Synergy Pharmaceuticals (United States)

BackgroundDespite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment.MethodThis preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2–19), and following (Study Days 20–21) residential treatment.DiscussionThis manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. Trial registration: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728.Protocol Version10 May 2023

<div>Abstract<p>Emerging evidence supporting the activation of the Akt-mammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment. Indeed, rapamycin, a clinically relevant mTOR inhibitor, promotes the rapid regression of HNSCC-tumor xenografts in mice. However, rapamycin does not affect the growth of HNSCC cells <i>in vitro</i>, thus raising the possibility that, as for other cancer types, rapamycin may not target cancer cells directly but may instead act on a component of the tumor microenvironment, such as tumor-associated vasculature. Here, we used a retroinhibition approach to assess the contribution of cancer cell–autonomous actions of rapamycin to its antitumor activity in HNSCC. A rapamycin-resistant form of mTOR (mTOR-RR) was expressed in HNSCC cells while retaining the wild-type (rapamycin-sensitive) mTOR (mTOR-WT) alleles in host-derived endothelial and stromal cells. Expression of mTOR-RR prevented the decrease in phospho-S6 levels caused by rapamycin through mTOR in HNSCC cells but not in stromal cells, and rendered HNSCC xenografts completely resistant to the antitumoral activity of rapamycin. This reverse pharmacology strategy also enabled monitoring the direct consequences of inhibiting mTOR in cancer cells within the complex tumor microenvironment, which revealed that mTOR controls the accumulation of hypoxia-inducible factor-1α (HIF-1α) and the consequent expression of vascular endothelial growth factor and a glucose transporter, Glut-1, in HNSCC cells. These findings indicate that HNSCC cells are the primary target of rapamycin <i>in vivo</i>, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells. [Cancer Res 2008;68(4):1144–53]</p></div>

ABSTRACTBACKGROUNDThere were increased SARS-CoV2 hospitalizations and deaths noted during Omicron (B.1.1.529) variant surge in the UK despite decreased cases, and the reasons are unclear.METHODSIn this retrospective observational study, we analyzed reported SARS-CoV2 cases, hospitalizations, and deaths during the COVID-19 pandemic in the UK. We also analyzed variables that affect the outcomes (including ethnicity, deprivation score, vaccination disparities, and pre-existing conditions). We also analyzed the vaccine effectiveness among those ≥18 years of age (from August 16, 2021 to March 27, 2022).RESULTSOf the total cases (n= 22,072,550), hospitalizations (n=848,911), and deaths (n=175,070) due to COVID-19 in the UK; 51.3% of cases (n=11,315,793), 28.8% of hospitalizations (n=244,708), and 16.4% of deaths (n=28,659) occurred during the Omicron variant surge as of May 1, 2022. During the latter part of the Omicron variant surge (February 28 - May 1, 2022 period), we observed a significant increase in the proportion of cases (23.7% vs 40.3%; RR1.70 [1.70-1.71]; p<0.001) and hospitalizations (39.3% vs 50.3%; RR1.28 [1.27-1.30]; p<0.001) among ≥50 years of age, and deaths (67.89% vs 80.07%; RR1.18 [1.16-1.20]; p<0.001) among ≥75 years of age compared to the earlier period (December 6, 2021-February 27, 2022) during the Omicron variant surge. Using the available data from vaccine surveillance reports, we compared the Omicron variant surge (December 27, 2021-March 20, 2022) with the Delta variant surge (August 16-December 5, 2021). Our comparative analysis shows a significant decline in case fatality rate (all ages [0.21% vs 0.39%; RR 0.54 (0.52-0.55); p<0.001], over 18 years of age [0.25% vs 0.58%; RR 0.44 (0.43-0.45); p<0.001], and over 50 years of age [0.72% vs 1.57%; RR 0.46 (0.45-0.47); P<0.001]) and the risk of hospitalizations (all ages [0.62% vs 0.99%; RR 0.63 (0.62-0.64); p<0.001], over 18 years of age [0.67% vs 1.38%; RR 0.484 (0.476-0.492); p<0.001], and over 50 years of age [1.45% vs 2.81%; RR 0.52 (0.51-0.53); p<0.001]). Both the unvaccinated (0.41% vs 0.77%; RR 0.54 (0.51-0.57); p<0.001) and vaccinated (0.25% vs 0.59%; RR 0.43 (0.42-0.44); p<0.001) populations of over 18 years of age showed a significant decline in the case fatality rate during the Omicron variant surge when compared to the Delta variant surge. In summary, a significant decline in the risk of hospitalizations was observed both among the unvaccinated (1.27% vs 2.92%; RR 0.44 (0.42-0.45); p<0.001) and vaccinated (0.65% vs 1.19%; RR 0.54 (0.53-0.55); p<0.001) populations of over 18 years of age during the same period. We observed negative vaccine effectiveness (VE) for the third dose since December 20, 2021, with a significantly increased proportion of SARS-CoV2 cases hospitalizations, and deaths among the vaccinated; and a decreased proportion of cases, hospitalizations, and deaths among the unvaccinated. The pre-existing conditions were present in 95.6% of all COVID-19 deaths. We also observed various ethnicity, deprivation score, and vaccination rate disparities that can adversely affect hospitalizations and deaths among the compared groups based on vaccination status.CONCLUSIONSThere is no discernable optimal vaccine effectiveness among ≥18 years of age and vaccinated third dose population since the beginning (December 20, 2021) of the Omicron variant surge. Other data including pre-existing conditions, ethnicity, deprivation score, and vaccination rate disparities need to be adjusted by developing validated models for evaluating VE against hospitalizations and deaths. Both the vaccinated and unvaccinated populations showed favorable outcomes with a significant decline in case fatality rate and risk of hospitalizations during the Omicron variant surge. The suboptimal vaccine effectiveness with an increased proportion of cases among the vaccinated population was associated with a significantly increased proportion of hospitalizations and deaths during the Omicron variant surge. This underscores the need to prevent infections, especially in the elderly vaccinated population irrespective of vaccination status by employing uniform screening protocols and protective measures.

ABSTRACTObjectivesCare Homes faced crisis during the SARS-CoV2 pandemic with increased mortality and various corrective interventions were undertaken. The impact of current SARS-CoV2 B.1.617.2 (Delta variant) outbreak on COVID-19 deaths in Care Homes is not completely known.DesignObservational studySetting and ParticipantsWe included nationwide data of deaths from all causes and COVID-19 in England and Wales during March 7, 2020-November 26, 2021.MethodsImpact of COVID-19 deaths in Care Homes, Hospital and Homes relative to total deaths from all causes was investigated.ResultsDuring March 7-August 28,2020; 15,414 (29.8%) of the 51,740 COVID-19 deaths occurred in Care Homes. During August 29, 2020-May 28, 2021, there were significant decrease in COVID-19 deaths in Care Homes ([19.2%]; RR 0.64; 95%CI 0.63-0.65;p<0.0001], which significantly declined further ([8.9%]; RR 0.46; 95%CI 0.43-0.48;p<0.0001) during May 29-November 26, 2021. During the March 7-August 28, 2020; 20.0% (15,514/76,906) of all Care Home deaths were caused by COVID-19, which significantly declined to 18.5% (RR 0.92; 95%CI 0.90-0.93; p<0.0001) during August 29, 2020-May 28, 2021 and declined further to 2.5% (RR 0.13; 95% CI 0.12-0.14;p<0.0001) during May 29-November 26, 2021. Increased percentages of COVID-19 deaths occurred in Hospitals ([72.3%]; RR 1.14; 95% CI 1.1-1.15;p<0.0001) and Homes ([6.3%]; RR 1.33; 95% CI 1.27-1.40; p<0.0001) during August 29, 2020-May 28, 2021 and further increases in the Hospitals ([80.8%]; RR 1.11; 95% CI 1.10-1.12; p<0.0001) and Homes ([8.8%]; RR 1.39; 95% CI 1.31-1.47; p<0.0001) during May 29-November 26, 2021.Conclusions and ImplicationsThere was a significantly lower number of COVID-19 deaths occurred in Care Homes and a significantly lower number of Care Homes deaths caused by COVID-19 during the Delta variant surge in England and Wales than the prior surges. Care Home residents are at highest risk for mortality, continuous monitoring and research on COVID-19 preventive interventions are essential.

PARP inhibitors have been used to treat numerous diseases, but these agents have been approved the longest for use in ovarian cancer. All trials of PARP inhibitor maintenance in newly diagnosed ovarian cancer are positive for prolonged progression-free survival (PFS), but patients with BRCA mutations consistently derive the most benefit. Testing for homologous recombination deficiency may provide information regarding the degree of PFS benefit. In individuals without a BRCA mutation, PARP inhibition also prolongs PFS after chemotherapy for platinum-sensitive, PARP-naïve disease. As in the up-front setting, patients with BRCA mutations derive the most benefit in these trials. Finally, PARP inhibitors are active as monotherapy in PARP-naïve, BRCA-mutated relapsed disease, with increased activity observed in platinum-sensitive versus platinum-resistant disease.

A retrospective clinical case series study was conducted to evaluate the use of a novel, spherical bioactive glass bone graft (BioSphere Putty) as a graft material for cervical and lumbar interbody fusion. Data was collected from a single surgeon using BioSphere Putty along with standardized hardware in anterior cervical decompression and fusion (ACDF), transforaminal lumbar interbody fusion (TLIF), and anterior lumbar interbody fusion (ALIF) surgical procedures. BioSphere Putty was used in combination with cancellous allograft (ACDF and ALIF) or in combination with autograft (TLIF). Clinical outcomes were assessed at 1- and 2-year using radiographic imaging and the visual analog pain scale (VAS). VAS scores at the 1- and 2-year follow-up periods were statistically compared to pre-operative scoring. Successful clinical outcomes were determined by a combination of the presence of a complete radiographic fusion and a decrease in VAS at 1-year and 1- and 2-year follow-up periods. The retrospective review of the patient data identified 248 cases that had either 1- or 1- & 2-year follow-up. This consisted of 115 ACDF procedures and 133 lumbar fusion procedures. Lumbar fusion cases were further sub-grouped with 103 patients undergoing TLIF procedures and 30 patients undergoing ALIF procedures. The global results for the series as a whole showed clinical outcomes comparative to other advanced biologic bone grafts. Radiographically all patients demonstrated fusion (100% fusion rate) and there were no clinical adverse events, infections, or graft-related complications in any of the patients in the series. One-year VAS scores were consistent with historical norms and demonstrated significant decreases in pre-operative pain for both ACDF patients (78% decrease) and lumbar patients (66% decrease TLIF/ALIF) (t test, P<0.05). By 2 years, VAS scores continued to drop with significant decreases for the ACDF patients (96%), TLIF patients (82%), and ALIF patients (80%) (t test, P<0.05). VAS scores were also assessed for each individual patient. The data showed a VAS score decrease from pre-operative levels in 93% of the ACDF patients and 89% of the lumbar patients. Combined with the 100% radiographic fusion rate in all patients, this resulted in a in a clinical success rate of 93% for the ACDF patients and 89% for the lumbar patients. The results of this clinical case series demonstrated that BioSphere Putty is a clinically effective and versatile synthetic bone graft material in the spine.

Although studies have shown that spent coffee ground (SCG) extracts have antioxidant activity, no systematic study has been reported under actual storage conditions. The purpose of this study is to estimate the feasibility of practical application of SCG extracts as natural antioxidants for soybean oil and fish oil. An ethanol extract (EE), an acetone extract (AE), and polar compounds isolated from oil (PCO) are prepared and their activity is compared to a synthetic antioxidant, butylated hydroxytoluene (BHT). EE shows the strongest radical scavenging activity for 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) radicals and the highest total phenolic content (TPC) followed by AE and then PCO. However, during storage of soybean oil and fish oil at 35 and 50 °C, AE has the strongest antioxidant activity as determined by peroxide value, conjugated diene value, p‐anisidine value, and headspace volatile analyses. In soybean oil, 0.25% AE has antioxidant activity that is equal to or better than 0.02% BHT. In fish oil, the antioxidant activity of 0.25% AE is inferior to that of 0.02% BHT. However, increased concentrations of AE show improved antioxidant activity. This study shows that SCG extracts can be practically used as natural antioxidants for vegetable oils and omega‐3 oils.Practical Application: Due to lack of information about the antioxidant activity of spent coffee ground (SCG) extracts, this study is specifically aimed and designed to provide information on their activity toward soybean oil and fish oil during actual storage. This study shows that 0.25% acetone extract has equal or better protective effects than BHT in soybean oil at 35 and 50 °C. The activity is further improved with increasing concentration. The activity of the acetone extract in fish oil is not as strong as in soybean oil, but higher concentrations further improve the antioxidant activity. In this study, it is clearly demonstrated that the SCG extracts can have practical use as natural antioxidants for vegetable oils and oils with high concentration of omega‐3 fatty acids.Among spent coffee ground (SCG) extracts, the acetone extract (AE) has the strongest antioxidant activity. In soybean oil, 0.25% AE has antioxidant activity that is equal to or better than 0.02% butylated hydroxytoluene (BHT). This study shows that SCG extracts can be practically used as natural antioxidants for edible oils.

Chronic idiopathic constipation (CIC) is a prevalent disorder affecting productivity, quality of life, and health care resource utilization. Nurse practitioners (NPs) play a critical function in managing patients presenting with CIC, with roles including evaluation, diagnosis, treatment decisions, and patient education. For adults with inadequate response or tolerability issues using over-the-counter treatments, three prescription agents (plecanatide, linaclotide, and lubiprostone) are available in the United States to treat CIC, of which plecanatide was mostly recently approved. This review provides NPs with a current overview and summary of plecanatide in the current treatment landscape for CIC. PubMed was searched for the literature regarding clinical practice guidelines and published trial data for lubiprostone, linaclotide, and plecanatide in CIC. Efficacy and safety comparisons between prescription agents are limited beacause of the differences in trial duration and primary end points (all different). Generally, plecanatide and linaclotide demonstrated similar efficacy, with plecanatide demonstrating lower rates of adverse events. The success of CIC treatment can be affected by patient adherence to the regimen, which is dependent on the efficacy and tolerability of treatment. Plecanatide is a promising option for patients whose CIC symptoms are not adequately controlled using their current treatment approach.

Introduction: Uroguanylin (UG) is an endogenous natriuretic peptide that binds and activates GC-C receptors located on the luminal side of the GI tract to stimulate cGMP synthesis, a second messenger that regulates electrolytes and fluid transport, maintains epithelial cell homeostasis and facilitates barrier function in the GI tract. The biologically active UG (16 amino acid) assumes several distinct topological isomers in aqueous solution and only one of those are biologically active. Based on thermal bond energy calculations, 3-D structure modeling and results from molecular simulation studies, we determined that the substitution of L-Asp amino acid at the 3rd position in UG with L-Glu imparts α-helical stability to the resulting peptides such as plecanatide and SP-333. In this study, we demonstrate therapeutic potentials of these GC-C agonists for GI disorders and diseases. Methods: Several analogs of uroguanylin and plecanatide in which natural amino acids were replaced with D-amino acids were evaluated in T84 bioassay and in intestinal loop assay in rats. Effect of oral treatment with plecanatide and SP-333 on bowel movement was evaluated in mice and monkeys. Results: SP-333 in which L-Asp at the N-terminal and L-Leu at the C-terminal of plecanatide were replaced with D-Asp and D-Leu, respectively, was found to be the most stable and potent analog of uroguanylin. Single substitutions with D-amino acid on other positions and double-substitutions with D-Cys4/D-Cys12 and D-Cys7/D-cyc15 resulted in complete loss in potency of the resulting peptides. Importantly, the substitution of L-Glu at the third position with D-Glu caused drastic reduction in potency, suggesting that the optical orientation of the amino acid at this position is crucial. Oral administration of plecanatide or SP-333 stimulated fluid secretion in the intestinal loop assay in rats and promoted bowel movement (BM) in monkeys.Figure 1Conclusion: Our results demonstrate that plecanatide and SP-333, potent analogs of uroguanylin, are promising GC-C agonists for treatment of GI disorders and diseases in human. Plecanatide is currently being evaluated in phase III clinical trials in chronic constipation and irritable bowel syndrome-constipation, whereas SP-333 is in phase II clinical development for opioid-induced constipation and ulcerative colitis. Disclosure - Kunwar Shailubhai, John Foss, Stephen Comiskey and Vaseem Palejwala are employees of Synergy Pharmaceuticals.