Morphine Exacerbates Experimental Colitis-Induced Depression of Nesting in Mice

Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are excellent analgesics, but recent clinical evidence suggests that these drugs might worsen disease severity in Crohn's disease patients, limiting their clinical utility for treating Inflammatory Bowel Disease (IBD). One indicator of change in well-being from conditions such as IBD is behavioral depression and disruption to activities of daily living. Preclinical measures of behavioral depression can provide an indicator of changes in quality of life and subsequent modification by candidate analgesics. In mice, nesting is an adaptive unconditioned behavior that is susceptible to disruption by noxious stimuli, and some types of pain related nesting depression are responsive to opioid and NSAID analgesics. Here we show that a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) model of experimental colitis depresses nesting behavior in mice, and we evaluated effects of morphine, an opioid, and ketoprofen, a NSAID, on TNBS-induced nesting depression. In Swiss Webster mice, TNBS significantly reduced nesting that peaked on Day 3 and recovered in a time-dependent manner with complete recovery by Day 7. In the absence of colonic inflammation, daily treatment with morphine (1–10 mg/kg) did not decrease nesting except at 10mg/kg/day. However, in TNBS-treated mice 3.2 mg/kg/day morphine significantly exacerbated TNBS-induced nesting depression and delayed recovery. While 3.2 mg/kg/day morphine alone did not alter locomotor activity and TNBS-induced depression of locomotion recovered, the combination of TNBS and 3.2 mg/kg/day morphine significantly attenuated locomotion and prevented recovery. Daily treatment with 3.2 or 10 mg/kg ketoprofen in TNBS-treated mice did not prevent depression of nesting. These data suggest that opioid analgesics but not NSAIDS worsen colonic inflammation-induced behavioral depression. Furthermore, these findings highlight the importance of evaluating analgesic effects in models of colonic inflammation induced depression of behavior.

High slew rate pulsed electromagnetic field enhances bone consolidation and shortens daily treatment duration in distraction osteogenesis

Aims Distraction osteogenesis (DO) is a useful orthopaedic procedure employed to lengthen and reshape bones by stimulating bone formation through controlled slow stretching force. Despite its promising applications, difficulties are still encountered. Our previous study demonstrated that pulsed electromagnetic field (PEMF) treatment significantly enhances bone mineralization and neovascularization, suggesting its potential application. The current study compared a new, high slew rate (HSR) PEMF signal, with different treatment durations, with the standard Food and Drug Administration (FDA)-approved signal, to determine if HSR PEMF is a better alternative for bone formation augmentation. Methods The effects of a HSR PEMF signal with three daily treatment durations (0.5, one, and three hours/day) were investigated in an established rat DO model with comparison of an FDA-approved classic signal (three hrs/day). PEMF treatments were applied to the rats daily for 35 days, starting from the distraction phase until termination. Radiography, micro-CT (μCT), biomechanical tests, and histological examinations were employed to evaluate the quality of bone formation. Results All rats tolerated the treatment well and no obvious adverse effects were found. By comparison, the HSR signal (three hrs/day) treatment group achieved the best healing outcome, in that endochondral ossification and bone consolidation were enhanced. In addition, HSR signal treatment (one one hr/day) had similar effects to treatment using the classic signal (three three hrs/day), indicating that treatment duration could be significantly shortened with the HSR signal. Conclusion HSR signal may significantly enhance bone formation and shorten daily treatment duration in DO, making it a potential candidate for a new clinical protocol for patients undergoing DO treatments. Cite this article: Bone Joint Res 2021;10(12):767–779.

Alternate-Day Dosing of Caplacizumab for Immune-Mediated Thrombotic Thrombocytopenic Purpura

Background: The anti-VWF nanobody caplacizumab directly prevents the fatal microthrombi formation in immune-mediated thrombotic thrombocytopenic purpura, thereby adding a new therapeutic principle to the treatment of this autoimmune disorder. However, real-world treatment modalities beyond clinical trials remain heterogeneous. Methods: Here, we describe the risks and benefits of an alternate-day dosing regimen for caplacizumab, by thoroughly analyzing the timing and outcome of this treatment approach in a retrospective cohort of 25 iTTP patients treated with caplacizumab in Austria and Germany between 2018 and 2021. Results: Alternate-day dosing of caplacizumab appeared feasible and led to persisting normal platelet counts in the majority of patients, who were converted after a median time of 17 days daily treatment. Four patients experienced iTTP exacerbations or relapses that led to the resumption of daily caplacizumab application and/or other therapies. VWF activity was repeatedly measured in 17 out of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 hours, in line with published pharmacokinetics. Conclusion: Extension of caplacizumab injection intervals from daily to alternate-day dosing may be safely considered in selected patients after 30 days of daily treatment. Earlier modifications may be considered in low-risk patients, but require close monitoring for clinical and laboratory features of thrombotic microangiopathy. Disclosures Völker: Sanofi-Genzyme: Honoraria, Other: counselling fees.

Inhibition of extracellular signal-regulated kinase pathway suppresses tracheal stenosis in a novel mouse model

Tracheal stenosis is a refractory and recurrent disease induced by excessive cell proliferation within the restricted tracheal space. We investigated the role of extracellular signal-regulated kinase (ERK), which mediates a broad range of intracellular signal transduction processes in tracheal stenosis and the therapeutic effect of the MEK inhibitor which is the upstream kinase of ERK. We histologically analyzed cauterized tracheas to evaluate stenosis using a tracheal stenosis mouse model. Using Western blot, we analyzed the phosphorylation rate of ERK1/2 after cauterization with or without MEK inhibitor. MEK inhibitor was intraperitoneally injected 30 min prior to cauterization (single treatment) or 30 min prior to and 24, 48, 72, and 96 hours after cauterization (daily treatment). We compared the stenosis of non-inhibitor treatment, single treatment, and daily treatment group. We successfully established a novel mouse model of tracheal stenosis. The cauterized trachea increased the rate of stenosis compared with the normal control trachea. The phosphorylation rate of ERK1 and ERK2 was significantly increased at 5 min after the cauterization compared with the normal controls. After 5 min, the rates decreased over time. The daily treatment group had suppressed stenosis compared with the non-inhibitor treatment group. p-ERK1/2 activation after cauterization could play an important role in the tracheal wound healing process. Consecutive inhibition of ERK phosphorylation is a potentially useful therapeutic strategy for tracheal stenosis.

Dosimetric benefits of daily treatment plan adaptation for prostate cancer stereotactic body radiotherapy

Background Hypofractionation is increasingly being applied in radiotherapy for prostate cancer, requiring higher accuracy of daily treatment deliveries than in conventional image-guided radiotherapy (IGRT). Different adaptive radiotherapy (ART) strategies were evaluated with regard to dosimetric benefits. Methods Treatments plans for 32 patients were retrospectively generated and analyzed according to the PACE-C trial treatment scheme (40 Gy in 5 fractions). Using a previously trained cycle-generative adversarial network algorithm, synthetic CT (sCT) were generated out of five daily cone-beam CT. Dose calculation on sCT was performed for four different adaptation approaches: IGRT without adaptation, adaptation via segment aperture morphing (SAM) and segment weight optimization (ART1) or additional shape optimization (ART2) as well as a full re-optimization (ART3). Dose distributions were evaluated regarding dose-volume parameters and a penalty score. Results Compared to the IGRT approach, the ART1, ART2 and ART3 approaches substantially reduced the V37Gy(bladder) and V36Gy(rectum) from a mean of 7.4cm3 and 2.0cm3 to (5.9cm3, 6.1cm3, 5.2cm3) as well as to (1.4cm3, 1.4cm3, 1.0cm3), respectively. Plan adaptation required on average 2.6 min for the ART1 approach and yielded doses to the rectum being insignificantly different from the ART2 approach. Based on an accumulation over the total patient collective, a penalty score revealed dosimetric violations reduced by 79.2%, 75.7% and 93.2% through adaptation. Conclusion Treatment plan adaptation was demonstrated to adequately restore relevant dose criteria on a daily basis. While for SAM adaptation approaches dosimetric benefits were realized through ensuring sufficient target coverage, a full re-optimization mainly improved OAR sparing which helps to guide the decision of when to apply which adaptation strategy.

A Novel Fluorobenzyl Polyethylene Glycol Conjucated Tetraiodothyroacetic Acid (fb-PMT), Targeting Thyrointegrin αvβ3 in Treatment Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here we show the results of our pre-clinical study, in which we evaluate the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl Polyethylene glycol conjucated tetraiodothyroacetic acid (fb-PMT).Methods and Results: fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1-10 mg/kg body weight) subcutaneously (s.c.) for 3-4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using IVIS imaging, flowcytometry and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3-4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (P<0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells.Conclusion: our preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.

Cost Analysis and Rational Use of Anti Glaucoma Therapy in A Tertiary Hospital in Ghana

IntroductionGlaucoma is the leading cause of irreversible blindness worldwide. In Ghana, 19.4% of all blindness recorded is due to glaucoma. Reducing intraocular pressure medically (using eye drops) is the evidence-based therapeutic optionObjectives To determine the rational use and undertake cost analysis of anti-glaucoma drugs among patients attending clinic at the Lions International Eye Centre, Korle bu Teaching Hospital (LIEC).MethodsIn this cross sectional study, we reviewed all prescriptions presented to the pharmacy unit from 01/12/015 to 31/03/2016. The dispensed drops were classified and all anti-glaucoma drugs were identified. This was followed by cost analysis.ResultsA total of 588 prescriptions were captured, 27.3% (161/588) contained an anti-glaucoma medication. The mean number of anti-glaucoma medications was1.71 of which 52.7% was prescribed to females.Prostaglandin analogues were the most prescribed (37% (102/276)), followed by beta blockers (25.4% (70/276)), carbonic anhydrase group of medicines (16.3% (45/276)), combined beta blockers (11.2% (31/276)), alpha agonists (8.7% (24/276)) and miotics (1.4% (4/276)). The median (IQR) average cost of anti-glaucoma therapy per prescription per month was GHC 65.00 (GHC38.5-GHC140). Azopt (Brimonidine) was the most expensive with daily treatment cost of GHC 5.8 (about US$ 1.45), whilst the least expensive drug with a daily treatment cost of GHC 0.14 (about US$ 0.035) was timolol eye drops. ConclusionsProstaglandins analogues remain the most preferred treatment for managing glaucoma at the Korle-Bu Eye Centre in Ghana but are also the most costly. This may adversely affect treatment among the poor since prostaglandins are currently not reimbursed.

Hypertension knowledge and treatment initiation, adherence, and discontinuation among adults in Chennai, India: a cross-sectional study

IntroductionA substantial share of urban Indians with diagnosed hypertension do not take regular treatment, potentially due to poor knowledge of hypertension consequences and treatment options. We describe hypertension knowledge and beliefs, treatment patterns, and reported reasons for treatment non-use among adults with diagnosed hypertension in Chennai, India.MethodsWe collected data on 833 adults ages 30+ with physician diagnosed hypertension using a door-to-door household survey within randomly selected wards of Chennai. We described the proportion of individuals who were not taking daily medications and their reported reasons for not doing so. Next, we described individuals’ knowledge of hypertension consequences and how to control blood pressure (BP) and assessed the association between knowledge and daily treatment use.ResultsOver one quarter (28% (95% CI 25% to 31%)) of diagnosed individuals reported not taking daily treatment. The largest proportion (18% (95% CI 16% to 21%)) were individuals who had discontinued prior treatment use. The primary reason individuals reported for non-daily use was that their BP had returned to normal. Just 23% (95% CI 20% to 26%) of individuals listed BP medications as the most effective way to reduce BP; however, these individuals were 11% points (95% CI 4% to 19%) more likely to take daily medications. Conversely, 43% (95% CI 40% to 47%) of individuals believed that BP medications should be stopped from time to time and these individuals were 15% points (95% CI −0.21 to –0.09) less likely to take daily treatment. While awareness of the consequences of hypertension was poor, we found no evidence that it was associated with taking daily medications.ConclusionsThere were large gaps in consistency of BP medication use which were strongly associated with knowledge about BP medications. Further research is needed to identify whether addressing beliefs can improve daily treatment use among individuals with diagnosed hypertension.