, 7, 14, and 21 days after an electrocautery injury. Sites with adhesions (between 36 and 46/time point) underwent lysis of adhesions. Fourteen days later, a reviewer blinded to the treatment assessed adhesion formation, including adhesions not present at early second-look lysis of adhesions (eg, de novo adhesions). RESULTS: The rate of adhesion formation was 49% of control sites, unchanged when the early second-look lysis of adhesions was performed at 5 (44.4%) and 7 (39.5%) days, reduced at 14 days (28.6%), and increased at 21 days (74%). The pattern of de novo adhesions was similar, 17.6% when the early second-look lysis of adhesions was performed at 5 days, 10% at 7 days, 0% at 14 days, and 28.6% at 21 days. The only histologic difference between the groups was neovascularity at day 21. CONCLUSIONS: Early second-look lysis of adhesions was effective in reducing postoperative adhesions only when performed at 14 days in this model, suggesting that the specific cellular events occurring at the time of the early second-look lysis of adhesions are critical to efficacy.

A barrier composed of chemically cross-linked hyaluronic acid (Incert) reduces postoperative adhesion formation.

OBJECTIVE: To test whether a barrier of chemically cross-linked pure hyaluronic acid reduces postoperative adhesion formation. DESIGN: The material was evaluated in the murine uterine horn model using excision and electrocautery injuries and in animals who had amounts of material inserted into the abdomen to evaluate toxicity. SETTING: Academic medical center. SUBJECT(S): Mice. INTERVENTION(S): Insertion of the barrier between uterine horns and into the peritoneal cavity. MAIN OUTCOME MEASURE(S): Adhesion formation at 14 days; the histology of the peritoneum, liver, and spleen at 42 days; and the number, differential count, morphology, and flow cytometry of peritoneal leukocytes 3 days postoperatively. RESULT(S): Fewer adhesions were present when excision injuries were separated by the barrier (12 of 28 sites [43%] versus 23 of 26 control sites [88%]), whereas the number of adhesions was unchanged after electrocautery injuries (14 of 26 sites [54%] versus 17 of 26 control sites [65%]). The uterine horn sites covered by the barrier were histologically indistinguishable from controls. No adverse impact on the peritoneum and peritoneal fluid leukocyte population was observed with barrier insertion. CONCLUSION(S): The use of a barrier composed of a chemically cross-linked hyaluronic acid derivative (Incert, Anika Therapeutics, Inc., Woburn, MA) reduced postoperative adhesion formation in this model without any adverse impact on the peritoneum and peritoneal leukocyte population. This barrier material shows promise in preventing postoperative adhesions and deserves clinical evaluation.

Financial analysis of telemedicine in a prison system.

OBJECTIVE: To quantify the costs and benefits of medical care under a telemedicine agreement. METHODS: Two telemedicine contracts between the North Carolina Central Prison (NCCP) and the East Carolina University School of Medicine were analyzed, first from the point of view of the prison using break-even analysis and second from the societal point of view examining whether the arrangements were positive for the taxpayers of North Carolina. RESULTS AND CONCLUSIONS: While the prison system never broke even with the first contract, the break-even was attainable, as it would have required an average of only one consultation per day. The prison system attained break-even status in the latest year of the second contract, and simple forecasts indicate a good chance that usage will grow beyond the break-even point. From the societal point of view, the contracts are merely transfers of funds from one state agency to another. Therefore, the differences in them are irrelevant. What is relevant is a measure of average fixed and variable spending for telemedicine and what this expenditure buys in terms of avoided costs. Thus, we examined the average full cost per visit, as determined from the actual or estimated expenditures, and concluded that the program paid back its cost during year 4.

The peritoneal response to expanded polytetrafluoroethylene and oxidized regenerated cellulose surgical adhesion barriers.

OBJECTIVE: To determine the peritoneal response to the surgical adhesion barriers expanded-polytetrafluoroethylene (ePTFE) and oxidized regenerated cellulose (ORC). STUDY DESIGN: The barriers were retrieved from the peritoneal cavities of women and mice 2 hours to 14 days after insertion and subjected to histology and electronmicroscopy. RESULTS: Macrophages and mesothelial cells rapidly appeared on the surface of both materials. ePTFE was covered by 3 days, with the macrophages gradually being replaced by mesothelium and disappearing thereafter. By 7 days, a delicate membrane with surface mesothelial cells completely enveloped the ePTFE, creating a "pseudoperitoneum". The membrane was difficult to recover as it was fragile and not adherent to the ePTFE. ORC was rapidly infiltrated and degraded by leukocytes and disappeared by 5 days in mice and from all but 1 of 20 women by 11 days. CONCLUSIONS: ePTFE is rapidly encapsulated by a non-adherent membrane resembling peritoneum while ORC is rapidly infiltrated and degraded by peritoneal fluid leukocytes.

Nitric oxide inhibition of human sperm motility.

OBJECTIVE: To determine the effect of nitric oxide (NO) on sperm motility in vitro. DESIGN: Normal human sperm separated by centrifugation through a discontinuous Percoll gradient and subsequent swim-up were incubated for up to 24 hours with NO donors, with and without the known NO quencher hemoglobin, as well as with agents that raise intracellular cyclic 3',5'-guanosine monophosphate (cGMP). Sperm respiration was determined by a tetrazolium-formazan spectrophotometric assay. SETTING: Andrology laboratory. MAIN OUTCOME MEASURES: Absolute sperm motility and respiration. RESULTS: Sperm incubated with the NO donors 1 mM nitroprusside, 100 to 125 microM 3-morpholinosydnonimine, and 25 to 125 microM pure nitric oxide gas dissolved in buffer were inhibited in motility in a dose-dependent fashion. The inhibition could be reversed by the NO quencher hemoglobin. Agents that raise cellular cGMP (dibutyryl cGMP or 8-bromo-cGMP) did not inhibit motility. Nitric oxide inhibited sperm respiration, as measured by the tetrazolium-formazan assay. CONCLUSIONS: Nitric oxide reduces sperm motility, possibly by a mechanism involving inhibition of cellular respiration independent of an elevation of intracellular cGMP. Nitric oxide elaborated in the female or male genital tract in vivo could adversely influence sperm function and fertility.

Differential effects of interleukin-1 alpha, tumor necrosis factor-alpha, indomethacin, hydrocortisone, and macrophage co-culture on the proliferation of human fibroblasts and peritoneal mesothelial cells.

OBJECTIVE: We sought to determine whether human fibroblasts and peritoneal mesothelial cells (PMC) are under comparable proliferative controls. METHODS: Human PMC and human fibroblasts were obtained from primary culture of excised explants from infertile women. The proliferation of PMC, as determined by tritiated thymidine incorporation, was compared with that of fibroblasts in the presence of human peritoneal macrophages, interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF), indomethacin, and hydrocortisone. Data were analyzed by one-way and multifactorial analyses of variance, with Bonferroni adjustments for multiple comparisons. RESULTS: Disparate proliferation was observed between fibroblasts and mesothelial cells with the additives studied. Proliferation of fibroblasts was inhibited (P < .001) when co-cultured with macrophages, IL-1, and TNF. Indomethacin and hydrocortisone overcame the inhibitory effects of macrophage co-culture. By contrast, PMC increased proliferation when cultured with macrophages (P < .001) but were unaffected by IL-1 or TNF and were not altered when indomethacin or hydrocortisone was added to the macrophage co-culture. CONCLUSION: Human PMC and fibroblasts differentially proliferate in response to putative regulatory controls. This suggests that these cells, which play critical roles in peritoneal wound repair, should be considered separately in developing medical strategies to prevent postsurgical adhesions.

An elicited intraperitoneal inflammatory response has no effect on the establishment of pregnancy in the mouse.

OBJECTIVE: To determine the impact of intraperitoneal inflammation on reproduction in the mouse. DESIGN: The effect of an elicited sterile intraperitoneal inflammatory exudate and the passive intraperitoneal transfer of activated syngeneic leukocytes on mating efficiency and uterine implantations was evaluated in mice. SETTING: Research laboratory. INTERVENTIONS: Intraperitoneal injection of thioglycolate was used to elicit large numbers of activated peritoneal macrophages (mean 24.4 x 10(6) leukocytes/animal) in female CD-1 mice. The impact of this intraperitoneal exudate on mating efficiency and number of uterine horn implantations after gonadotropin-stimulated ovulation was determined. In separate experiments, the ovarian bursa present in this species was opened surgically to provide direct access of peritoneal constituents to the genital tract and the experiments repeated. Identical endpoints were evaluated in a third group of experiments using C3H/HEN syngeneic mice after passive transfer of 2, 5, and 10 x 10(6) similarly activated syngeneic peritoneal leukocytes. RESULTS: Neither the elicitation of a peritoneal inflammatory exudate nor the passive transfer of up to 10 x 10(6) activated syngeneic peritoneal macrophages reduced the mating efficiency or the number of uterine implantations. Furthermore, surgically opening the ovarian bursa did not alter these results, although it was associated with anatomic distortion and lowered the number of implantations in all groups. CONCLUSIONS: We could not confirm the previously published reports suggesting a profound adverse impact of intraperitoneal inflammation on reproduction in mice, even when providing direct continuity between the peritoneal cavity and the genital tract. Consequently, the usefulness of this model needs to be re-evaluated before considering it an adequate paradigm for evaluating potential mechanisms of infertility in women.

The formation of coalescing peritoneal adhesions requires injury to both contacting peritoneal surfaces.

OBJECTIVE: To determine whether surgical trauma to one or both contacting peritoneal surfaces is necessary to cause coalescing adhesions. SETTING: Research laboratory. DESIGN: The abdominal wall peritoneum and one or both contacting medial peritoneal surfaces of surgically approximated uterine horns in mice were injured by electrocautery, cutting, scratching, or scraping. Adhesion formation was assessed visually and histologically 3 and 7 days later. RESULTS: Regardless of the type of peritoneal injury, few adhesions resulted when only a single injury was made to the abdominal wall (< or = 6%) or to one uterine horn (< or = 13%). When both opposing uterine surfaces were injured, however, adhesions formed at 57% of the sites after electrocautery, 100% after cutting, 100% after scratching, but 0% after scraping. When previously created uterine adhesions were lysed, they reformed at 15 of 15 sites with and 12 of 13 (92%) sites without electrocautery for hemostasis at the time of lysis. CONCLUSIONS: In this murine model, the development of postsurgical adhesions required surgical trauma to both contacting peritoneal sites, regardless of the type of injury, the mobility of the opposing peritoneal surfaces or whether hemostasis was achieved. The clinical implications are that more attention needs to be focused on protecting contacting normal peritoneal surfaces from inadvertent injury during surgery and that different therapeutic strategies may be required for prevention of adhesion formation and reformation because of the high probability of contact between injured peritoneal surfaces with the latter.

Expanded-polytetrafluoroethylene but not oxidized regenerated cellulose prevents adhesion formation and reformation in a mouse uterine horn model of surgical injury.

OBJECTIVE: To evaluate the ability of the two currently available surgical barriers, oxidized regenerated cellulose and expanded-polytetrafluoroethylene (PTFE), to prevent postsurgical adhesions. DESIGN: Murine uterine horns were approximated in the midline and the contacting uterine surfaces injured by electrocautery, cutting, and scratching, with and without barriers interposed. Sham-operated and experimental animals had adhesions assessed visually and histologically 7 days postoperatively. In another group, adhesions were created and then lysed 7 days later with barriers interposed. Readhesion formation was assessed 14 days after lysis with the PTFE being removed 7 days after lysis. SETTING: Research laboratory RESULTS: Adhesions occurred at 58.5% of the electrocautery sites without barriers, 100% of the readhesion sites with recautery for hemostasis, and 92% of the recautery sites without hemostasis. None of the sham-operated sites developed adhesions. When oxidized regenerated cellulose was interposed, adhesions were observed at 36% of uninjured uterine horn sites, 62% with single and 92% with double electrocautery injuries and 90% of the reformation sites. The PTFE did not cause adhesions in uninjured controls and completely prevented adhesion formation and reformation, regardless of the type of injury or whether hemostasis was achieved. A thin cellular membrane, continuous with the uterine serosa, enveloped the PTFE. CONCLUSIONS: Expanded-polytetrafluoroethylene, but not oxidized regenerated cellulose, prevents adhesion formation and reformation in this murine uterine horn model. Additionally, oxidized regenerated cellulose was adhesiogenic even without surgical injury.

Comparison of the peritoneal cells elicited by oxidized regenerated cellulose (Interceed) and expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane) in a murine model.

OBJECTIVE: The peritoneal fluid cell responses to the available barriers used to prevent postoperative adhesions, oxidized regenerated cellulose (interceed) and expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane), were compared. STUDY DESIGN: Oxidized regenerated cellulose and expanded polytetrafluoroethylene were inserted into the peritoneal cavity of mice and the peritoneal fluid cell number, differential cell count, morphologic type, adherence to plastic, and phorbol-12,13-myristate acetate-stimulated hydrogen peroxide production evaluated. Peritoneal fluid cell attachment to oxidized regenerated cellulose and expanded polytetrafluoroethylene was evaluated by electron microscopy. RESULTS: Oxidized regenerated cellulose promptly elicited increased numbers of large, morphologically activated peritoneal fluid macrophages that adhered more rapidly and produced more hydrogen peroxide than controls. Expanded polytetrafluoroethylene gradually increased the number of normal-appearing peritoneal fluid macrophages with increased hydrogen peroxide production but normal adherence. Macrophages rapidly attached to both materials in vivo, with oxidized regenerated cellulose being rapidly degraded. CONCLUSION: Oxidized regenerated cellulose, to a greater extent than expanded polytetrafluoroethylene, elicits an acute peritoneal fluid inflammatory exudate in the mouse, which may contribute to the oxidized regenerated cellulose-induced peritoneal injury and de novo adhesions observed in this model.

Murine peritoneal injury and de novo adhesion formation caused by oxidized-regenerated cellulose (Interceed [TC7]) but not expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane).

STUDY OBJECTIVE: To evaluate the impact of the materials contained in the available adhesion prevention barriers on the peritoneum. STUDY DESIGN, SETTING, PATIENTS: A murine paradigm was used, placing oxidized-regenerated cellulose (Interceed [TC7]) and expanded polytetrafluoroethylene (PTFE; Gore-Tex Surgical Membrane) in the peritoneal cavity for intervals up to 14 days. INTERVENTIONS AND MAIN OUTCOME MEASURES: The appearance of the peritoneum on scanning and transmission electron microscopy and the presence of de novo adhesions were the end-points used. RESULTS: Oxidized-regenerated cellulose caused localized sloughing of the mesothelial cell layer and leukocyte infiltration of the deeper tissue leading to the formation of adhesions to the bowel and liver in 58% of the animals. The surface of the oxidized-regenerated cellulose-injured peritoneum healed in 5 to 7 days. Neither peritoneal injury nor adhesions were noted in sham-operated animals or animals with PTFE. CONCLUSIONS: Oxidized-regenerated cellulose but not PTFE has a localized injurious effect on the peritoneum of the mouse, resulting in de novo adhesions. The impact of the barrier material itself on normal peritoneum may be an important consideration in designing surgical barriers for the prevention of postoperative adhesions.

Clinical trials with human tumor necrosis factor: in vivo and in vitro effects on human mononuclear phagocyte function.

The purpose of this investigation was to understand the biological effects of recombinant human tumor necrosis factor used as therapy for cancer. We studied changes in mononuclear phagocyte function following exposure to this cytokine in vitro or in vivo. Tumor necrosis factor increased phorbol myristate acetate-induced hydrogen peroxide production 8- to 20-fold in peripheral blood monocytes and peritoneal macrophages in vitro in a dose-dependent manner. Similarly, tumor necrosis factor increased phorbol myristate acetate-induced peroxide production 2.3-fold in monocytes isolated from nine patients following an i.v. infusion of this cytokine (40 to 200 micrograms/m2). In addition, tumor necrosis factor induced a 2.3-fold increase in tissue factor-like activity in mononuclear phagocytes in vitro. In vivo, tumor necrosis factor induced a trend toward higher procoagulant activity in monocytes, although this change was not statistically significant. We also noted a trend toward increased activated partial thromboplastin times and the presence of fibrin D-dimer in patients treated with tumor necrosis factor, demonstrating activation of the coagulation and fibrinolytic systems. Thus, in vivo treatment of humans with i.v. recombinant human tumor necrosis factor induced functional changes in mononuclear phagocytes similar to those noted with in vitro treatment.