TD Treatment Research Articles

(329) Exploring the Incidence of Sexual and Reproductive Health Concern in Men with Cystic Fibrosis and CBAVD: An Analysis of a Multi-Institutional Database

Abstract Introduction Cystic Fibrosis (CF) is a genetically inherited disease with a highly variable phenotype that results from a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Manifestations of CF include impacts on function of the lungs, liver, pancreas, and reproductive system. While CF is known to be associated with infertility due to congenital bilateral absence of the vas deferens (CBAVD), men with CF also frequently report additional sexual and reproductive health issues, often linked to low testosterone levels. Objective In this study we aimed to investigate the prevalence of low testosterone (T) in men with CF and CBAVD, and hypothesized hypothesized that low T would be under-evaluated and under-treated in the CF population compared to CBAVD and the general population. Methods We used TrinetX, a multi-institutional insurance claims database, to create a cohort of men over 18 years old with CF or CBAVD. We then queried each cohort to assess how many men had a T level measured, and if hypogonadal (below 300 ng/dL), how many received T therapy (TT). Results There were 14,033 men over age 18 years with a diagnosis of CF and 3,439 men over age 18 with a diagnosis of CBAVD in the TriNetX database. Serum T levels were measured in 10.1% of men with CF and 8.9% of men with CBAVD. While mean serum T level in both groups was within the normal range (defined as a total testosterone >300 ng/dL), 32.7% (n=464) of the men with CF and 43% (n=132) of the men with CBAVD were hypogonadal. The majority of men with T<300 ng/dL went on to appropriately receive TT: 59.3% of men with CF and 78% with CBAVD (figure 1). Conclusions Our data suggests that hypogonadism is highly prevalent in men with CF and CBAVD. These data suggest that despite a high rate of infertility in men with CF and CBAVD, the majority do not undergo hormonal evaluation. Investigation and appropriate treatment of TD may significantly improve quality of life. Disclosure No.

The Tardive Dyskinesia Impact Scale (TDIS), a novel patient-reported outcome measure in tardive dyskinesia: development and psychometric validation

BackgroundTardive dyskinesia (TD), a movement disorder in which patients experience abnormal involuntary movements, can have profound negative impacts on physical, cognitive, and psychosocial functioning. The Abnormal Involuntary Movement Scale (AIMS), a clinician-rated outcome, is considered the gold standard for evaluating treatment efficacy in TD clinical trials. However, it provides little information about the impacts of uncontrolled movements from a patient perspective and can be cumbersome to administer in clinical settings. The Tardive Dyskinesia Impact Scale (TDIS) was developed as a patient-reported outcome measure to fulfill the need for a disease-specific impact assessment in TD. The objective of the present study was to develop and evaluate the psychometric properties of the TDIS to determine whether it is fit-for-purpose to measure TD impact.MethodsData from qualitative studies and phase 3 trials of a VMAT2 inhibitor for the treatment of TD (KINECT3 and KINECT4) were used to determine the psychometric properties of the TDIS. Qualitative research included concept elicitation and cognitive debriefing interviews with TD patients and their caregivers in order to assess how well the TDIS captured key domains of TD impact. Quantitative analyses to examine the psychometric properties of the TDIS included assessing construct validity (factor structure, known groups, and predictive validity) and responsiveness to change.ResultsQualitative results showed that the TDIS captures the key TD impacts reported by patients and caregivers and that the TDIS was interpreted as intended and relevant to patients’ experiences. Quantitative results found evidence of 2 underlying domains of the TDIS: physical and socioemotional (Comparative Fit Index > 0.9). Known groups and predictive validity indicated that, compared with the AIMS, the TDIS captures unique content (correlation between AIMS and TDIS = 0.2–0.28). The TDIS showed responsiveness to change in treatment, with TDIS scores improving over 48 weeks in the 2 phase 3 trials.ConclusionsThe TDIS captures relevant information about the impact of TD and is easily administered in a clinician’s office or patient’s home. It may be used longitudinally to show changes in TD burden over time. The TDIS complements the AIMS; using these assessments together provides a more holistic assessment of TD.

Analysis of clinical characteristics of thyroid disorders in patients with chronic hepatitis B treated with pegylated-interferon alpha

BackgroundThyroid disorders (TD) is a common complication of pegylated-interferon alpha (Peg-IFNα) therapy. Few studies have investigated the relationship between TD and the efficacy of interferon therapy for chronic hepatitis B (CHB). Therefore, we analyzed the clinical characteristics of TD in patients with CHB treated with Peg-IFNα, and evaluated the correlation between TD and Peg-IFNα treatment efficacy.MethodsIn this retrospective study, the clinical data of 146 patients with CHB receiving Peg-IFNα therapy were collected and analyzed.ResultsDuring the course of Peg-IFNα therapy, positive conversion of thyroid autoantibodies and TD occurred in 7.3% (85/1158) and 8.8% (105/1187) patients, respectively, and was diagnosed more often in women. The most common thyroid disorder was hyperthyroidism (53.3%), followed by subclinical hypothyroidism (34.3%). We found that thyroid function returned to normal in 78.7% of patients with CHB, and thyroid antibody levels returned to the negative range in approximately 50% of patients after interferon treatment cessation. Only 25% of patients with clinical TD required treatment. Compared with patients with hypothyroidism/subclinical hypothyroidism, patients with hyperthyroidism/subclinical hyperthyroidism showed greater reduction and seroclearance of hepatitis B surface antigen (HBsAg) levels.ConclusionsTD are not an absolute contraindication for interferon therapy; however, patients should be monitored closely during interferon therapy. In pursuit of functional cure, a balance between efficacy and safety must be achieved.

Treatment Success and Psychiatric Stability in Adults With Tardive Dyskinesia: Post Hoc Analyses of Two Long-Term Valbenazine Studies

AbstractIntroductionTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Effective and comprehensive treatment of TD requires reducing patients’ abnormal involuntary movements without disrupting their psychiatric stability. This can be especially challenging when patients have complex psychiatric conditions (e.g., >1 psychiatric diagnosis) and are taking multiple medications. Valbenazine, a highly potent and selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved for the once-daily treatment of TD. This post hoc analysis of two long-term studies (KINECT 3, KINECT 4) was conducted to evaluate changes in psychiatric status and clinician- and patient-reported treatment success in study participants who received valbenazine (40 or 80 mg) for 48 weeks.MethodsData from KINECT 3 and KINECT 4 were pooled and analyzed in participants categorized by their primary psychiatric diagnosis: schizophrenia/schizoaffective disorder (“SCHZ”) or mood disorder (“MD”). Concomitant medications needed for managing these and other psychiatric or medical conditions were allowed. Treatment success was defined as achieving a rating of “much improved” or “very much improved” at Week 48, as assessed using the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) and Patient Global Impression of Change (PGIC). Psychiatric stability was monitored using the following scales: Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) in the SCHZ subgroup; Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) in the MD subgroup. Suicidal ideation/behavior was monitored using the Columbia-Suicide Severity Rating Scale.ResultsMore than 75% of study participants in the SCHZ subgroup achieved treatment success with valbenazine, based on clinician assessment (CGI-TD, 79.7%) and patient self-report (PGIC, 78.0%). Mean changes from baseline to Week 48 for PANSS scores (positive symptoms [-0.7], negative symptoms [‑0.6], general psychopathology [-1.9], total [-3.2]) and CDSS total score (-0.5) indicated maintenance of psychiatric stability in the SCHZ subgroup. Similar treatment success rates were found in the MD subgroup for both CGI-TD (77.6%) and PGIC (84.5%), with mean changes from baseline in YMRS total score (-1.0) and MADRS total score (+0.3) indicating psychiatric stability was maintained. No emergence of suicidal ideation/behavior was observed during the studies.ConclusionsPooled analyses from two 48-week studies indicate that long-term treatment of TD with once-daily valbenazine resulted in substantial clinician- and patient-reported global improvements in TD, while psychiatric stability was maintained regardless of primary psychiatric condition.FundingNeurocrine Biosciences, Inc.

Complete in vitro Dissolution of Valbenazine as Either Whole Capsules or Crushed Capsule Contents

AbstractIntroductionTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Three valbenazine capsule strengths (40 mg, 60 mg, 80 mg) are approved for the once-daily treatment of TD. However, some patients with TD, especially in elderly populations, have trouble swallowing due to orolingual movements. This study was conducted to evaluate two different dissolution methods for valbenazine: whole intact capsules versus crushed capsule contents.MethodsSamples were prepared using two commercial lots (Lot-A, Lot-B) for two doses (40 mg, 80 mg), with six replicate samples per lot and dose. The whole capsules were weighed, put into a sinker, and added to a dissolution bath containing 900 mL of 0.1N HCl at 37±0.5° Celsius. Testing on the crushed capsule contents commenced after opening the capsules, weighing and crushing the contents, and transferring the contents to the dissolution bath. Samples were collected (at 10, 15, 20, 30, 45, and 60 min) with a paddle speed of 50 rpm and analyzed using high performance liquid chromatography. Standards were prepared at nominal concentrations of 0.044 mg/mL (for 40 mg) and 0.089 mg/mL (for 80 mg).ResultsCapsules were opened easily by manual manipulation, and contents were crushed easily between spoons. Very rapid (>85% in 15 min) and complete drug release was observed in all samples, independent of capsule strength (40 mg, 80 mg) or preparation (whole intact capsule or crushed capsule contents). For 40-mg capsules, average percent release at first and last collection timepoints were as follows (whole vs crushed): 10 min (98.4% vs 98.6% [A], 93.7% vs 97.6% [B]); 60 min (102.3% vs 100.5% [A], 100.9% vs 100.6% [B]). Results for 80-mg capsules were as follows: 10 min (98.2% vs 99.6% [A], 99.4% vs 97.9% [B]); 60 min (102.0% vs 101.6% [A], 103.2% vs 100.9% [B]).ConclusionsCrushing the capsule contents did not impact the in vitro dissolution performance of valbenazine. Many patients with TD, particularly elderly patients, have difficulty swallowing and may benefit from alternative delivery methods for valbenazine, especially if other TD medications cannot be crushed. More research is needed to better understand if and how crushing the capsule contents of valbenazine affects their stability when mixed with food or delivered through a feeding tube.FundingNeurocrine Biosciences, Inc.

Anticholinergics Should Not Be Used to Treat Tardive Dyskinesia: Insights From an Expert Panel of Psychiatry and Neurology Healthcare Professionals

AbstractIntroductionTardive dyskinesia (TD) is a persistent and often disabling hyperkinetic movement disorder associated with prolonged exposure to dopamine receptor blocking agents (e.g., antipsychotics, antiemetics). The use of anticholinergics for the treatment of movement disorders including TD is a common practice, despite a lack of supportive evidence and the potential to worsen TD. Moreover, there are now FDA-approved medications specifically indicated for TD. Two virtual meetings were held with movement disorder experts from neurology and psychiatry to better understand the real-world use of anticholinergics for TD.MethodsIn November 2020, a panel of eight experts was convened to gather insights on the challenges of differentiating TD from other drug-induced movement disorders (DIMDs) and to discuss appropriate treatments for TD and other DIMDs. A follow-up meeting was held in June 2021 to consolidate these insights. Key recommendations based on the panel discussions are presented.ResultsThe panel emphasized that while anticholinergics can help with managing some DIMDs, current evidence indicates that they are not effective in TD and may even worsen symptoms. Therefore, FDA-approved vesicular monoamine transporter 2 (VMAT2) inhibitors like valbenazine were recommended by the panel as first-line TD therapies. The panel noted that TD is often grouped under the term “extrapyramidal symptoms,” which leads to difficulty in differentiating TD from other DIMDs and the inappropriate treatment of TD with anticholinergics. The panel agreed that prophylaxis with anticholinergics is only appropriate in patients at high risk of acute dystonia. However, chronic anticholinergic use should be avoided whenever possible due to potentially serious adverse effects (e.g., cognitive difficulties) and anticholinergic burden, particularly in older patients. The potential for abuse, addiction, and diversion should also be considered when prescribing anticholinergics. Abrupt anticholinergic discontinuation can result in cholinergic rebound, which is characterized by sleep disturbances, gastrointestinal problems, urinary urgency, and manifestations of DIMDs. Thus, when used appropriately (e.g., for acute dystonia), anticholinergics should be prescribed at minimally effective doses and slowly tapered for successful discontinuation.ConclusionsThese findings align with the current TD treatment guidelines, including the lack of evidence for anticholinergic use and recommended first-line treatment with approved VMAT2 inhibitors. Conclusions from this panel highlight educational needs across HCPs on the phenomenology of DIMDs, the inappropriate use of anticholinergics for TD, TD risks and assessment, and treatment strategies for TD.FundingNeurocrine Biosciences, Inc.

Evaluation of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent Low Risk Del(5q) MDS Patients. Final Results of Sintra-REV Phase III International Multicenter Clinical Trial

Background: Most MDS patients with del(5q) develop RBC TD or need treatment for symptomatic anemia early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH 2016). Lenalidomide (LEN) is a reference treatment in MDS-del(5q) but approved in many countries only when RBC-TD occurs. No randomized trials before Sintra-Rev had explored the role of LEN in the setting of non-TD anemia in del(5q) MDS. Interim analysis of Sintra-Rev (Lopez Cadenas et al abstract 536 ASH 2020) showed that early treatment with LEN prolongs the Transfusion Free survival (p=0.021), with a high percentage of erythroid (72%) and cytogenetic responses (80%) among LEN treated patients. Material: Sintra-Rev is a phase III multicenter trial in low-risk MDS-del(5q) patients with anemia without TD. Patients were randomized (2:1) in a double-blind design to LEN (5mg/day continuously) vs placebo for 2 years of treatment and 2y of follow-up. The primary endpoint was the time to TD. 2º endpoints included erythroid (HI-E), cytogenetic response (CyR), overall survival (OS), event free survival (EFS), time to AML and mutational analysis (NGS). Here, we report the final results of this clinical trial once all patients have completed their participation in the study and after extending follow-up to explore long-term AML transformation and/or death. Results: Main clinical characteristics of the 61 patients (ITT population) included are summarized in Table 1: In 32% of patients no somatic mutation was identified (NGS), compared to 36% with one mutation and 32% with ≥ 2 mutations. TP53mut was present at diagnosis in 17.2% and 27.8% of LEN and Placebo patients (p=0.48). The evaluable population included 54 patients (7 patients were excluded due either to screening failure [1 pat] or failure to complete at least 12w of treatment [6 pat] without progression disease). Median time on treatment was 66 weeks (3-121), 95w in the LEN arm and 42w in the placebo arm (p=0.392). Forty-seven percent patients in the LEN arm successfully completed the study compared to 33% in the placebo arm. After a median follow up of 60.6 months (Q1 32.3-Q3 73.9), median OS was 101.2m (95CI 54.8 - 147.7) without statistically significant differences between the two treatment groups (p=0.529). In relation to the primary objective of this trial, Time to TD (ITT-pop) was 66.3mo (95CI 37 - 95.5) for LEN patients and 11.6mo for the placebo arm (HR 0.414 95CI 0.196- 0.875, p=0.021) (Figure 1). EFS was 60.2mo (CI95% 45-74) for LEN compared to 20.2mo (CI95% 0 - 51) for Placebo (p=0.058) in the ITT Population (HR 0.46, CI95% 0.2 - 0.948, p=0.035 in the evaluable population). HI-E was observed in 70% of LEN patients (ITT-pop) compared to 0% in the placebo arm (p<0.001). Median Hemoglobin improvement in responders was 2.7 g/dL. Eighty percent of LEN patients (ITT-pop) achieved a cytogenetic response (CyR) (87.5% complete CyR) compared to 0% of patients receiving placebo (p<0.001). AML evolution was identified in 6/40 (15%) and 5/21 (23.8%) for LEN and Placebo patients respectively (p=0.488). NGS analysis during follow up showed the mean number of mutations per patient to be reduced in the LEN arm at week 12 (0,84 mutations compared to 1,21 previous to treatment; (p<0.01)), while no differences were found in the Placebo group (p=0.59). In addition, no differences were identified regarding clonal evolution for LEN and Placebo patients during study follow-up. Fifty-eight patients developed at least one adverse event (AE) during the trial (no differences between the LEN and placebo arm), related to the drug 86.8% in the LEN and 33.3% in the placebo arm, respectively (p<0.001). Severe AEs were the same as those collected in the interim analysis (abstract 536 ASH 2020). Conclusions: This final analysis of the Sintra-Rev clinical trial confirms that low dose LEN (5 mg), in anemic non-TD low risk MDS del(5q) patients, prolongs time to TD from the beginning of treatment (66.6 mo vs 11.6mo), improves Hb levels (70% of ER) and induces good quality clonal responses (80% CyR), ie potentially more responses than in historical series of MDS del(5q) treated with LEN at time of TD, with a manageable safety profile, and no increased progression rate or clonal evolution. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A new era in the diagnosis and treatment of tardive dyskinesia.

Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.

Psychotherapy Combined with Western Medicine in the Treatment of Children with Tic Disorder: Systematic Review and Meta-Analysis.

Objective To evaluate the efficacy of psychotherapy in children with tic disorder and to provide basis for the application of psychotherapy in the treatment of children with tic disorder. Methods A detailed search was conducted based on PubMed, Cochrane library database, CNKI, Wanfang Data, and VIP database to determine the randomized controlled trial (RCT) of psychotherapy combined with drugs and oral drugs in the treatment of tic disorder. The search time was from the establishment of the database to August 20, 2021. All kinds of extracted data are meta analyzed, and the statistical software used is Review Manager 5.3 software. Results According to the inclusion and exclusion criteria, 14 clinical trials were finally included, including 513 TD children, including 267 in the psychological intervention group and 246 in the control group. All trials were conducted in China and published from 2013 to 2021. In terms of clinical efficacy, compared with the control group, the psychotherapy combined with drugs group had more advantages in improving the effective rate (RR = 3.25, 95% CI: 2.17~4.85, Z = 5.74, P < 0.00001) and improving the clinical symptoms of children with TD (WM = −5.36, 95% CI: -6.41 ~ -4.30, Z = 9.97, P < 0.00000 1). Conclusion Psychotherapy as an adjuvant therapy for clinical treatment of TD can improve the clinical efficacy, but due to the low methodological quality of the existing trials, the research may have potential bias. In the future, large sample, multicenter, and double-blind randomized controlled trials need to be carried out to provide further support.

P-192: Circularly permuted TRAIL (CPT) combined with Thalidomide and Dexamethasone in patients with relapsed/refractory Multiple Myeloma: a randomized, double-blind, placebo-controlled phase 3 study

<h3>Background</h3> CPT, a recombinant permuted human TNF-related apoptosis-inducing ligand (TRAIL), is a 1rst-in-human anti-myeloma drug targeting death receptor 4/5. In order to verify the effectiveness and safety of CPT, we have conducted this multi-center, double-blind, placebo-controlled phase 3 study. <h3>Methods</h3> In this study, 417 RRMM patients previously treated with two or more lines of therapies were randomly assigned (2:1) to receive CPT+TD (CPT group) vs. placebo+TD (control group). CPT or placebo at a dose of 10 mg/kg was intravenously administered on days 1 to 5, both groups receive dexamethasone 40 mg orally on days 1 to 4, and thalidomide 150mg daily, 28 days per cycle until to disease progressions or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the key secondary endpoints overall survival (OS), overall response rate (ORR), and safety. <h3>Results</h3> Of the 417 patients enrolled, 415 patients received CPT+TD (n=276) or placebo+TD (n=139) treatment. The demographic, baseline disease and clinical characteristic of the two groups were comparable. The median age of the patients was 59 years, and the median time from the initial diagnosis of multiple myeloma (MM) to participating this trial was 2.6 years. The median number of lines of prior therapies was 3. Proteasome inhibitors (PI) and immunomodulators (IMiD) were previously used in 74% and 86.5% of patients, respectively. At date cutoff, the primary endpoint of PFS was significantly longer in the CPT group than in the control group (median 5.5 vs. 3.1 months; hazard ratio [HR] 0.619; P3 lines of prior therapies. PFS and ORR were also significantly improved in the patients with PI and IMiD double-refractory MM. The serious adverse events (SAE) rates were similar in the CPT group and the control group (40.6% vs. 37.4%), as were the death rates during the treatments (7.6% vs. 8.6%). Treatment-emergent adverse events (TEAEs) with at least a 10% greater frequency in the CPT group vs. the control group were elevated alanine transaminase (ALT), elevated aspartate transaminase (AST), elevated lactate dehydrogenase (LDH), increased monocyte counts, hypocalcaemia and upper respiratory tract infections. <h3>Conclusions</h3> The combination of CPT with TD significantly prolonged the PFS and OS, increased the ORR. CPT combined with TD was well tolerated, the adverse events were mild, transient and reversible.

A disease severity scale for the evaluation of vaccine and other preventive or therapeutic interventions for travellers' diarrhoea.

Travellers' diarrhoea (TD) is the most common travel-related illness with an estimated 10 million people afflicted annually. Outcome measures to assess the efficacy of primary and secondary TD interventions were historically based on diarrhoea frequency with ≥1 associated gastrointestinal symptom. Furthermore, efficacy determination is often made on the presence or absence of TD, rather than on TD illness severity. Current severity classifications are based on subjective consideration of impact of illness on activity. We sought to develop a standardized scoring system to characterize TD severity to potentially apply as a secondary outcome in future field studies. Data on multiple signs and symptoms were obtained from a previously published multisite TD treatment trial conducted by the US Department of Defense (TrEAT TD). Correlation, regression and multiple correspondence analyses were performed to assess impact on activity and a TD severity score was established. Numerous signs and symptoms were associated with impaired function, with malaise and nausea most strongly associated [odds ratio (OR) 5.9-44.3, P < 0.0001 and OR 2.8-37.1, P < 0.0001, respectively). Based on co-varying symptomatology, a TD severity score accounting for diarrhoea frequency in addition to several signs and symptoms was a better predictor of negative impact on function than any single sign/symptom (X2 = 127.16, P < 0.001). Additionally, there was a significant difference (P < 0.0001) in the mean TD severity score between those with acute watery diarrhoea (3.9 ± 1.9) and those with dysentery or acute febrile illness (6.2 ± 2.0). The newly developed disease severity score better predicted a negative impact on activity due to TD than did any single sign or symptom. Incorporating multiple parameters into the TD severity score better captures illness severity and moves the field towards current recommendations for TD management by considering symptoms with high functional impact. Further validation of this score is needed in non-military travellers and other settings.

Tomatidine Suppresses the Destructive Behaviors of Fibroblast-Like Synoviocytes and Ameliorates Type II Collagen-Induced Arthritis in Rats.

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both in vitro and in vivo studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.

Impact of a pharmacist-driven tardive dyskinesia screening service.

IntroductionTardive dyskinesia (TD) is defined as involuntary movements that can develop with prolonged antipsychotic use. Regular monitoring using the Abnormal Involuntary Movement Scale (AIMS) is recommended to be conducted every 3 to 6 months for early recognition, although the AIMS is underused. Several studies have investigated risk factors that may be associated with TD, including age, sex, and long-term antipsychotic use. This study aimed to increase the monitoring and treatment of TD for those assessed to be at higher risk.MethodsThis was a prospective quality improvement study on the effectiveness of a psychiatric pharmacist–driven TD screening service (PPDTSS) in an inpatient psychiatric facility. Participants were composed of adult patients admitted between May and November 2018. Patients were screened daily by a clinical pharmacist and, if determined to be high risk based on studied risk factors, prioritized to receive a formal TD screening via the AIMS. The primary objective was to optimize standard of care by increasing the number of AIMS screenings conducted. The secondary objective was to increase the treatment of TD.ResultsA total of 402 patients were assessed prior to implementation of the PPDTSS, and 390 patients were screened following implementation. The PPDTSS increased the number of AIMS screenings attempted by 85.1% for high-risk individuals. Of the 75 patients who had an AIMS screening attempted in the postintervention group, 46 (61.3%) had an AIMS screening completed, of which 3 (6.5%) were positive.DiscussionThe results of this study demonstrate that psychiatric pharmacists can be used to improve the regular monitoring of patients at high risk for TD.

Fecal Microbiota Functional Gene Effects Related to Single-Dose Antibiotic Treatment of Travelers' Diarrhea.

Travelers' diarrhea (TD) is common among military personnel deployed to tropical and subtropical regions. It remains unclear how TD and subsequent antibiotic treatment impact the resident microflora within the gut, especially given increased prevalence of antibiotic resistance among enteric pathogens and acquisition of multidrug-resistant organisms. We examined functional properties of the fecal microflora in response to TD, along with subsequent antibiotic treatment. Fecal samples from US and UK military service members deployed to Djibouti, Kenya, and Honduras who presented with acute watery diarrhea were collected. A sample was collected at acute presentation to the clinic (day 0, before antibiotics), as well as 7 and/or 21 days following a single dose of antibiotics (azithromycin [500 mg], levofloxacin [500 mg], or rifaximin [1650 mg], all with loperamide). Each stool sample underwent culture and TaqMan reverse transcription polymerase chain reaction analyses for pathogen and antibiotic resistance gene detection. Purified DNA from each sample was analyzed using the HumiChip3.1 functional gene array. In total, 108 day 1 samples, 50 day 7 samples, and 94 day 21 samples were available for analysis from 119 subjects. Geographic location and disease severity were associated with distinct functional compositions of fecal samples. There were no overt functional differences between pre- and postantibiotic treatment samples, nor was there increased acquisition of antibiotic resistance determinants for any of the antibiotic regimens. These results indicate that single-dose antibiotic regimens may not drastically alter the functional or antibiotic resistance composition of fecal microflora, which should inform clinical practice guidelines and antimicrobial stewardship. NCT01618591.

Assessment of the Impact of Tardive Dyskinesia in Clinical Practice: Consensus Panel Recommendations.

PurposeTardive dyskinesia (TD) is a hyperkinetic movement disorder in which patients experience abnormal involuntary movements that can have profound negative impacts on physical, cognitive, and psychosocial functioning. Use of measures to assess the functional impact of TD in routine clinical practice is lacking. To address this gap, an advisory panel of experts in psychiatry and movement disorder neurology was convened to develop consensus recommendations on assessment of the impact of TD on patients’ functioning that can be used in clinical practice.MethodsAn advisory panel provided recommendations using an iterative process, beginning with a narrative literature review regarding current practices for assessing the impact of TD in clinical settings. A detailed summary was generated, and the advisory panel provided comments about the content and answered questions about assessing TD impact in clinical practice. The panelists’ responses were discussed during a virtual meeting held on August 28, 2020. A second meeting on September 25, 2020, focused on developing and refining recommendations for assessment of the impact of TD in clinical practice. At the conclusion of the second meeting, general consensus was reached on all recommendation statements.ResultsAs part of routine clinical practice, it is imperative to assess the impact of TD on the patient’s life to help guide treatment decisions. Key domains for assessing the overall impact of TD include social, physical, vocational, and psychological functioning and the impact of TD on the underlying psychiatric disorder. Assessment of TD impact should be performed at every patient visit. Impact assessments should include consultation with patients, caregivers, and family members. Shared decision-making to initiate TD treatment should consider impact.ConclusionThe impact of TD should be assessed routinely, including the key domains of social, physical, vocational, and psychological functioning and the impact of TD on the underlying psychiatric disorder.

Long-Term Safety and Efficacy of Deutetrabenazine in Younger and Older Patients With Tardive Dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that is more prevalent in older patients. However, there is limited information on TD treatment for this population. In two 12-week pivotal trials (ARM-TD and AIM-TD), TD patients demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) score with deutetrabenazine versus placebo. Patients who completed ARM-TD or AIM-TD enrolled in an open-label extension (OLE) study. This post hoc analysis assessed change and percent change from baseline in AIMS score, response rates for ≥50% AIMS improvement, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety in younger (<55years) and older (≥55 years) patients. This analysis included 119 younger and 218 older patients enrolled in the OLE. Data presented at Week 145 (mean±SE): total deutetrabenazine dose was 39.4±1.39mg/day and 39.5±1.04mg/day in younger and older patients, respectively. Changes from baseline in AIMS score were -6.7±0.62 and -6.5±0.47, respectively (percent changes of -61.4%±4.10% and -54.6%±3.01%). The majority of younger and older patients achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%) and achieved ≥50% AIMS response (76% and 62%). Deutetrabenazine was generally well tolerated in both groups. Exposure-adjusted incidence rates (incidence/patient-years) were <0.01 and 0.02 for akathisia, 0.07 (both) for somnolence and sedation, 0.04 and 0.11 for parkinson-like events, and 0.06 and 0.09 for depression in younger and older patients, respectively. Deutetrabenazine treatment was associated with sustained improvements in AIMS score and was well tolerated in both younger and older TD patients. Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.

N2O and CO2 Emissions from Bare Soil: Effect of Fertilizer Management

The paper presents the results of a laboratory experiment focused on the assessment of the effect of different methods of application of ammonium nitrate (TD—top dressing and DP—deep placement) on N2O and CO2 emissions from soil without crop cover. Nitrogen application increased soil N2O–N fluxes by 24.3–46.4%, compared to untreated soil (NIL). N2O–N emissions from TD treatment were higher by 12.7%, compared to DP treatment. Soil CO2–C fluxes from DP treatment were significantly higher by 17.2%, compared to those from NIL treatment. Nonetheless, the differences between soil CO2–C fluxes from DP and TD treatments, as well as from TD and NIL treatments, were of no statistical significance. The cumulative greenhouse gas (GHG) emissions (a sum of cumulative soil emissions of CO2–C and N2O–N after conversion to the equivalent of CO2–C) from both N-fertilized soils were similar, and higher by 20% than from untreated soil. The obtained data show that the effect of reduction of N2O–N soil emissions gained by deep placement of nitrogen fertilizer was completely lost through an increase in CO2–C emissions from the soil. This suggests that deep placement of nitrogen fertilizers in sandy soil without crop cover might not lead to a mitigation of soil GHG emissions.

Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients - Interim Analysis of the European Sintra-REV Trial

Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients - Interim Analysis of the European Sintra-REV Trial

Long-term treatment with valbenazine 40 mg once-daily in adults with Tardive dyskinesia

Background: Valbenazine, a novel and highly selective VMAT2 inhibitor, is approved for the treatment of TD in adults. Data from two long-term studies (KINECT 3 [K3], KINECT 4 [K4]) and a roll-over study (1506) were analyzed to better understand the effectiveness of valbenazine in patients who received the lower dose (40 mg) or required a dose reduction (80 to 40 mg).

Cardioprotective effect of the TD anti-apoptotic peptide: Study of the mechanisms of action

Apoptosis is a main contributor of reperfusion injury after myocardial infarction. In a previous study, we evidenced the cardioprotective effect of a synthetic peptide (TD) able to interfere with FAS-DAXX interaction specifically activated during reperfusion-induced apoptosis. The aim of our study was to study the mechanisms of action of the TD anti-apoptotic peptide. Hearts from C57Bl6 mice were subjected ex vivo (Langendorff) to 40 minute-ischemia (coronary ligation) and 1 hour reperfusion (IR protocol). TD peptide (1 μM) was perfused during reperfusion. At the end of the protocol, a proteomic analysis by western-blot was realized in TD- versus non-treated IR hearts. Upon TD treatment, the downstream activation of the JNK/caspase 3 pathway was down-regulated. A decrease in both the expression of BAD protein and the level of activated caspase 9, both mediators of the intrinsic pathway, was also observed. TD treatment was able to decrease the FADD-caspase 8 extrinsic pathway probably due to its impact on DAXX-FADD cooperativity within the DISC. Of great interest, TD peptide treatment was not associated neither with a deleterious reduction of DAXX protein level already described to trigger unexpected pro-apoptotic effects (siRNA DAXX) nor with a switch to the necroptotic pathway (RIP1-RIP3-MLKL). Protein levels of HSP70, a hallmark of proteotoxic stress, were also reduced. Interestingly, the anti-apoptotic TD treatment was also related to an activation of the Reperfusion Injury Salvage Kinase (RISK) pathway including ERK1/2 and PI3kinase-AKT. TD peptide treatment appears as a particularly relevant therapeutic strategy to target reperfusion-induced apoptotic pathways. Targeting FAS:DAXX interaction from the extrinsic pathway also indirectly reduced the activation of the intrinsic (JNK-BAX crosstalk) cascade thus allowing a complete inhibition of reperfusion injury with a single pharmacological administration.