Daily Dose Treatment Research Articles

Revisiting the question of the safety of glucocorticoids use of in the treatment of rheumatoid arthritis

Glucocorticoids (GCs) are one of the most commonly used drugs for the treatment of rheumatoid arthritis (RA), the effectiveness of which is beyond doubt. The review considers current literature data on the safety of GCs use, as well as the most common adverse events associated with such therapy. Most authors point to an increased risk of complications with an increase in the daily dose and/or duration of GCs treatment. At the same time, a safe dose of GCs has not been determined. Probably, the optimal tactic is the selection of an individual dose of GCs in each individual case, taking into account the activity of RA and the spectrum of comorbid conditions. In this case, the minimum effective doses and short courses of GCs should be used, regular monitoring of clinical and laboratory parameters should be carried out in order to detect adverse events early.

COVID-19 severity and risk factors in Iranian patients with rheumatic diseases

Since the beginning of COVID-19 pandemic, there was a concern whether patients with rheumatic diseases are at increased risk of severe COVID-19 in terms of the multi-system involvement, underlying comorbidities, and anti-rheumatic medications. We intended to evaluate the severity and mortality of COVID-19 in these patients, as well as the demographic, laboratory, and clinical risk factors associated with the disease. In patients with plasma chane reaction positive COVID-19 admitted to the hospital, laboratory and clinical measures after hospitalization and severity measures such as length of hospitalization, hospitalization in the intensive care unit, and mortality were compared between patients with and matched patients without a history of rheumatic disease. Moreover, risk factors associated with COVID-19 mortality in the case group were calculated by odds ratio (OR). We found no statistically significant difference in COVID-19 severity between the two groups (mortality rate of 22% in case and 25% in control groups, P-value = 0.83). Except for platelet markers, which were considerably greater in the case group despite not being related with the severity of the illness, the available laboratory measurements did not vary between these groups. In addition, we showed that age over 65 years (OR = 4.06), lactic dehydrogenase level, percentage of lung involvement and ischemic heart disease (OR = 6.24) were associated with poorer outcome in the patients with rheumatic diseases. Hence, we found that usage of conventional synthetic disease modifying anti-rheumatic drugs (OR = 2.3, P-value = 0.48) or daily treatment dose of prednisolone >10 mg/d (OR = 1.04) were not associated with COVID-19 mortality. Although the patients with rheumatic disease may be at increased risk of developing a COVID-19 infection, they do not experience more severe disease.

Antiviral activity of the HSP90 inhibitor VER-50589 against enterovirus 71

Enterovirus 71 (EV71) is the major pathogen responsible for hand, foot, and mouth disease (HFMD) outbreaks; to date, there is no specific anti-EV71 agent. HSP90 is a crucial host factor for the viral life cycle and an ideal therapeutic target for limiting viral proliferation. However, the specific role of HSP90 in EV71-related signaling pathways and anti-EV71 agents targeting HSP90 remains unclear. This study aimed to verify the role of HSP90 in signaling pathways involved in EV71 replication and investigate the antiviral effects of a small molecule of VER-50589, a potent HSP90 inhibitor, against EV71 both in vitro and in vivo. Viral plaque assay, western blotting, and qPCR results showed that VER-50589 diminished the plaque formation induced by EV71 and inhibited EV71 mRNA and protein synthesis. A single daily dose of VER-50589 treatment significantly improved the survival rate of EV71-infected mice (p < 0.005). Interestingly, VER-50589 also exhibits activities against a series of human enteroviruses, including Coxsackievirus B3 (CVB3), Coxsackievirus B4-5 (CVB4-5), Coxsackievirus B4-7 (CVB4-7), and Echovirus 11 (Echo11). EV71 infection activated the AKT and ERK signaling pathways, and phosphorylation of AKT and RAF/MEK/ERK was weakened by VER-50589 administration. Thus, VER-50589 exhibits robust antiviral activity by inhibiting HSP90 and mediating the AKT and RAF/MEK/ERK signaling pathways. Considering that there are no effective antivirals or vaccines for the prevention and cure of HFMD in a clinical setting, the development of an anti-EV71 agent would be a straightforward and feasible therapeutic approach.

995. Acute Kidney Injury Rates Before and After Implementation of Integrated Bayesian Software for Vancomycin Dosing

Abstract Background Therapeutic drug monitoring of vancomycin with Bayesian models is recommended to maximize efficacy and minimize nephrotoxicity by targeting a 24-hour area under the curve (AUC24) of 400-600mg*h/L. Minimal real-world evidence exists on the impact of this strategy. In 2020, we integrated Bayesian software from DoseMeRx into Epic OneChart and converted from trough-based vancomycin to AUC-guided dosing. We assessed the incidence of acute kidney injury (AKI) in patients receiving vancomycin before and after this change and sought to establish an efficient method of assessment. Methods This was a retrospective, single-center quasi-experimental study. Patients were divided into pre-Bayesian software (trough guided dosing, Jan-Jun 2018) and post- (Jan-Jun 2021). Preliminary data showed 10% &amp; 6% AKI rates, respectively. Therefore, a sample of 1442 patients was needed to detect a difference. Adults were included with a baseline Scr ≤2 mg/L, who received ≥3 vancomycin doses and had ≥1 vancomycin level measured. The primary outcome was AKI incidence assessed using AKIN criteria. Patients were reviewed in each period until 500 met inclusion criteria. This sample was used to determine the feasibility and accuracy of using EHR-generated reports. Results Of the 1,000 patients reviewed, baseline characteristics were similar; however, indications varied as pneumonia was more common in the pre-group and skin and soft tissue infection was more common in the post-group (Table 1). Initial daily dose and duration of vancomycin treatment were not different between groups. Incidence of AKI was decreased in the post-integration group, although this was not significant by bivariate analysis (15.4% vs. 12.6%, p=0.20). Fewer trough concentrations were drawn in the post-group (2 vs. 1.8, p=0.005), with overall lower vancomycin levels (13.2 vs. 12.1 mg/L, p=0.04). Conclusion The rate of AKI was numerically lower in patients monitored and dosed with Bayesian AUC-guided dosing software for vancomycin. Trough levels were lower, and vancomycin levels were needed less often. AKI incidence was higher than in our pilot but similar to what is reported in other studies. Further investigation is required to establish statistical significance and whether the assessment process can be automated. Disclosures Bryan T. Alexander, PharmD, BCIDP, AAHIVP, Astellas Pharma: Advisor/Consultant Trevor C. Van Schooneveld, MD, bioMerieux: Advisor/Consultant|bioMerieux: Grant/Research Support|Insmed: Grant/Research Support|Merck: Grant/Research Support|Thermo-Fischer: Advisor/Consultant Scott J. Bergman, PharmD, BCIDP, FCCP, FIDSA, Merck &amp; Co., Inc: Advisor/Consultant|Merck &amp; Co., Inc: Grant/Research Support|Merck &amp; Co., Inc: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria.

DARolutamide ObservationaL (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

e17029 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor that significantly increased median metastasis-free survival by ̃2 years and improved overall survival with a 31% reduction in risk of death vs placebo in men with nmCRPC in ARAMIS (NCT02200614), with a favorable tolerability profile. DARO significantly improved survival in men with metastatic hormone-sensitive prostate cancer (mHSPC) in ARASENS. The ongoing DAROL trial (NCT04122976) is designed to support results from the phase 3 ARAMIS study and to provide insight into the safety and effectiveness of DARO and the management of nmCRPC in the real-world setting. We report results of the first prespecified interim analysis. Methods: DAROL is an international, single-arm, non-interventional study. Eligible patients (pts) are DARO naïve, ≥18 years of age, with confirmed nmCRPC, for whom the decision to treat with DARO was made before enrollment. Treatment dose and duration are per investigator’s routine practice. The primary endpoint is safety, including treatment-emergent adverse events (TEAEs). Prostate-specific antigen (PSA) response was an exploratory objective. Descriptive statistics are reported for the first prespecified interim analysis (cut-off: September 23, 2021) performed after ̃100 pts (from US, Canada, Japan) completed ≥6 months of treatment or discontinued treatment. Results: All 100 pts were evaluable for safety: median age 78.0 years; White/Black/Asian/other/not reported, 59%/11%/27%/1%/2%; North America/Asia Pacific, 79%/21%; baseline ECOG performance status 0–1/2–4/not reported, 72%/5%/23%; median (Q1–Q3) time from initial diagnosis to castration-resistant, 89.1 mo (39.1–130.6 mo); Gleason score at initial diagnosis ≤6/7/8–10, 15.8%/38.9%/45.3%; baseline PSA ≤10/ &gt; 10 ng/mL, 75.3%/24.7%; PSA doubling time ≤6/ &gt; 6 mo, 58.2%/41.8%. Median (Q1–Q3) duration of treatment was 11.3 mo (8.4–14.4 mo); median (Q1–Q3) follow-up time was 12.3 mo (9.6–15.6 mo). Median starting dose and daily treatment dose was 1200 mg daily. 28% of pts had TEAEs of any grade, with 3% grade 3; no grade ≥4. 2% of pts had serious adverse events (AEs). Incidence rates of AEs were generally low, consistent with the safety profile observed in ARAMIS, and those that occurred in ≥2% of pts were fatigue (5%), diarrhea (5%), asthenia (2%), muscle weakness (2%), anemia (2%), and rash (including rash pruritic, 2%). TEAEs led to permanent study drug discontinuation in 7% of pts. Of 93 pts evaluable for efficacy, the percentage with a PSA response of ≥30%, ≥50%, and ≥90% at any time during follow-up was 81.7%, 77.4% and 52.7%, respectively. Conclusions: At the first interim analysis of the DAROL observational study in the real-world setting, the safety and tolerability of DARO was consistent with the favorable tolerability profile observed in the randomized ARAMIS trial. Clinical trial information: NCT04122976.

Possibilities of Correcting Iron Deficiency Anemia Caused by Chronic Kidney Disease Complicated by Chronic Heart Failure

Abstract: The study evaluated the effectiveness of intravenous administration of iron saccharate (Sufer® preparation) for 2 weeks in 12 patients with iron deficiency anemia due to chronic kidney disease, who were examined and treated in the nephrology department of the Dnepropetrovsk Regional Clinical Hospital named after I.I. Mechnikov. Inclusion of iron (III) hydroxide sucrose complex into therapy led to a significant increase in hemoglobin, ferritin, iron in blood plasma, and contributed to a decrease in creatinine levels (p&lt;0.01). The increase in hemoglobin level began already from the 5th day of treatment. After 2 weeks, the hemoglobin level increased by 13% (p&lt;0.01). When using the drug, there were no significant side effects that required a change in its daily dose or discontinuation of treatment. The therapeutic effect and good tolerance of iron (III) sucrose complex hydroxide allow us to recommend it as the drug of choice for iron deficiency anemia in patients with chronic kidney disease. Keywords: chronic kidney disease, iron deficiency anemia, iron saccharate, Sufer®.

Several nAChRs gene variants are associated with phenotypes of heroin addiction in Chinese Han population

Heroin addiction is a chronic and complex brain disease. Nicotinic acetylcholine receptors (nAChRs) have been shown as major control points in many of the neurological and physiological disorders involved in heroin addiction. In the present study, thirty-three SNPs across nine nAChR genes were selected and probed for their associations with heroin addiction phenotypes in 801 unrelated northwestern Chinese Han patients. We found that rs2565055 in CHRNA2 gene was associated with daily dose of methadone treatment, and rs2672215, rs2672216 and rs2741865 in CHRNA10 gene were associated with the duration of the transition from first use to dependence (DTFUD). Cox multivariable regression analysis revealed that rs3743075, rs6495309 in CHRNA3, rs2304297 in CHRNA6, and rs1948 in CHRNB4 were associated with sexual desire in patients with heroin addiction. These findings were further supported by the identification of a haplotype block spanning CHRNA5, CHRNA3, and CHRNB4 that is correlated with changes in sexual desire after long-term heroin use. Our findings highlight associations between polymorphisms in nAChRs genes and the phenotypes of heroin addiction in the Chinese Han population. We suggest several nAChRs subunits as potential novel targets for the treatment of heroin addiction.

When to Use Amisulpride in Adolescents: A Retrospective Chart Examination of Inpatients.

Despite increasing interest in amisulpride, current knowledge about its use in the pediatric population is scarce. This chart review aimed to investigate the use of amisulpride in a naturalistic adolescent population. Electronic medical records of a tertiary care adolescent inpatient unit were screened between January 2015 and April 2021. Sociodemographic data and all clinical information were collected via data collection forms, and targeted symptoms were obtained from patients' files. Patients with early-onset psychotic disorders (n = 58), bipolar I disorder (n = 29), major depressive disorder (n = 14), and other psychiatric diagnoses (n = 9) were included. Treatment response was defined as a Clinical Global Impression-Improvement of at least much improvement after treatment. Median titration rate of amisulpride was 400 mg/wk, and the maximum administered daily dose ranged between 100 and 1200 mg/d. The maximum daily dose and number of previous antipsychotics were higher in the early-onset psychotic disorder group. Persistent positive symptoms and resistance to previous treatments were leading causes for amisulpride treatment. Other indications were also impulsive/disruptive behaviors, antipsychotic adverse effects, depressive symptoms, somatic complaints, and abnormalities in liver function tests. Finally, patients with lower daily treatment doses and more previous antipsychotic trials are less likely to benefit from the treatment. Persistent psychotic/mood symptoms, impulsive/disruptive behaviors, and abnormalities in liver function tests were reasons for the amisulpride treatment in adolescents. Randomized placebo-controlled trials are needed to evaluate the efficacy and safety of the treatment in adolescents.

Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.

Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.

Outcomes of Ottawa, Canada's Managed Opioid Program (MOP) where supervised injectable hydromorphone was paired with assisted housing.

The Ottawa Inner City Health's Managed Opioid Program is the first, to our knowledge, to pair injectable opioid agonist hydromorphone treatment with assisted housing for people experiencing homelessness with severe opioid use disorder (OUD) and injection drug use. We aimed to describe this program and evaluate retention, health, and social wellbeing outcomes. We retrospectively assessed the first cohort of clients enrolled in the Managed Opioid Program between August 2017-2018. The primary outcome was retention at 12 months. Secondary outcomes included injectable and oral opioid dose titration, non-prescribed opioid use, overdoses, connection with behavioural health services, and social well-being. Descriptive statistics were used to summarize baseline demographics and secondary outcomes. Actuarial survival analysis was used to assess retention among participants. The study sample included 26 participants: median age was 36 years, 14 were female, 22 were White, eight had alcohol use disorders, 25 had stimulant use disorders, and all had a history of concurrent psychiatric illness. Retention at 12 months was 77% (95% CI 62-95). Throughout the first-year participants' opioid treatment doses increased. The median daily dose of injectable hydromorphone was 36mg [17-54mg] and 156mg [108-188mg] at enrollment and one year respectively. The median daily dose of oral opioid treatment was 120-milligram morphine equivalents [83-180 mg morphine equivalents] and 330-milligram morphine equivalents [285-428 mg morphine equivalents] at enrollment and one year respectively. Over half had no overdoses and there were no deaths among participants who remained enrolled. At one year, 45% stopped non-prescribed opioid use, 96% connected to behavioral health services, 73% reconnected with estranged families, and 31% started work or vocational programs. Individuals with severe OUD engaged in injectable hydromorphone treatment and housing showed high retention in care and substantive improvements in patient-centered health and social well-being outcomes.

Effect of Steroid Treatment on the Diagnostic Yield of Baseline PET CT in Aggressive B Cell Lymphoma

Aggressive B cell lymphomas often require prompt steroid treatment prior to baseline 18f-fluorodeoxyglucose positron-emission tomography (PET CT) scan and definitive treatment in order to alleviate symptoms and/or prevent organ damage. Since lymphomas are a steroid sensitive malignancy, there is a concern that steroid prophase might affect PET CT results and diagnostic yield.We conducted a retrospective cohort study to evaluate the effect of steroid treatment prior to baseline PET CT scan on the standardized uptake value (SUV) max and additional PET CT parameters by examining two groups of patients: steroid-naïve and steroid-treated patients. The effect of steroid administration on SUV max was examined across different daily and weekly steroid doses and durations of treatment.Between January of 2017 and May 2020, 187 newly diagnosed patients with aggressive B cell lymphoma who had a pre-treatment PET CT scan were evaluated. 160 patients (85.5%) had Diffuse large B-cell lymphoma (DLBCL)/ High-grade B-cell lymphoma, 13 patients (7%) had primary mediastinal (thymic) large B-cell lymphoma, 9 patients (4.8%) had primary DLBCL of the central nervous system and 5 patients (2.7%) had Burkitt lymphoma.132 patients (70.6%) were included in the steroid-naïve group and 55 patients (29.4%) in the steroid-treated group. In the steroid-treated group, the mean duration of steroid treatment was 10.49 (±9.28) days. Average daily dose of steroid treatment was equivalent to 72.27 (±36) mg of prednisone and the mean cumulative prednisone dose during the week prior to PET CT scan was equivalent to 367.95 (±239.9) mg of prednisone.There was no statistical significant difference between the groups in age, gender or KI67. However, patients in the steroid treated group had a significantly higher stage of disease compared to the steroid-naïve group (mean 3.44 compared to 2.99, respectively, p=0.01). The steroid-treated group also had a trend towards a higher IPI score (mean 2.45 versus 2.08, p=0.08) and a trend towards a higher LDH level (mean 2309.89 U/L, range 250-81374 versus mean 877.65 U/L, range 272-22036, p= 0.07), as depicted in table 1.There was no statistical difference in SUV max between the steroid-naïve and steroid-treated groups (p=0.97). This was consistent across various steroid treatment durations and dosage regimes. Patients in the steroid-treated group had a trend towards a higher tumor burden and a larger tumor volume compared to the steroid-naïve group, however it did not reach statistical significance. Mean tumor volume was 179.04 cm 3 in the steroid naïve group and 337.06 cm 3 in the steroid treated group (p=0.17). Mean tumor burden was 1944.84 in the steroid-naïve group and 3016.94 in the steroid-treated group (p=0.09).There was no difference in additional PET CT parameters including SUV mean, SUV max and SUV mean of liver and mediastinum between the groups as depicted in table 2.In conclusion, in aggressive B cell lymphoma, pre-treatment with steroids prior to initial PET CT scan does not affect SUV max or other PET CT parameters and does not reduce PET CT diagnostic yield. [Display omitted] DisclosuresGurion: Medison: Consultancy; Gilead Sciences: Consultancy; Takeda Pharmaceuticals: Consultancy; JC Health Care: Honoraria; Roche: Honoraria.

P595 Finding predictors of azathioprine-induced pancreatitis in patients with inflammatory bowel disease

Abstract Background Azathioprine (AZA)-induced pancreatitis (AIP) is a common, idiosyncratic side effect, whose incidence, clinical course and risk factors data in inflammatory bowel disease (IBD) patients are scarce. We aimed to establish the incidence, describe the clinical course and identify risk factors for AIP. Methods Retrospective study including all IBD patients on AZA between January 2013 and July 2020. Patients with AIP were considered. Demographic, clinical, biochemical and imaging data were collected. Results AIP occurred in 33 patients (7.5%; 442 patients on AZA): 81.8% had Crohn’s disease, 54.5% were male, and the mean age was 35±13 years. The mean time under AZA till AIP was 25±11 days, with a mean dosage of 88±44mg. Eighteen patients (54.4%) were hospitalized, with a mean hospital stay of 4±2days. All patients had a mild course of disease which resolved with suspension of AZA, and with no complications or need of invasive interventions or complications. Smoking (p=0.02), single daily dose of AZA (p&amp;lt;0.001) and concomitant treatment with budesonide (p=0.001) were risk factors for AIP. In multivariate analysis, concomitant treatment with budesonide (OR: 5.3; p=0.002) and single daily dose of AZA (OR: 4.8; p=0.002) were the only predictors of AIP. Conclusion Although AIP was a relatively common side effect, it presented a mild course in all patients. Smoking, concomitant treatment with budesonide and single daily dose of AZA were risk factors for AIP. This study suggests that smoking, concomitant use of budesonide and single dose regimen of AZA should be avoided in IBD patients treated with AZA.

Clinical and psychological factors associated with interdose opioid withdrawal in chronic pain population

BackgroundThe DSM-5 diagnostic criteria for Prescription Opioid-Use Disorder (POUD) have undergone some significant changes. One of the most controversial changes has been the elimination of the withdrawal symptoms criterion when opioid use is under appropriate medical supervision. For this reason, the goal of this study was to analyze factors associated with opioid withdrawal in patients with chronic non-cancer pain (CNCP). MethodsThis cross-sectional descriptive study involved 404 patients who use prescription opioids for long-term treatment (≥90 days) of CNCP. Measures included sociodemographic and clinical characteristics, POUD, withdrawal symptoms, craving, anxiety-depressive symptoms, and pain intensity and interference. ResultsForty-seven percent (n = 193) of the sample reported moderate-severe withdrawal symptoms, which were associated with lower age, higher daily morphine dose and duration of treatment with opioids, moderate-severe POUD, use of psychotropic drugs, higher anxiety-depressive symptoms, and greater pain intensity and interference (p < .05). Binary logistic regression analysis showed that moderate-severe POUD (OR = 2.82), anxiety (OR = 2.21), depression (OR = 1.81), higher pain interference (OR = 1.05), and longer duration of treatment with opioids were the strongest factors associated with moderate-severe withdrawal symptoms (p < .05). ConclusionPsychological factors seem to play a key role in the severity of withdrawal symptoms. Since greater intensity of these symptoms increases the risk of developing POUD, knowing the factors associated with withdrawal may be useful in developing preventive psychological interventions.

Colchicine efficacy and safety for the treatment of cardiovascular diseases.

The emerging role of colchicine in the treatment of cardiovascular diseases is a strong demand for a comprehensive understanding of its efficacy and safety. This meta-analysis and systematic review aimed to study the efficacy in the reduction of adverse cardiovascular outcomes (CO), and the risk of colchicine-related adverse events (CRAEs). Fourteen thousand and nine eighty three patients from 22 randomized controlled trials (RCTs) were included, 9 in patients with coronary artery disease—CAD, 9 in patients with pericarditis, 4 in patients with atrial fibrillation—AF or heart failure. Colchicine was efficacious in the reduction of adverse CO across different settings: pericardial diseases (reduced risk of recurrent pericarditis, 17.6% vs. 35%, RR 0.50, 95% CI 0.41–0.61), CAD (reduced risk of cardiac death, myocardial infarction, stroke,coronary revascularization or hospitalization, 6.1% vs. 8.5%, RR 0.73, 95% CI 0.64–0.83), AF (reduced risk of arrhythmia recurrence, 14.2% vs. 22.7%, RR 0.62, 95% CI 0.44–0.88). Colchicine was associated with increased risk of gastrointestinal CRAEs (11.2% vs. 8.8%, RR 1.87, 95% CI 1.41–2.47) and drug discontinuation (5.4% vs. 3.7%, RR 1.58, 95% CI 1.25–1.99). In both cases, the risk was proportional to the daily dose or duration of treatment, possibly due to early drug discontinuation or tolerance. Other CRAEs (muscle-related, liver,hematologic,cutaneous, infections) were not increased by colchicine, as long as all-cause death (2.2% vs. 1.9%, RR 1.11, 95% CI 0.79–1.54) or non-cardiovascular death (1.5% vs. 1%, RR 1.43, 95% CI 0.93–2.19). Colchicine is efficacious and safe for the treatment of cardiovascular diseases. The risk of gastrointestinal CRAEs and drug discontinuation is not significant if colchicine is used at lower doses (0.5 mg daily) or for longer periods of time (> 6 months). Supplementary InformationThe online version contains supplementary material available at 10.1007/s11739-021-02654-7.

Using patient-specific bolus for pencil beam scanning proton treatment of periorbital disease.

PurposeA unique mantle cell lymphoma case with bilateral periorbital disease unresponsive to chemotherapy and with dosimetry not conducive to electron therapy was treated with pencil beam scanning (PBS) proton therapy. This patient presented treatment planning challenges due to the thin target, immediately adjacent organs at risk (OAR), and nonconformal orbital surface anatomy. Therefore, we developed a patient‐specific bolus and hypothesized that it would provide superior setup robustness, dose uniformity and dose conformity.Materials/MethodsA blue‐wax patient‐specific bolus was generated from the patient's face contour to conform to his face and eliminate air gaps. A relative stopping power ratio (RSP) of 0.972 was measured for the blue‐wax, and the HUs were overridden accordingly in the treatment planning system (TPS). Orthogonal kV images were used for bony alignment and then to ensure positioning of the bolus through fiducial markers attached to the bolus and their contours in TPS. Daily CBCT was used to confirm the position of the bolus in relation to the patient's surface. Dosimetric characteristics were compared between (a) nonbolus, (b) conventional gel bolus and (c) patient‐specific bolus plans. An in‐house developed workflow for assessment of daily treatment dose based on CBCT images was used to evaluate inter‐fraction dose accumulation.ResultsThe patient was treated to 24 cobalt gray equivalent (CGE) in 2 CGE daily fractions to the bilateral periorbital skin, constraining at least 50% of each lacrimal gland to under 20 Gy. The bolus increased proton beam range by adding 2–3 energy layers of different fields to help achieve better dose uniformity and adequate dose coverage. In contrast to the plan with conventional gel bolus, dose uniformity was significantly improved with patient‐specific bolus. The global maximum dose was reduced by 7% (from 116% to 109%). The max and mean doses were reduced by 6.0% and 7.7%, respectively, for bilateral retinas, and 3.0% and 13.9% for bilateral lacrimal glands. The max dose of the lens was reduced by 2.1%. The rigid shape, along with lightweight, and smooth fit to the patient face was well tolerated and reported as “very comfortable” by the patient. The daily position accuracy of the bolus was within 1 mm based on IGRT marker alignment. The daily dose accumulation indicates that the target coverage and OAR doses were highly consistent with the planning intention.ConclusionOur patient‐specific blue‐wax bolus significantly increased dose uniformity, reduced OAR doses, and maintained consistent setup accuracy compared to conventional bolus. Quality PBS proton treatment for periorbital tumors and similar challenging thin and shallow targets can be achieved using such patient‐specific bolus with robustness on both setup and dosimetry.

Eurycoma longifolia Root Aqueous Extract Augments the Testosterone Level and Spermatogenesis in Adult Male Rats

Introduction The Eurycoma longifolia (EL) root aqueous extract has long been used as an enhancer of male sexual performance. However, data from previous studies in both human males and experimental male animals on the testosterone level in those given the EL extract orally were at best insufficiently conclusive. Materials and Method Sixty-four healthy adult male Sprague Dawley rats were acclimatized, and randomized into six test groups and one control group. All rats where given either the aqueous EL extract or distilled water via metal gavage needle. The first three test groups received the low (50mg/kg bw), medium (100mg/ kg bw) and high (200mg/kg bw) doses respectively of the EL daily for 15 days only. The second three test groups continued receiving the same daily treatment doses for 30 days. The controls were given distilled water only. At the end of each of the study period, blood samples were collected via cardiac puncture and the rats were euthanized. The testicles were obtained, weighed, and processed for histological examination. Results The sera testosterone levels were higher in animals which received the medium and high doses for both treatment duration. Rats which received medium and high oral doses of EL showed an increase of spermatogenesis and mature spermatozoa. Conclusion The optimal enhancing effect on sera testosterone levels and testicular spermatogenesis of EL treatment in adult male rats was observed with the medium dose of 100mg/kg bw given once daily for both 15 and 30 days.

Meta-analysis on safety of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis

To systematically evaluate the adverse drug reaction(ADR) of Tripterygium Glycosides Tablets(TGT) in the treatment of rheumatoid arthritis(RA). Four Chinese databases(CNKI, VIP, WanFang, SinoMed) and three English databases(Cochrane Library, EMbase, PubMed), from the time of database establishing to August 2019, were systematically retrieved to collect literature on the treatment of all types of RA with TG. Screening literature and extracting data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria, with data being extracted and Meta-analyzed. There were 79 studies included, randomized controlled trials(RCT) containing TGT in the treatment group, non-randomized controlled trials(non-RCT), case series, case reports, and RCT containing TGT only in the control group were covered. There were in the control group; 765 ADR of 2 214 patients in 30 RCT(treatment group given TGT), 11 non-RCT and 7 case reports. The results of Meta-analysis of these 48 literatures showed that the overall incidence of ADRs was 0.23(95%CI[0.22,0.24]); ADR mainly occured in the reproductive, gastrointestinal, skin and accessories, blood, hepatobiliary system damage and the incidence of ADR in systems mentioned about respectively were 0.14(95%CI[0.12,0.17]),0.07(95%CI[0.06,0.08]),0.06(95%CI[0.04,0.07]),0.04(95%CI[0.03,0.05]),0.04(95%CI[0.03,0.05]). Further subgroup analysis results showed that the incidence of total ADR, especially the gastrointestinal, reproductive and cutaneous ADR of patients with treatment alone was higher than that in those paients with MTX or MTX+LEF therapy; The incidence of ADR, especially the gastrointestinal ADR, was also positively correlated with daily dose and course of treatment, while the incidence of different systems ADR was also correlated with different drug manufacturers, for instance, damage on the female reproductive system occurs most frequently in Hunan manufacture TGT administration, same as the damage on skin and accessories induced by TGT from Jiangsu manufacture. Above all, The clinical treatment of TGT for RA will cause multi-system ADR, with the highest incidence in the reproductive system, followed by the gastrointestinal system, which is closely related to the way of medication(monotherapy), daily dose, course of medication and drug manufacturer. Therefore, it is recommended that, in the treatment of RA, using TGT in combination, low dose or short-course medication, take measures to protect the reproductive system, stomach and liver, and paying attention to the drug manufacturer as well response of patients during administration should be valued to avoid ADRs to the maximum possibility.

Relationship between metformin use and vitaminB12 status in patients with type2 diabetes in Japan.

Aims/IntroductionMetformin therapy has been associated with vitamin B12 (VB12) deficiency, but information regarding this adverse effect in Asian populations is limited. We have now examined the relationship between metformin use and VB12 status in individuals with type 2 diabetes mellitus in Japan.Materials and MethodsThis cross‐sectional study was carried out with type 2 diabetes mellitus patients treated (Met group, n = 122) or not treated (control group, n = 63) with metformin. The primary end‐point was the difference in the serum concentration of homocysteine, a marker of VB12 activity, between the two groups. The serum concentrations of VB12, blood hemoglobin level and mean corpuscular volume were also compared between the groups. Subset analysis was carried out with individuals aged ≥70 years. The potential correlation between the daily dose or duration of metformin treatment and the other measured parameters was also examined.ResultsThe level of homocysteine, as well as the VB12 level, hemoglobin concentration and mean corpuscular volume, did not differ significantly between the control and treated with metformin groups. The level of homocysteine was positively and that of VB12 negatively correlated with the daily dose of metformin. Among elderly individuals, the hemoglobin level was significantly lower in the treated with metformin group than in the control group, although the mean corpuscular volume was similar in the two groups.ConclusionsThe risk of VB12 deficiency during metformin treatment appears to be low in Japanese type 2 diabetes mellitus patients. However, high doses of metformin might result in a moderate decrease in the circulating VB12 level, as well as in anemia in elderly individuals.

Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma.

Introduction:Nephrilin peptide is a designed inhibitor of Rictor complex (also known as mTORC2), an evolutionarily conserved assembly believed to modulate responses to cellular stress. We previously demonstrated the ability of nephrilin peptide to suppress neuroinflammation, loss of body mass, glycaemic control and kidney function in a rat scald model, as well as sepsis mortality in a mouse model. The present study explores the effect of nephrilin plus iron formulations on clinically relevant outcomes in the rat scald model.Methods:Animals were treated with nephrilin by subcutaneous bolus injection on post-burn days 1–7. Equimolar ferric iron in the formulation improved the positive systemic effects of nephrilin on kidney function, glycaemic control, oxidative stress, early hyperinflammation, late inflammasome activation, hyperangiogenesis and body mass, all variables previously shown to bear upon clinically relevant burn injury outcomes. The sparing effects of nephrilin-iron were demonstrated in both sexes.Discussion:Surprisingly, optimum daily treatment doses were in the range of 2–4 mg/kg, while 8 mg/kg was less effective, suggesting the possibility of marginal pro-oxidant effects from the ‘free’ iron fraction. Thus, although ferric iron in the nephrilin formulation is clearly helpful, care must be exercised to select an optimum treatment dose.Conclusion:Iron increases the efficacy of nephrilin peptide in burns.

Peanut Gastrointestinal Delivery Oral Immunotherapy in Adolescents: Results of the Build–up Phase of a Randomized, Double–Blind, Placebo-Controlled Trial (PITA Study)

To assess the efficacy and safety using a new approach to oral immunotherapy in which high-risk peanut-allergic adolescents ingested sealed capsules of incrementally increasing amounts of peanut protein. In most published studies, peanut is administered in a vehicle food. The authors hypothesized that bypassing the upper digestive tract could improve efficacy because the lower digestive tract, the main anatomic site of oral tolerance, would be targeted, and sealed capsules would circumvent taste aversion.Adolescents with peanut allergy were recruited for the study. Inclusion criteria included having a clinical reaction within 60 minutes after ingestion of peanut and demonstration of sensitization either by skin prick test (wheal >3 mm) or serum immunoglobulin E >12 IU/mL for peanut or >5.8 IU/mL for Ara h2 peanut component. Exclusion criteria included a teenager’s history of severe anaphylaxis requiring ICU support; severe persistent asthma; poorly controlled atopic dermatitis; concomitant severe food allergy to egg, milk, nuts, or sunflower seed; and/or inability to manage a severe allergic reaction. All patients underwent an initial double-blind, placebo-controlled food challenge (DBPCFC) with sealed capsules containing peanut protein; to be included in the study, the adolescent had to have a convincing objective reaction occurring after a cumulate intake of >20 and ≤400 mg of peanut protein.Patients were randomly assigned 2:1 to active treatment (peanut) or placebo (sunflower). Patients ingested a daily treatment dose of peanut protein or placebo via sealed gelatin capsules starting at 2 mg; doses were incrementally increased every 2 weeks up to 400 mg over a 24-week period. A second DBPCFC was performed at the end of the build-up phase. Cumulative ingestion of >400 mg of peanut protein without symptoms was the definition of desensitization.Fifty-one patients were screened, 21 patients were excluded because they tolerated 400 mg of peanut protein at the initial DBPCFC, and 30 patients were enrolled because they had a positive initial DBPCFC. Of these 30 enrolled patients, 21 were allocated to the peanut group and 9 were allocated to the placebo group. Two patients assigned to the peanut group withdrew from the study because of side effects; 1 of these patients experienced a severe adverse event (AE) but had inadvertently ingested twice the investigated amount. An additional 2 patients in the peanut group were unable to increase their intake threshold >400 mg but did increase their threshold level six- and sevenfold, respectively. Unresponsiveness to >400 mg of peanut protein was achieved in 17 of 21 (81%) patients with peanut allergy. Only 1 of 9 patients in the placebo group achieved this level of unresponsiveness. The number of patients experiencing AEs was not different between the 2 groups, but in the treated group, the number of AEs per patient was higher and AEs were more severe. Digestive AEs were more frequent in the treated group (P = .02). Oropharyngeal symptoms were equally frequent in both groups; no dysphagia or signs of eosinophilic esophagitis were noted.The PITA trial demonstrated an effective and safe way to induce peanut desensitization in high-risk adolescents with peanut allergy by using sealed capsules of peanut protein.Parents ask me every day when they can start their child on oral immunotherapy; they are worried if they wait too long that they will miss the window of opportunity for their child to overcome their food allergy. This study is promising because the researchers specifically targeted high-risk adolescents with peanut allergy, demonstrating that even older children and teenagers can successfully be desensitized. Food aversion (taste and smell) is a significant issue for many patients with food allergy; using the sealed capsules made this a moot point. Additional studies are warranted to further explore the safety and efficacy of this approach in larger groups of patients.