Favorable Adverse Effect Profile Research Articles

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 .

Randomized Controlled Trial of Paliperidone Extended Release Versus Risperidone for the Treatment of Methamphetamine-Associated Psychosis in Chinese Patients.

BackgroundThe efficacy or tolerability of paliperidone extended release (ER) in the treatment of methamphetamine (METH)-associated psychosis (MAP) is unknown. This study was designed to assess the tolerability and efficacy of paliperidone ER and risperidone for the treatment of MAP in China.MethodsThis 25-day randomized clinical trial involved 120 patients with acute MAP symptoms who were randomized to receive either paliperidone ER or risperidone from baseline to day 25 of an inpatient hospital stay. The primary outcome was changes in the severity of psychosis, which were assessed using the Positive and Negative Syndrome Scale (PANSS) total score changes from baseline to endpoint.ResultsOverall, 84% of the patients completed the entire study protocol. The PANSS total score, the Clinical Global Impressions-Severity of Illness scale (CGI-S) score, and a METH craving score assessed by a visual analog scale (VAS) showed statistically significant improvements from baseline for the patients in both groups (p < 0.01). The Simpson-Angus Scale (SAS) and the Barnes Akathisia Rating Scale (BARS) scores increased from baseline during treatment in both groups (p < 0.01); there were statistically significant differences between the treatment groups in the SAS scores (p < 0.01). Measures of hypermyotonia, salivation, and dizziness were significantly higher in the risperidone-treated patients than in the paliperidone ER-treated patients (all p < 0.05).ConclusionPaliperidone ER and risperidone had similar efficacy and were generally tolerable in the treatment of MAP; however, paliperidone ER had a more favorable adverse event profile than risperidone, particularly regarding extrapyramidal and prolactin-increasing effects.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT01822730. Full date of first registration:03/28/2013.

Stability of ceftolozane and tazobactam in different peritoneal dialysis solutions.

Peritonitis is a common and serious complication of peritoneal dialysis (PD). PD-associated peritonitis (PDAP) caused by Pseudomonas is usually resistant to most antibiotics, resulting in high failure rates. Ceftolozane/tazobactam (C/T) has been shown to be effective in treating urinary tract and intra-abdominal infections caused by beta-lactam resistant Pseudomonas and other gram-negative bacteria. Given its favourable adverse effects profile, it has a potential role in the treatment of PDAP caused by Pseudomonas species resistant to other antibiotics. Intraperitoneal administration of antibiotics admixed with PD solutions for the treatment of PDAP is associated with superior outcomes. However, there is a lack of published data on the stability of C/T in PD solutions. Therefore, this study investigated the physical and chemical stability of C/T in commonly used PD solutions at different temperatures. A total of 27 PD bags (3 PD bags for each type of PD solution including Dianeal®, Extraneal®, Balance® and Physioneal® PD bags) containing C/T were prepared and stored at 25°C for 6 h, followed by 4°C for 168 h and then 37°C for 12 h. An aliquot from each PD bag was withdrawn, and the concentration of C/T before (0 h) and after predefined time points was determined using a stability-indicating high-performance liquid chromatography assay. Samples were also assessed for pH, colour change and particulate matter immediately after preparation and on each day of analysis. C/T retained more than 97% of their initial concentration when stored at 25°C for 6 h followed by storage at 4°C for 168 h and then at 37°C for 12 h. Particle formation was not detected at any time under the tested storage conditions. The pH and colour remained essentially unchanged throughout the study. These results provide a platform for clinical studies to determine the safety and therapeutic efficacy of intraperitoneal C/T for the treatment of PDAP caused by resistant Pseudomonas species.

A053 Early Single-Centre Experience of a Nurse-led Sacubitril/Valsartan Initiation and Titration Clinic: A Retrospective Analysis

Background: Sacubitril/valsartan has changed the landscape of the pharmacological therapy of heart failure with reduced ejection fraction (HFrEF). We present our single-centre nurse-led initiation and titration clinic findings from Waikato Hospital. Method: Our retrospective analysis includes 149 consecutive patients with HFrEF who were commenced on sacubitril/valsartan by the Heart Failure Clinical Nurse Specialist (HF CNS) clinic between 1 October 2018 and 30 September 2019. Statistical analyses for Wilcoxon signed-rank test (two-tailed) were performed using Prism 8. Results: Our cohort of 149 patients were predominantly male (81%) with a median age of 68. The majority were either European (72%) or Māori (25%). Two-thirds (64%) were aetiologically non-ischaemic. Mean systolic blood pressure, mean GFR, mean weight and mean serum K+ were similar at baseline and at 6 month follow-up. 69% achieved target dose and 6% had withdrawal of sacubitril/valsartan. 36% had reduction in loop diuretic dose and 18% had mineralocorticoid antagonist withdrawn. Statistically significant differences were observed with decrease in NYHA Class (z = -7.961; p <.00001), decrease in NT-pro BNP (z = -6.441; p <.00001) and improvement in LVEF (z = -6.052; p <.00001) across the cohort. 10% (n = 15) were hospitalised for HF and 3.4% died (n = 5) within 6 months of commencing sacubitril/valsartan. Conclusion: Our early, single-centre experience with a nurse-initiated and led sacubitril-valsartan clinic has yielded results in keeping with the data from the PARADIGM-HF trial, whereby patients experience an improvement clinically (NYHA Class), biochemically (NT-pro BNP) and echocardiographically () with a favourable adverse effect profile. Further insights will be gleaned with longer-term follow-up in our cohort. [Formula presented]

Update on noninvasive neuromodulation for migraine treatment-Vagus nerve stimulation.

Noninvasive neurostimulation methods are particularly suited for migraine treatment thanks to their most favorable adverse event profile. Among them, noninvasive vagus nerve stimulation (nVNS) has raised great hope because of the role the vagus nerve is known to play in pain modulation, inflammation and brain excitability. We will critically review the clinical studies performed for migraine attack treatment and migraine prevention with the GammaCore® device, which allows cervical vagus nerve stimulation. nVNS is effective for the abortive treatment of migraine attacks, although the effect size is modest and numbers-to-treat appear not superior to those of other noninvasive neurostimulation methods, and inferior to those of oral triptans. The effect of nVNS with the GammaCore® in migraine prevention is not superior to sham stimulation, except possibly in patients with high adherence to the treatment. Both in acute and preventive trials, nVNS was characterized by an outstanding tolerance and safety profile, like the other noninvasive neurostimulation techniques. In physiological animal and human studies, cervical nVNS was shown to generate somatosensory evoked responses, to modulate pain perception and several areas of the cerebral pain network, and to inhibit experimental cortical spreading depression, which are relevant effects for migraine therapy.

Timeliness of care and adverse event profile in children undergoing general anesthesia or sedation for MRI: An observational prospective cohort study.

Background and Aims:Anaesthesia for children undergoing magnetic resonance imaging (MRI) ranges from moderate to deep sedation in order to facilitate uninterrupted completion of the scan. While various intravenous and inhalational techniques of anaesthesia have their own merits and demerits, there is a paucity of comparative literature between the two in children undergoing diagnostic MRI.Materials and Methods:This prospective observational cohort study was conducted at the Radiology suite of a 2800-bedded tertiary care hospital, wherein 107 unpremedicated children between the ages of 6 months to 15 years received either sedation with propofol infusion (Group GSP, n = 57) or inhalational anaesthesia with a laryngeal mask airway (Group GAL, n = 50). Primary outcome measures included time to induction and time to recovery. Secondary outcomes comprised the incidence of respiratory and non-respiratory adverse events in the two groups.Results:The median time to induction was significantly shorter in GSP than GAL [7.00 (IQR 5.0, 10.0) versus 10.00 minutes (IQR 8.8, 13.0), P < 0.001]; the incidence of desaturation [8 (16.0%) in GAL, 1 (1.8%) in GSP, P = 0.012], laryngospasm [11 (22.4%) in GAL, 1 (1.8%) in GSP, P = 0.001] and emergence delirium (5 (10%) in GAL, 0 in GSP, P = 0.047) were significantly greater in the GAL group. There was no difference in the time to emergence, nausea and vomiting or bradycardia between the two groups.Conclusion:Sedation with propofol infusion during paediatric MRI scan offers a short turnover time and favourable adverse event profile when compared to inhalational anaesthesia with an LMA.

Carfilzomib Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (&gt;VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, &gt;VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, &gt;VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, &gt;VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, &gt;VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, &gt;VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, &gt;VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, &gt;VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, &gt;VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, &gt;VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though &gt;VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common &gt;grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common &gt;grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions.

Efficacy and safety of erenumab have been evaluated in a comprehensive clinical development program resulting in approval for migraine prevention in over 40 countries to date. This integrated safety analysis included four double-blind randomized trials and their extensions (up to three-plus years). Safety endpoints included exposure-adjusted patient incidences of adverse events, serious adverse events, and anti-erenumab antibodies. In all, 2375 of the patients randomized across the four studies received at least one dose of erenumab (70 mg or 140 mg), with cumulative exposure of 2641.2 patient-years. Exposure-adjusted adverse event rates during the double-blind treatment phase were similar to placebo, with the exception of injection-site reactions (17.1 vs. 10.8 per 100 patient-years), constipation (7.0 vs. 3.8 per 100 patient-years), and muscle spasm (2.3 vs. 1.2 per 100 patient-years). During the long-term extensions, adverse events reported were similar to those observed during the double-blind treatment phase, and rates of injection site reactions, constipation, and muscle spasm were reported at lower rates than in the double-blind treatment phase. There were two deaths reported, both confounded by pre-existing conditions. This pooled safety analysis revealed a favorable and stable adverse event profile over time for erenumab with more than three years of exposure. ClinicalTrials.gov NCT01952574, NCT02483585, NCT02456740, NCT02066415, and NCT02174861.

Modeling of usage and estimation of cost for efinaconazole 10% topical solution in the treatment of onychomycosis

To the Editor: Onychomycosis is a fungal infection of the nail caused by dermatophytes, nondermatophyte molds, and yeasts. It accounts for half of all nail diseases, with toenails more commonly affected than fingernails.1 Oral medications are often used, although topical therapy may be preferred due to a favorable adverse effect profile. Ciclopirox 8% nail lacquer, efinaconazole 10% solution, and tavaborole 5% solution are approved by the US Food and Drug Administration for the treatment of onychomycosis.

EP1.14-11 Real-Life Data of Osimertinib in Pretreated Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR T790M Mutation

Several clinical trials have demonstrated the efficacy and safety of osimertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring EGFR T790M resistance mutation. However, clinical real-world data on patient characteristics and efficacy of the drug is limited. We reviewed the medical records of T790M mutation-positive lung cancer patients treated with osimertinib between May 2016 and February 2019 in our institution. We calculated progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. The study included 22 patients with a mean age of 59.6 years. 59% (13/22) were female and 100% had adenocarcinoma histology. We had an unusual high frequency of tobacco use in our series as 40.9% (9/22) of our patients were smokers (3/22) o former-smokers (6/22), with a mean of 35 pack-year (sd, 28.5). 45.5% (10/22) had exon 21 L858R mutations, whereas 54.5% (12/22) harboured exon 19 deletions (19del). One patient simultaneously had an exón 19 deletion and exon 20 S768I mutation. Osimertinib was used in second, third and fourth line in 50% (11/22), 27% (6/22) and 23% (5/22) of patients, respectively. All patients had liquid biopsy blood samples obtained prior to the start of the treatment, and T790M mutation could be detected in 86.4% (19/22), with a mean mutant-allele fraction of 4,11% (standard deviation 8.65, min 0, max 37.7). T790M was detected only in tissue in 2 patients and exclusively in cerebrospinal fluid in 1 of them. At the time of starting osimertinib, patients had a median of 3 metastatic sites (min 1, max 6), being the most frequent locations the lung (73%), the bone (64%), the pleura (59%), the central nervous system (23%) and the peritoneum (14%). Median follow-up duration was 10 months (IQR, 4.7-22.67). To the date, 63% (14/22) have experienced progression of the disease. Median PFS in our series was 8.9 (95% CI, 4.9-17.9 ) months, whereas median OS since osimertinib initiation was 18.2 (95% CI, 8.8-NE) months. Regarding to toxicity, 12 patients referred adverse events, 82.6% of which were mild (G1), being the most frequent toxicities neutropenia (9%), diarrhoea (9%), hypertransaminasemia (9%) and asthenia (9%). Only 1 G3 event was recorded (asymptomatic hyperamilasemia). The efficacy of osimertinib in real-world practice was similar the observed in clinical trials, with a favourable adverse effect profile. Liquid biopsy is an effective non-invasive method to assess the presence of the T790M resistance mutation prior to the start of osimertinib.

Treatment of Facial Telangiectases With Glycerin Sclerotherapy.

Sclerotherapy is used to treat varicosities and telangiectases. Glycerin is a sclerosing agent that has been used off-label for years with a favorable adverse effect profile. However, the treatment of facial telangiectases with sclerotherapy is controversial given the potential for necrosis and embolization in relation to the complex vascular anatomy of the face. To determine the safety and efficacy of glycerin sclerotherapy for the treatment of facial telangiectases. The authors report a series of 8 patients with facial telangiectases treated with glycerin sclerotherapy. Glycerin mixed with lidocaine and epinephrine was used. The telangiectases were measured and identified as targets for treatment. The patients ranged in age from 45 to 88 years. Between 0.5 and 1 mL was used to treat telangiectases of the nose and malar cheek area per session. Five of the patients achieved satisfactory results after 1 treatment, whereas patients with more extensive telangiectases required up to 3 sessions with 4-week intervals between each session. Injection site pain was the only reported adverse effect, and no evidence of necrosis or blindness was observed. Glycerin sclerotherapy seems to be a safe and effective modality for the treatment of facial telangiectases.

Computed tomography–guided platinum microcoil lung surgery: A cross-sectional study

ObjectiveThe study objective was to provide a 5-year update on our tertiary-level institutional experience with computed tomography–guided platinum microcoil lung surgery. MethodsA retrospective cross-sectional study was conducted. All patients admitted to the Thoracic Service at Vancouver General Hospital to undergo computed tomography–guided microcoil lung surgery were included. Key primary outcome variables were successful nodule localization and severity of adverse events associated with placement. Secondary outcomes included nodule characteristics on preoperative computed tomography chest and nodule surgical pathology. Continuous variables were reported as mean (± standard deviation), and counts were reported as proportions n (%). ResultsA total of 97 lung nodules were resected in 92 patients. Mean age was 65.3 (±10.6) years, and 59 (61%) were female. All 97 nodules (100%) were successfully localized using video-assisted thoracic surgery wedge resection. There were 59 cases (60.8%) of placement-related events noted on computed tomography of the chest. All were minor and self-limited in nature and did not require treatment: pneumothorax 45 (46.4%), lung hematoma 18 (18.6%), dislodgement 4 (4.1%), and hemoptysis 2 (2.1%). Mean nodule diameter was 13.2 mm (±6.7). Density was nonsolid in 27 (27.8%) and semi-solid in 27 (27.8%). There was a single case of positive surgical margin, and 4 (4.1%) went on to completion lobectomy. Non–small lung cancer was identified in 66 nodules. ConclusionsComputed tomography–guided platinum microcoil lung surgery is safe with a favorable clinical adverse event profile and is suitable for poor-risk patients. The method is efficient, yielding 100% diagnostic localization in our 5-year update. It eliminates the need for thoracotomy and palpation to localize worrisome subpleural tiny nodules. It is ideal for the management of changing nodules concerning for early lung cancer and diagnosis of small indeterminate lung nodules or metastases.

Absorption Characteristics of Novel Compound Calcium Carbonate Granules: Effects of Gastric Acid Deficiency and Exogenous Weak Acids.

Calcium carbonates are commonly administered as supplements for conditions of calcium deficiency. We report here pharmacokinetic characteristics of a novel formulation, calcium carbonate compound granules (CCCGs), forming complexes of calcium carbonate and calcium citrate in water. CCCGs were compared to a kind of commonly-used calcium carbonate D3 preparation (CC) in the market in 5-week-old mice that had been treated with omeprazole, to suppress gastric acid secretion, and in untreated control mice. The results showed that: (1) CCCGs had better water solubility than CC in vitro; (2) In control mice, calcium absorption rates after CCCGs administration were comparable to those after CC administration; (3) Inhibition of gastric acid secretion did not affect calcium absorption after CCCGs, but moderately decreased it after CC; (4) The presence of phytic acid or tannin did not affect calcium absorption rates after CCCGs but did for CC; and (5) In normal mice, CCCGs did not inhibit gastric emptying and intestinal propulsion, and did not alter the gastrointestinal hormones. The results suggest that CCCGs may be therapeutically advantageous over more commonly used calcium supplement formulations, particularly for adolescents, because of their stable calcium absorption characteristics and their relatively favorable adverse effect profile.

A meta-analysis of levetiracetam for randomized placebo-controlled trials in patients with refractory epilepsy.

ObjectiveThe objective of this study was to investigate the efficacy and safety profile of levetiracetam as add-on therapy in patients with refractory epilepsy.MethodsWeb of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar were systematically searched to identify potential eligible randomized controlled trials by two reviewers independently. Pooled estimates of risk ratios (RRs) for 50%, 75%, and 100% reduction from baseline were calculated using the fixed-effect model or random-effect model. Quality of included studies was assessed with the Cochrane Collaboration’s Risk of Bias tool. Serious adverse events and withdrawals induced by interventions and the most common side effects were analyzed.ResultsSeventeen trials with a total of 3,205 participants were included in this meta-analysis, including 14 trials for adulthood and three trials for children. Pooled estimates suggested that levetiracetam was an effective anti-epileptic drug at 1,000–3,000 mg/day (RR =2.00 for 1,000 mg/day, RR =2.68 for 2,000 mg/day, RR =2.18 for 3,000 mg/day) for adults and 60 mg/kg/day (RR =2.00) for children compared to placebo in terms of 50% reduction from baseline. Likewise, as for seizure freedom rate, levetiracetam had an advantage over placebo at 1,000–3,000 mg/day (RR =5.84 for 1,000 mg/day, RR =4.55 for 2,000 mg/day, RR =4.57 for 3,000 mg/day, respectively) for adults and 60 mg/kg/day (RR =4.52) for children. Regarding safety profile, patients treated with levetiracetam had significantly higher occurrence than placebo for somnolence, asthenia, dizziness, infection, nasopharyngitis, anxiety, and irritability; however, most studies reported that these adverse events were mild and transient.ConclusionLevetiracetam is an effective anti-epileptic drug for both adults and children with generalized or partial-onset refractory seizures at 1,000–3,000 or 60 mg/kg/day, with a favorable adverse event profile.

Analysis of Morbidity and Outcomes Associated With Use of Subdural Grids vs Stereoelectroencephalography in Patients With Intractable Epilepsy

A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown. To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center. Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy. Procedures were performed from November 1, 2004, through June 30, 2017, and data were analyzed in June 2017 and August 2018. Implantation of SDE using standard techniques vs SEEG using a stereotactic robot, followed by resection or laser ablation of the seizure focus. Length of surgical procedure, surgical complications, opiate use, and seizure outcomes using the Engel Epilepsy Surgery Outcome Scale. Of the 260 cases included in the study (54.6% female; mean [SD] age at evaluation, 30.3 [13.1] years), the SEEG (n = 121) and SDE (n = 139) groups were similar in age (mean [SD], 30.1 [12.2] vs 30.6 [13.8] years), sex (47.1% vs 43.9% male), numbers of failed anticonvulsants (mean [SD], 5.7 [2.5] vs 5.6 [2.5]), and duration of epilepsy (mean [SD], 16.4 [12.0] vs17.2 [12.1] years). A much greater proportion of SDE vs SEEG cases were lesional (99 [71.2%] vs 53 [43.8%]; P < .001). Seven symptomatic hemorrhagic sequelae (1 with permanent neurological deficit) and 3 infections occurred in the SDE cohort with no clinically relevant complications in the SEEG cohort, a marked difference in complication rates (P = .003). A greater proportion of SDE cases resulted in resection or ablation compared with SEEG cases (127 [91.4%] vs 90 [74.4%]; P < .001). Favorable epilepsy outcomes (Engel class I [free of disabling seizures] or II [rare disabling seizures]) were observed in 57 of 75 SEEG cases (76.0%) and 59 of 108 SDE cases (54.6%; P = .003) amongst patients undergoing resection or ablation, at 1 year. An analysis of only nonlesional cases revealed good outcomes in 27 of 39 cases (69.2%) vs 9 of 26 cases (34.6%) at 12 months in SEEG and SDE cohorts, respectively (P = .006). When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I or II) for SEEG compared with SDE were similar (57 of 121 [47.1%] vs 59 of 139 [42.4%] at 1 year; P = .45). This direct comparison of large matched cohorts undergoing SEEG and SDE implantation reveals distinctly better procedural morbidity favoring SEEG. These modalities intrinsically evaluate somewhat different populations, with SEEG being more versatile and applicable to a range of scenarios, including nonlesional and bilateral cases, than SDE. The significantly favorable adverse effect profile of SEEG should factor into decision making when patients with pharmacoresistant epilepsy are considered for intracranial evaluations.

Erenumab: A First-in-Class Monoclonal Antibody for Migraine Prevention.

Objective: To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy. Data Sources: A MEDLINE/PubMed search (January 2000 to January 2019) was conducted using the keywords erenumab-aooe, erenumab, migraine, migraine prophylaxis, migraine prevention, and chronic migraine. Additional articles were identified by hand from references. Study Selection and Data Extraction: We included English-language articles (excluding poster presentations) evaluating erenumab pharmacology, efficacy, or safety in humans for migraine prevention. Data Synthesis: Erenumab is a CGRP inhibitor that inhibits vasodilation in response to acute migraines, which decreases pain perception during the migraine. Erenumab efficacy and safety has only been compared with placebo, but its reduction in monthly migraine days (MMDs) and medication response (≥50% reduction in MMDs) are comparable to current recommended off-label therapies for migraine prevention in short-term treatment studies. Additionally, erenumab is associated with low adverse event burden with no difference found compared with placebo per published clinical trials. Relevance to Patient Care and Clinical Practice: Erenumab is the first medication approved in the United States for the prevention of migraines in adults. No head-to-head data are available, but existing data suggest that erenumab is at least as effective as current off-label products and with reduced adverse effects. Conclusion: Erenumab is an effective once-monthly injectable agent for migraine prevention in patients with chronic or episodic migraine. It is also effective for patients who have previously failed migraine preventive therapy. Erenumab has a favorable adverse effect profile, which may improve patient adherence.

Prospects for the Use of Cannabinoids in Oncology and Palliative Care Practice: A Review of the Evidence.

There is an increased interest in the use of cannabinoids in the treatment of symptoms in cancer and palliative care patients. Their multimodal action, in spite of limited efficacy, may make them an attractive alternative, particularly in patients with multiple concomitant symptoms of mild and moderate intensity. There is evidence to indicate cannabis in the treatment of pain, spasticity, seizures, sleep disorders, nausea and vomiting, and Tourette syndrome. Although the effectiveness of cannabinoids is limited, it was confirmed in neuropathic pain management and combination with opioids. A relatively favorable adverse effects profile, including no depressive effect on the respiratory system, may make cannabis complement a rather narrow armamentarium that is in the disposition of a palliative care professional.

CGRP ligand and receptor monoclonal antibodies for migraine prevention: Evidence review and clinical implications.

Monoclonal antibodies that target calcitonin gene-related peptide or the canonical calcitonin gene-related peptide receptor have emerged as effective and well tolerated for the preventive treatment of migraine. These large molecules appear ideally suited for migraine prevention. They have an extended biological half-life, are administered either monthly or quarterly either by subcutaneous injection or intravenous infusion, require minimal or no dose-titration and have the potential for a rapid onset of effect compared to conventional oral preventive drugs. There is high selectivity and they target an important mediator in the pathogenesis of migraine. Phase II and pivotal phase III studies have all yielded positive results with a favorable adverse event profile. No serious treatment-related adverse outcomes have thus far been reported in controlled or long-term open-label extension studies. This tolerability profile promises to improve adherence and, possibly, long-term outcomes. Calcitonin gene-related peptide monoclonal antibodies are effective and well tolerated for the preventive treatment of migraine. They have distinct advantages over currently available oral preventive drugs. While treatment-related serious adverse events have not been observed in open-label extension studies, long-term outcomes and safety will require broad exposure in heterogeneous patient populations in clinical practice. In addition, their safety in women, especially during pregnancy, will require longitudinal surveillance. Given the overlapping mechanism(s), the effectiveness of existing (triptans) and emerging (calcitonin gene-related peptide receptor antagonists) acute therapies in those using a calcitonin gene-related peptide mAb will require further study.

Incidence Rates of Infection and Malignancy of Patients Treated With Vedolizumab for Inflammatory Bowel Disease in Clinical Practice

Introduction: The gut-specific integrin antagonist mechanism of vedolizumab (VDZ) is thought to have a favorable adverse effect profile, including a low rate of infection and malignancy. However, data from real-world clinical practice regarding these outcomes is limited. Our aim is to characterize a cohort of patients with IBD and receiving VDZ; to examine the incidence of infection and malignancy; and to identify risk factors associated with the development of these outcomes. Methods: This is a retrospective analysis conducted at a tertiary academic medical center with a center for inflammatory bowel disease. Patients with Crohn's disease or ulcerative colitis and treated with vedolizumab were identified using ICD-9 and 10 codes. Baseline anthropologic, serologic, and clinical data was obtained. Results: Seventy-eight patients were identified, with a mean age and BMI of 43 ± 17 and 27.5kg/m2 ± 5.1. Forty-two (54%) of the patients were female, and 25 patients (32%) were current or prior smokers. Forty-two patients (54%) had ulcerative colitis. A total of 21 patients (27%) had prior IBD-related surgery. Forty-five patients (58%) had accelerated VDZ dosing intervals of either Q4 or 6 weeks. The median VDZ exposure time was 119 weeks (IQR 52-161), totaling 159.4 patient-years of VDZ exposure among all patients. A total of 2 (3%) malignancies were diagnosed (basal cell carcinoma and chronic lymphocytic leukemia), correlating to a malignancy incidence of 1.3 per 100 patient-years of exposure to VDZ. There were 10 infections (13%) diagnosed, making for an incidence of infection of 6.3 per 100 patient-years of exposure to VDZ (Table 1). Older age (> 50 years old), obesity (BMI > 30), smoking status, IBD type, prior IBD surgery, and concomitant immunomodulator use at start of VDZ initiation were not associated with increased risk of either malignancy or infection. Using Kaplan-Meier survival analysis, patients with accelerated dosing (Q4-6 weeks) had similar time to infection versus those with standard dosing (Q8 weeks), P=0.09 (Figure 1).611_A Figure 1. Summary of safety outcomes (development of infections and malignancies) after VDZ initiationConclusion: In this cohort of patients in clinical practice on vedolizumab, the incidence of infection and malignancy were low. No patient characteristics were identified as risk factors for developing either malignancy or infection in this group of patients, including concomitant use of an immunomodulatory at induction with vedolizumab. No significant difference in time to infection as noted with accelerated vedolizumab dosing.611_B Figure 2. Time to infection in patients on VDZ accelerated dosing (Q4W or Q6W) versus those with standard VDZ dosing interval (Q8W)