Favorable Adverse Effect Profile Research Articles

A systematic review of comparative time to all cause discontinuation of antipsychotic medications in first episode psychosis

AimsPrompt treatment with medication and intensive psychosocial support are interventions that have been shown to improve function and prognosis in patients with First Episode Psychosis. NICE guidelines state that patients with a first episode of Psychosis should remain on an antipsychotic medication for 1–2 years to reduce risk of relapse, yet most patients stop long before 2 years. This systematic review explores the comparative time to all cause discontinuation of antipsychotics, often used as a marker of real-world treatment effectiveness, in First Episode Psychosis patients.MethodA literature search was performed across multiple healthcare databases from 1980 to present day in the English Language. Inclusion criteria covered patients with a First Episode of Psychosis aged 14 years and over, and studies that were randomised controlled trials or observational in nature. The primary outcome measure was time to discontinuation of antipsychotic medication. Bias was assessed using the GRADE approach.Result11 studies and 3840 patients were included in the review. Seven studies were randomised clinical trials; three were blinded, and four open-label. The remaining four were observational studies. All but one of the studies had a minimum follow-up period of one year (with a maximum of three years). Due to significant methodological heterogeneity across studies, it was not possible to perform meta-analysis. Narrative analysis of the results showed that Olanzapine performed ranked best, and wasbeing taken for the longest time period by patients, followed by Risperidone.ConclusionMultiple reviews exist on the efficacy of antipsychotics in First Episode Psychosis, but this is the first one to focus on time to discontinuation as a distinct outcome measure. The review encompasses a large sample size across North America, Eastern Asia and Europe. The interaction of time to discontinuation of antipsychotics with associated symptom levels and medication doses remains an area for further research. The review highlighted the significant differences in statistical methodology across studies in this emerging field, and the need for standardisation in ongoing research. Whilst effectiveness may therefore be greatest for olanzapine, this is outweighed in current guidance by its least favourable metabolic adverse effects profile.

Effect of Low dose Naltrexone versus Naproxen Extended-release for Pain Relief in knee osteoarthritis, a Triple-blinded, Non-inferiority Phase II Randomized Controlled Trial (FREEDOM) - Study Protocol

Background and objectives: Osteoarthritis (OA) is a degenerative articular disease that affects approximately 240 million people worldwide, with knee OA accounting for 80% of this burden. One of the aims of pharmacological treatment in OA is to reduce pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective for pain relief in OA but have considerable renal, hepatic, cardiovascular, and gastrointestinal adverse effects, with the resultant increase in morbidity and mortality. Naltrexone is an orally activated opioid antagonist that has varied dose-dependent pharmacodynamic effects: Analgesic and anti-inflammatory effects are exhibited only at low dosage ranges of 0.5mg to 4.5mg (Low Dose Naltrexone LDN) while retaining a favorable adverse effect profile. This study aims to test the non-inferiority of LDN against Naproxen. Methodology: This is a prospective phase II triple-blinded, two-arm, parallel-group, non-inferiority randomized controlled trial. The intervention group will receive low dose naltrexone 4.5 mg once daily, and the control group will receive extended-release naproxen 1000 mg once daily during the 12 week trial duration. Our sample size will be 118 patients recruited from a single Orthopedic referral center in the USA. Discussion: The use of LDN for pain relief in osteoarthritis (OA) may be beneficial due to its favorable adverse effect profile. To the best of our knowledge, there is no published data on LDN use in OA even though preliminary evidence has documented its safety and tolerability in a variety of chronic pain conditions.

Prostate-Specific Membrane Antigen (PSMA)-Targeted Radionuclide Therapies for Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) is a promising investigational treatment for metastatic castration-resistant prostate cancer (mCRPC). This review describes the available data with PSMA TRT. Conjugates used for PSMA TRT include antibodies or small molecules PSMA-radiolabeled with beta (most commonly 177Lu) or alpha emitters (commonly 225Ac). 177Lu-J591 demonstrated accurate targeting of known metastatic sites, based on post-treatment scintigraphy, in study populations that were not selected for PSMA expression, with evidence of dose-response and dose-limiting myelosuppression. Early phase studies of 177Lu-PSMA-617 have demonstrated favorable adverse event profiles and signs of clinical activity as evidenced by PSA responses and other short-term outcomes. A phase II randomized study of 177Lu-PSMA-617 showed a superior PSA50 response rate (66 vs 37%) over cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC selected by PSMA and FDG PET/CT scans. PSMA TRT is emerging as a promising investigational therapy for mCRPC. The first randomized data with 177Lu-PSMA-617 (phase 2) have been presented, and the first phase 3 trial has completed accrual with radiographic progression-free and overall survival as dual primary endpoints. Multiple additional phase 3 trials of PSMA-TRT are starting and studies investigating optimal patient selection and combination therapy continue.

Preemptive Versus Reactive Topical Clobetasol for Regorafenib-Induced Hand-Foot Reactions: A Preplanned Analysis of the ReDOS Trial.

Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported. Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.

High-Dose Intravenous Hydroxocobalamin for Persistent Vasoplegic Syndrome after Cardiac Surgery

Vasoplegic syndrome is a vasodilatory shock characterized by significant hypotension, normal or high cardiac output, and increased requirement for intravenous fluid resuscitation and vasopressors. It is a relatively common complication following cardiac surgery. We describe the case of a 77-year-old man who developed prolonged vasoplegic syndrome which was refractory to high doses of conventional vasopressors following coronary artery bypass graft surgery. Given the possible increased risk of serotonin syndrome associated with concurrent administration of methylene blue and tramadol, we elected not to administer methylene blue in favor of hydroxocobalamin due to its favorable adverse effect profile.

Migraine Preventive Therapy; Focus on β-blockers; Literature Review

Migraine is an unpleasant neurological disorder characterized by frequent severe headache attacks associated with nausea, phonophobia, or photophobia with or without aura. Preventive treatment is an essential part of migraine management if it is indicated in certain circumstances. β-blockers are widely used for reducing migraine attacks frequency and severity for a long time with favorable adverse effects profile. The prevalence of migraine is approximately 12% in the general adult pop

Exanthematous Drug Eruption as a Side Effect of Teneligliptin.

Sir, Teneligliptin – a novel dipeptidyl peptidase-4 (DPP-4) inhibitor is a widely used medication for managing Type 2 diabetes mellitus as a single agent or as an add-on therapy with other oral antidiabetic agents (OADs). Teneligliptin is a cost-effective drug compared to other Gliptins and has a favourable adverse effect profile. There have been anecdotal reports of increased allergic events with the usage of various DPP-4 inhibitors.[1] This case report highlights one such case that we encountered when Teneligliptin use, in a known diabetic on Glimepiride and Metformin therapy, precipitated an exanthematous drug eruption. A 63-year-old gentleman presented with a history of Type 2 diabetes mellitus for the past 4 years along with hypertension and benign prostatic hypertrophy. He had been previously treated with a combination of Metformin 500 mg/Glimepiride 2 mg once a day along with Telmisartan 20 mg OD and Tamsulosin 0.4 mg OD for his other comorbidities. His body mass index was 25.51 kg/m2. Lab investigations revealed that his fasting plasma glucose was 189 mg/dL and his HbA1 C was 8.0%. Due to poor glycaemic control, the Endocrinologist added Tab. Teneligliptin 20 mg OD to his present oral antidiabetic regime. After starting Teneligliptin, he presented with an exanthematous rash which appeared a few hours after starting the medication. He did not take the tablet on the second day. He had rashes persisting on the second day and the third day. The dermatologist saw him and documented pruritic maculo-papular rashes on his trunk and limbs with erythema of the palms. There were no target lesions or oral lesions. Hence Teneligliptin was discontinued. He was given topical steroids (Betamethasone 0.1% w/w 20 g cream), white soft paraffin 13.2% and light liquid paraffin 10.2% 100 g cream for 7 days. The lesions disappeared gradually after discontinuation of the drug without leaving any residual skin lesions. Adverse drug reactions were assessed based on Naranjo Algorithm and it showed a score of 7 and this is a probable risk. Table 1 shows the application of the Naranjo scale for this particular patient.[2]Table 1: Naranjo nomogram as applied to this patientTeneligliptin is a widely used DPP-4 inhibitor in India due to its economic pricing and easy availability. Teneligliptin is not approved by the US food and drug administration. It is approved in Japan, Argentina, Korea, and India.[1] Most of the DPP-4 inhibitors have occasionally been reported to cause cutaneous reactions. In a study by Prabhat Agrawal et al.,[3] Teneligliptin induced diffuse erythematous pruritic cutaneous rash all over the limbs and trunk within 2 days after administration of the drug. Then the drug was stopped and Fexofenadine 120 mg once daily and topical emollients were started. The rash disappeared within 5–7 days and the symptoms reappeared when the drug was re-administered. Hence the drug was stopped in that particular person. Kaori Nakatani reported a Sitagliptin-induced drug eruption which occurred 6 months after initiation of the drug and gradually subsided after the cessation of Sitagliptin; except small itchy erythematous eruptions continued to appear due to photosensitive reaction of the drug. This is probably due to the structure and adsorption spectrum of Sitagliptin. It has three adsorptive peaks; both the 199.0 and 265.0 nm wavelengths are within the UV-C spectrum, while the 400.1 nm absorbance peak absorbs UV-A–visible light. Thus, Sitagliptin could cause persistent photosensitive eruption after cessation of the drug even with protection from UV light by hapten formation with subcutaneous protein.[4] The UV absorption spectrum of Teneligliptin is 244.80 nm.[5] Wavelengths within the UV-A (320–400 nm) and UV-B (290–320 nm) range are more likely to cause drug-induced photosensitivity reactions.[6] Here the patient presented with idiosyncratic delayed hypersensitivity pruritic exanthematous rashes and the dermatologist documented it as generalized pruritic maculo-papular rashes on the trunk and limbs with erythema of the palms. The lesions were not confined to sun-exposed areas and the mucosa was spared. CONCLUSION In the present case, generalized skin reactions appeared after the administration of Teneligliptin within a day and the symptoms disappeared after the cessation of the drug with anti-allergic treatment. Hence we suggest that the skin reaction observed in this case is Teneligliptin induced and close attention should be maintained for patients who are prescribed with Teneligliptin for any adverse cutaneous events. In addition, DPP-4 drugs are known to have photosensitive reactions, and hence this group of drugs should be administered cautiously in patients who are known to have photosensitive reactions with other medications. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Role of Monoclonal Antibodies against Calcitonin Gene-Related Peptide (CGRP) in Episodic Migraine Prevention: Where Do We Stand Today?

Medications targeting the calcitonin gene-related peptide (CGRP) pathway are exciting and novel therapeutic options in the treatment of migraine. In this article, we have reviewed the role of these CGRP monoclonal antibodies in patients with episodic migraine. We did an extensive literature search for all phase 2 and 3 studies involving CGRP monoclonal antibodies in episodic migraine. Erenumab, fremanezumab, galcanezumab, and eptinezumab have all undergone phase 3 trials and have been found to be effective for episodic and chronic migraine. They have the advantage of being targeted therapies for migraine with very favorable adverse effect profiles comparable to placebo. Importantly, they are effective in subgroups of patients who have failed previous preventive therapies. Increasing use of these medications will certainly revolutionize the treatment and outlook for patients with migraine all over the world.

Feasibility of in-office MRI-targeted partial gland cryoablation for prostate cancer: an IDEAL stage 2A study

ObjectivesCryoablation for prostate cancer is typically performed under general anaesthesia. We explore the safety, feasibility and costs of in-office MRI-targeted prostate partial gland cryoablation (PGC) under local anaesthesia. We hypothesise...

Surgical Management of Stage IIIA Non-small Cell Lung Cancer

There remains equipoise regarding the optimal treatment approach for patients with stage IIIA non-small cell lung cancer (NSCLC). The purpose of this review is to examine the role of surgery as a modality in the management of stage IIIA NSCLC. Over the last two decades, several studies including randomized controlled trials have established the importance of multimodality therapies in the management of locally advanced NSCLC. Significant disparities exist in the reported advantages of surgery between observational and randomized controlled studies of stage IIIA patients. While some of these differences are likely due to patient selection bias, differences in the study design and treatment-related factors may also contribute to these trends. Preliminary results from studies assessing molecular therapies and immunotherapies in this population indicate a favorable adverse event and clinical response profile. As the therapeutic armamentarium for stage IIIA disease expands, continued evaluation of surgery within multimodality treatment protocols will be increasingly important.

Are Beta 3 Adrenergic Agonists Now the Preferred Pharmacologic Management of Overactive Bladder?

This paper discusses the recent evidence supporting beta 3 adrenergic agonists as the preferred pharmacological management of overactive bladder syndrome. Mirabegron has a similar efficacy profile to first-line antimuscarinics with favorable adverse effects profile. Treatment of OAB with beta-3 adrenergic agonist should be favored in patients at higher risk of anticholinergic adverse events. The efficacy and tolerability of beta-3 adrenergic agonists are consistently reported in older OAB patients, whether used alone or with other antimuscarinics. Mirabegron is cost-effective in treating OAB unless the symptoms were severe or refractory. Combination therapy of mirabegron and other pharmacotherapy has proven to be efficient in controlling OAB symptoms without inducing serious add-on adverse effects. While beta-3 adrenergic agonists bear favorable advantages in OAB treatment, physicians should perform a thorough and careful pre-treatment planning to optimize treatment benefits and adherence.

Targeted therapy for metastatic renal cell carcinoma

Targeted therapy for metastatic renal cell carcinoma

TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma

Treatment with tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (RCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile. We report final results from TiNivo, a phase Ib/II study of tivozanib combined with nivolumab. In phase Ib, patients with metastatic RCC received tivozanib 1.0 mg once daily (QD) for 21 days followed by 7 days off treatment (n= 3) or tivozanib 1.5 mg QD (n= 3) plus nivolumab 240 mg every 2 weeks. The maximum tolerated dose was determined to be tivozanib 1.5 mg, and 22 additional patients were enrolled at the maximum tolerated dose for phase II. Primary end points included safety and tolerability, with secondary end points of objective response rate, disease control rate, and progression-free survival. In total, 25 patients were treated with tivozanib 1.5 mg QD [12 (48%) treatment-naïve; 13 (52%) previously treated]. Treatment-related grade 3/4 AEs were reported in 20 patients (80%); 4 patients (17%) experienced AEs that led to dose reduction, and 8 (32%) discontinued due to AEs. The objective response rate was 56% (including one complete response) and disease control rate was 96%, with a median time to best response of 7.9 weeks. Twenty patients (80%) had tumor shrinkage. With a median follow-up of 19.0 months (range, 12.6-22.8), median progression-free survival was 18.9 months (95% confidence interval 16.4-not reached) in all patients and was similar in treatment-naïve and previously treated patients. Tivozanib plus nivolumab combination therapy showed a generally tolerable AE profile and promising antitumor efficacy. These results support further development of tivozanib combined with nivolumab as a treatment option in patients with treatment-naïve or previously treated metastatic RCC. NCT03136627.

Fostemsavir: A Novel Attachment Inhibitor for Patients With Multidrug-Resistant HIV-1 Infection.

To review the efficacy and safety of fostemsavir (FTR) for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults who are failing their current antiretroviral regimen. Clinical trials and review articles were obtained through PubMed (2015 to July 2020) using the search terms fostemsavir, BMS-663068, and GSK3684934. All relevant articles, trials, and abstracts in the English language were included. FTR demonstrates a novel mechanism of action, preventing virus attachment to the host CD4 receptor. FTR extended-release 600-mg tablets every 12 hours orally has proven beneficial in obtaining viral suppression for heavily treatment-experienced patients with multidrug-resistant infection refractory to other agents, as indicated in phase 3 trials. Treatment courses were evaluated to 96 weeks with significant viral load reductions noted within the first 24 weeks. Adverse events commonly reported include nausea, vomiting, diarrhea, fatigue, and headache. Serious events and fatality were not attributed to FTR and occurred because of advancement of HIV or other acute infection. FTR presents a new treatment option for patients with multidrug resistance and intolerability to other medications. The favorable adverse effect profile of FTR alongside the limited drug interaction profile makes it a viable option in a salvage regimen. FTR provides an alternative agent when composing a regimen for patients with multidrug-resistant HIV-1 infection. It is generally well tolerated, with few significant interactions, and neither renal nor hepatic dose adjustments are required.

MCL-113: IBRORS-MCL Study: A Spanish Retrospective and Observational Study of Relapsed/Refractory Mantle-Cell Lymphoma (MCL) Treated with Ibrutinib in Routine Clinical Practice

Context: Ibrutinib is a first-in-class oral inhibitor of Bruton's tyrosine kinase, has been established as a standard-of-care (SOC) treatment for R/R MCL. The clinical benefits with ibrutinib has been demonstrated in multiple trials and real-world studies.1-3 Objective: To describe ibrutinib outcomes in real-world patients in Spain. Design: IBRORS is a retrospective multicentre observational study of patients with confirmed diagnosis of R/R MCL who were treated with ibrutinib from January 2016 to March 2019 (6 months prior to the start of the study). The primary end point was PFS. Disease characteristics, previous therapies used, response rates, and survival outcomes with ibrutinib were also evaluated. Patients or other participants: The analysis included 66 evaluable patients from 24 centres in Spain. Median age at diagnosis was 64.5 years (range 57-72), and 78.8% were male. Baseline comorbidities of interest include: hypertension (47%), dyslipidemia (36.4%), and cardiovascular disorders (21.2%). Interventions: Patients had a median of 2 prior lines of therapy (range 1-8). Among the pre-ibrutinib treatments used, the most common treatment was bendamustine plus rituximab in 20.7% of cases, followed by R-CHOP-like combinations in 19.3% and Hyper-CVAD in 16.4%. Results: With a median follow-up of 14.2 months after Ibrutinib initiation, Ibrutinib treatment led to an ORR of 67.8% with a complete response in 24 patients (36.4%) and partial response in 16 patients (24.2%). Median PFS was 20.0 months (95% CI, 8.8-31.1) and median OS was 32 months (95% CI, 22.6-41.3). Adverse events were reported in 43 patients (65.1%). Atrial fibrillation or associated cardiovascular diseases were reported in 2 patients and no major hemorrhages were reported. Conclusions: IBRORS provides information on the first real-world study of ibrutinib use in clinical practice in Spain. The results suggest that ibrutinib is mostly being used in first and second relapses. The data evaluated confirms the favorable adverse event profile and manageability of ibrutinib in real-world clinical practice.

Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys.

Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. Neither MCAM (0.32mg/kg) nor morphine (1-5.6mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7days. Scopolamine (0.01-0.056mg/kg) and phencyclidine (0.1-0.56mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.

Quality of life and adverse events in patients with nonmuscle invasive bladder cancer receiving adjuvant treatment with BCG, MMC, or chemohyperthermia

IntroductionChemohyperthermia (CHT) with mitomycin C (MMC) is together with Bacillus Calmette-Guérin (BCG), and passive MMC, a treatment option for patients with non muscle-invasive bladder cancer. There are no data published about the impact of CHT in quality of life (QoL). We evaluated QoL and adverse events (AE) in this 3-arm observational study. Patients and MethodsProspective observational study from September 2016 to March 2017, we recruited consecutive patients that received adjuvant treatment after transurethral resection of bladder tumor. Patients received induction courses of either BCG, CHT, or passive MMC. Patients filled the questionnaires Functional assessment of cancer therapy for bladder cancer patients (FACT-Bl) and International prostate symptom score (IPSS) before, during, and after the induction course. A urologist documented AE using Common Terminology Criteria for AE (CTCAE criteria). ResultsA total of 56 patients, receiving a total of 296 bladder instillations (BCG n = 27, CHT n = 14 and MMC n = 15). FACT-Bl showed statistically significant differences in the fourth week in favor of CHT versus BCG, IPSS did not show statistically significant differences before, during, and after induction course in all 3 arms. All patients recovered their baseline QoL at the end of the induction treatment. Overall 55.5%, 50% and 20% of patients presented any grade of AE in the BCG, CHT and MMC groups respectively. About 7% of patients in BCG and CHT arms had to discontinue treatment due to AE. BCG and CHT showed a similar rate of AE but in CHT were mostly grade I and BCG had grade I, II, and IV. Passive MMC had the safest profile. ConclusionThere are no clinically significant differences between BCG, CHT, and passive MMC regarding QoL and lower urinary tract symptoms during the induction course. CHT has a more favorable AE profile when compared with BCG.

Fadolmidine – Favourable adverse effects profile for spinal analgesia suggested by in vitro and in vivo models

Fadolmidine is an α2-adrenoceptor full agonist developed for spinal analgesia with a local mode of action. The purpose of this study was to demonstrate the safety of fadolmidine on known α2-adrenoceptor-related effects: kidney function, urodynamics and cardiovascular variables. Furthermore, the binding affinity of fadolmidine for the 5-HT3 receptor prompted functional studies on 5-HT3. According to the binding affinity data, fadolmidine demonstrated partial agonism on the 5-HT3 receptor in transfected cells and in guinea pig ileum preparation. However, intravenous (IV) fadolmidine did not produce any 5-HT3-related hemodynamic effects in anaesthetised rats. In urodynamic studies, intrathecal (IT) fadolmidine interrupted volume-evoked voiding cycles and induced overflow incontinence at high concentrations in anaesthetised rats; however, at the analgesic dose range, the effects were mild. The effects of fadolmidine on kidney function were studied in conscious rats after IV and IT dosing. While IT fadolmidine increased dose-dependent urine output, sodium ion concentration, IV doses increased only sodium ion concentration The effects of IT fadolmidine on heart rate (HR), mean arterial pressure (MAP) and sedation were evaluated in the home cage and in the open field using a telemetry system. In resting conditions, fadolmidine decreased HR dose-dependently and increased initial MAP, whereas in actively moving rats, there were no effects at analgesic doses. The results suggest that at anticipated analgesic clinical doses, IT fadolmidine provides analgesia without significant adverse effects on sedation, MAP or HR and with only modest effects on kidney function and urodynamics.

Cost-Effectiveness of Rifaximin Treatment in Patients with Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a complication of cirrhosis of the liver causing neuropsychiatric abnormalities. Clinical manifestations of overt HE result in increased health care resource utilization and effects on patient quality of life. While lactulose has historically been the mainstay of treatment for acute HE and maintenance of remission, there is an unmet need for additional therapeutic options with a favorable adverse event profile. Compared with lactulose alone, rifaximin has demonstrated proven efficacy in complete reversal of HE and reduction in the incidence of HE recurrence, mortality, and hospitalizations. Evidence suggests the benefit of long-term prophylactic therapy with rifaximin; however, there is a need to assess the economic impact of rifaximin treatment in patients with HE. To assess the incremental cost-effectiveness of rifaximin ± lactulose versus lactulose monotherapy in patients with overt HE. A Markov model was developed in Excel with 4 health states (remission, overt HE, liver transplantation, and death) to predict costs and outcomes of patients with HE after initiation of maintenance therapy with rifaximin ± lactulose to avoid recurrent HE episodes. Cost-effectiveness of rifaximin was evaluated through estimation of incremental cost per quality-adjusted life-year (QALY) or life-year (LY) gained. Analyses were conducted over a lifetime horizon. One-way deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty in results. The rifaximin ± lactulose regimen provided added health benefits despite an additional cost versus lactulose monotherapy. Model results showed an incremental benefit of $29,161 per QALY gained and $27,762 per LY gained with rifaximin ± lactulose versus lactulose monotherapy. Probabilistic sensitivity analyses demonstrated that the rifaximin ± lactulose regimen was cost-effective ~99% of the time at a threshold of $50,000 per QALY/LY gained, which falls within the commonly accepted threshold for incremental cost-effectiveness. The clinical benefit of rifaximin, combined with an acceptable economic profile, demonstrates the advantages of rifaximin maintenance therapy as an important option to consider for patients at risk of recurrent HE. This analysis was funded by Salix Pharmaceuticals, a division of Bausch Health US. Salix and Xcenda collaborated on the methods, and Salix, Xcenda, Jesudian, and Ahmad collaborated on the writing of the manuscript and interpretation of results. Bozkaya and Migliaccio-Walle are employees of Xcenda. Ahmad reports speaker fees from Salix Pharmaceuticals, unrelated to this study. Jesudian reports consulting and speaker fees from Salix Pharmaceuticals, unrelated to this study. The results from this model were presented at AASLD: The Liver Meeting 2014; November 7-11; Boston, MA.

Results of a phase Ib study investigating durvalumab in combination with eribulin in patients with metastatic HER2-negative breast cancer and recurrent ovarian cancer.

e15120 Background: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a novel microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary anti-tumor activity of the combination in patients with previously treated HER2-negative MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3-6 patients with HER2-negative MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of dose limiting toxicities (DLTs) during cycle 1 and 2 of therapy. Secondary endpoints: AE rate, Objective Response Rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients [median age 63 (37-77)] with median 4 prior therapies for advanced disease were treated: 5 patients with HER2-negative MBC and 4 patients with ROC. The RP2D of eribulin was 1.4mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs ( > 50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1/2. There was one immune-related AE of grade ≥3 (hepatitis). Three patients discontinued study drug related to toxicity [neutropenia (n = 1), hepatic toxicity (n = 2)]. ORR was 55% (all partial response) and 4 additional patients experienced stable disease; all MBC patients experienced a response to therapy. Median PFS was 6.2 months. Median OS has not been reached. Conclusions: The combination of eribulin and durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early anti-tumor activity observed in this study suggests that further investigation of this combination is warranted. Clinical trial information: NCT03430518 .