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Pharmacokinetics and Safety of Lefamulin After Single Intravenous Dose Administration in Subjects with Impaired Renal Function and those Requiring Hemodialysis

Pharmacotherapy. 2021 Apr 2. doi: 10.1002/phar.2523. Online ahead of print.

ABSTRACT

STUDY OBJECTIVE: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed.

DESIGN: Open-label, Phase-1 pharmacokinetic study SETTING: Research Study Center PATIENTS: Twenty-three matched subjects were included, seven with “Normal” renal function (creatinine clearance >90 mL/min), eight with “Severe” renal impairment (glomerular filtration rate <30 mL/min/1.73 m2), and eight subjects requiring hemodialysis.

MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On-dialysis), as well as, on a non-dialysis day (Off-dialysis). Plasma, urine, and dialysate fluid was collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during On- and Off-dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate.

CONCLUSION: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.

PMID:33797776 | DOI:10.1002/phar.2523

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Digitomotography in children with orofacial dysfunction (OFD, orofacial myofunctional disorders) and childhood apraxia of speech (CAS)

J Oral Rehabil. 2021 Apr 2. doi: 10.1111/joor.13174. Online ahead of print.

ABSTRACT

Backround Orofacial dysfunctions (OFD; orofacial myofunctional disorders) in children and childhood apraxia of speech (CAS) often cause severe problems in articulation, chewing, swallowing and oral posture.

OBJECTIVES: Pathognomonic symptoms could yet not be identified, but central problems in planning, programming, timing and automating orofacial, as well as other fine motor skills, are assumed to be affected.

METHODS: To investigate the nature of motor and coordinative deficits in OFD and CAS, digitomotography was applied. The testing focused on recording frequency, force, rhythm and regularity of the index finger including speeded and metronome tapping tasks. 25 children with OFD (7 girls and 18 boys, age 7.9 ± 2.3) and 5 children with CAS (0 girls and 5 boys, age 7.6 ± 2.3) as well as 31 healthy controls were tested (12 girls and 19 boys, age 9.3 ± 2.2). Statistical significance was accepted at α = 0.05. Anova test, nonparametric Mann-Whitney U test, Kruskal Wallis test and Spearman’s rank correlation coefficient were used.

RESULTS: Cross-sectional data revealed consistent significant differences between children with OFD and healthy controls concerning frequency, force, rhythm and regularity of index finger tapping. Individuals with CAS showed particularly low results. Tapping results correlated with disease burden.

CONCLUSION: These findings support that underlying superordinated sensorimotor deficits exist. This may help phenotyping and influence diagnostical and therapeutical approaches.

PMID:33797781 | DOI:10.1111/joor.13174

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Impact of Higher Oxygen Saturation Levels on Postnatal Weight Gain to Predict Retinopathy of Prematurity

Acta Paediatr. 2021 Apr 2. doi: 10.1111/apa.15868. Online ahead of print.

ABSTRACT

Retinopathy of prematurity (ROP) is the leading cause of vision loss in children. A well-known risk factor for the development of ROP is duration of oxygen supplementation. Other postnatal factors have also been associated with ROP risk, including poor post-natal weight gain. The weight, insulin-like growth factor, neonatal retinopathy of prematurity (WINROP) algorithm predicts severe ROP based on postnatal weight gain and has been validated in several studies,1,2 including a high sensitivity for prediction of severe ROP in our local NICU populations. However, target oxygen saturation levels were subsequently increased in many NICUs based on results from the Neonatal Oxygen Prospective Meta-analysis (NeOProM) Collaboration, which showed statistically higher death and disability rates among preterm infants randomized to a lower oxygen-saturation target range (85 – 89%) versus a higher target range (91 – 95%),3 which may affect the incidence and severity of ROP4 as well as the validity of the WINROP algorithm. In 2018, Lundgren et al reported that the WINROP algorithm was no longer able to predict ROP requiring treatment at their institution after the implementation of higher target oxygen saturation levels, with a sensitivity of only 50%.5 The objective of this review was to evaluate WINROP’s ability to identify infants at risk for severe ROP at our institution after target oxygen saturation levels were increased in 2014.

PMID:33797784 | DOI:10.1111/apa.15868

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Late toxicities burden in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib

Endocrine. 2021 Apr 2. doi: 10.1007/s12020-021-02702-4. Online ahead of print.

ABSTRACT

PURPOSE: Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described.

METHODS: From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test.

RESULTS: Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62).

CONCLUSION: Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.

PMID:33797698 | DOI:10.1007/s12020-021-02702-4

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Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis

CNS Drugs. 2021 Apr 2. doi: 10.1007/s40263-021-00798-w. Online ahead of print.

ABSTRACT

Fingolimod (Gilenya) received regulatory approval from the US FDA in 2010 as the first-in-class sphingosine 1-phosphate (S1P) receptor (S1PR) modulator and was the first oral disease-modifying therapy (DMT) used for the treatment of the relapsing forms of multiple sclerosis (MS). Development of this new class of therapeutic compounds has continued to be a pharmacological goal of high interest in clinical trials for treatment of various autoimmune disorders, including MS. S1P is a physiologic signaling molecule that acts as a ligand for a group of cell surface receptors. S1PRs are expressed on various body tissues and regulate diverse physiological and pathological cellular responses involved in innate and adaptive immune, cardiovascular, and neurological functions. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are well known for their major role in MS pathogenesis and play an important regulatory role in the egress of lymphocytes from lymphoid organs to the lymphatic circulation. Thus, S1PR1-directed pharmacological interventions aim to modulate its role in immune cell trafficking through sequestration of autoreactive lymphocytes in the lymphoid organs to reduce their recirculation and subsequent infiltration into the central nervous system. Indeed, receptor subtype selectivity for S1PR1 is theoretically favored to minimize safety concerns related to interaction with other S1PR subtypes. Improved understanding of fingolimod’s mechanism of action has provided strategies for the development of the more selective second-generation S1PR modulators. This selectivity serves to reduce the most important safety concern regarding cardiac-related side effects, such as bradycardia, which requires prolonged first-dose monitoring. It has led to the generation of smaller molecules with shorter half-lives, improved onset of action with no requirement for phosphorylation for activation, and preserved efficacy. The shorter half-lives of the second-generation agents allow for more rapid reversal of their pharmacological effects following treatment discontinuation. This may be beneficial in addressing further treatment-related complications in case of adverse events, managing serious or opportunistic infections such as progressive multifocal leukoencephalopathy, and eliminating the drug in pregnancies. In March 2019, a breakthrough in MS treatment was achieved with the FDA approval for the second S1PR modulator, siponimod (Mayzent), for both active secondary progressive MS and relapsing-remitting MS. This was the first oral DMT specifically approved for active forms of secondary progressive MS. Furthermore, ozanimod received FDA approval in March 2020 for treatment of relapsing forms of MS, followed by subsequent approvals from Health Canada and the European Commission. Other second-generation selective S1PR modulators that have been tested for MS, with statistically significant data from phase II and phase III clinical studies, include ponesimod (ACT-128800), ceralifimod (ONO-4641), and amiselimod (MT-1303). This review covers the available data about the mechanisms of action, pharmacodynamics and kinetics, efficacy, safety, and tolerability of the various S1PR modulators for patients with relapsing-remitting, secondary progressive, and, for fingolimod, primary progressive MS.

PMID:33797705 | DOI:10.1007/s40263-021-00798-w

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The efficacy of manipulation as a treatment for myofascial pelvic pain

Int Urol Nephrol. 2021 Apr 2. doi: 10.1007/s11255-021-02840-8. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the effect of myofascial manipulation by observing the changes in pelvic floor myofascial scores and electromyography (EMG) data before and after treatment.

METHODS: A total of 106 patients with myofascial pelvic pain (MFPP) were enrolled in a treatment group, and 50 healthy women were enrolled in a control group. The changes in the pelvic floor EMG data in the two groups were monitored by using Myo Trac before and after treatment. Pelvic trigger points and their distribution in the MFPP patients were examined using a finger pressure test. The visual analogue scale was used to assess the severity of pain in both groups. After one course of manipulation (twice per week for a total of 10 times), the effectiveness of the manipulation was analyzed by comparing the changes in pain scores before and after treatment.

RESULTS: The main symptoms of MFPP in the study sample consisted of lower abdominal pain, lumbosacral pain, or mixed pain, which together accounted for 67% of all symptoms. Patients often had multiple trigger points, covering 47.17% of the body. The differences between the treatment group and control group in the changes in pelvic floor muscle strength, number of pain points, pain scores, resting EMG of pelvic floor muscles, and relaxation time after muscle contraction were all statistically significant (P < 0.05). The differences between the pre-treatment and post-treatment groups in the changes in pelvic floor muscle strength, number of pain points, pain scores, resting EMG of pelvic floor muscles, and relaxation time after muscle contraction were all statistically significant (P < 0.05) CONCLUSION: Manipulation is an effective treatment for MFPP and is worthy of further clinical promotion.

PMID:33797710 | DOI:10.1007/s11255-021-02840-8

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Efficacy and safety of a novel combined 1060-nm and 635-nm laser device for non-invasive reduction of abdominal and submental fat

Lasers Med Sci. 2021 Apr 2. doi: 10.1007/s10103-021-03288-z. Online ahead of print.

ABSTRACT

The aim of this study was to evaluate the safety and efficacy of combined 1060-nm diode laser and 635-nm low-level laser therapy (LLLT) device for non-invasive reduction of the abdominal and submental fat. Forty-two healthy subjects received single laser treatment on both the abdomen and submental area. Ultrasound images measuring the thickness of abdominal and submental fat were taken at baseline, follow-up at 4, 8, and 12 weeks after treatment. Waist circumference and body weight were also measured at all visits. Adverse events were recorded at all visits. Subjects completed a satisfaction questionnaire at the end of the trial. Twelve weeks after a single treatment with the investigational device, ultrasound images showed statistically significant (P < 0.0001) reductions in abdominal and submental fat by 18.62 and 26.4%, respectively. In addition, significant (P < 0.0001) reduction in waist circumference was observed. Ninety-six percent of subjects rated that they were satisfied. Noted side effects were transient mild to moderate tenderness which subsided within 1 to 3 weeks. No serious treatment-related adverse events were reported. The dual wavelength device combining 1060-nm diode laser with 635-nm LLLT was safe and effective for non-invasive reduction of both abdominal and submental fat.

PMID:33797649 | DOI:10.1007/s10103-021-03288-z

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Reproduction-related cognitive processing and distress among young adult women: the role of personal breast cancer history

Cogn Process. 2021 Apr 2. doi: 10.1007/s10339-021-01026-5. Online ahead of print.

ABSTRACT

Breast cancer diagnosis can threaten fertility and biological motherhood in women of reproductive age due to the gonadotoxic effects of treatments. Much evidence documents these women fertility-related concerns and distress, but no study has attempted to understand how implicit cognitive processes can contribute to this maladjustment. In this research, we explored whether reproduction-related stimuli interfere with cognition among cancer survivors with infertility risk using an emotional Stroop task. Furthermore, we investigated the relationship between reproduction-related cognitive processing and psychological morbidity. Young cancer survivors aged 18-40 years who received anticancer treatments and an age-matched non-cancer control group without known fertility problems were compared. Color-naming times and error rates were assessed. Participants in both groups were slower naming the color of reproduction-related words in comparison to unrelated negative valence words. Although in the same direction, this difference did not reach statistical significance for positive and neutral unrelated word lists. Further analysis suggested that biased attention toward reproduction-related information was associated with higher depression levels in young women with personal breast cancer history, but not in healthy women. These findings suggest that biased processing of reproduction-related cues might be a vulnerability factor after a breast cancer diagnosis. Additionally, this study puts in evidence the potential usefulness of using experimental tasks to investigate attentional bias in a context where fertility is at risk.

PMID:33797684 | DOI:10.1007/s10339-021-01026-5

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Factors predicting missing instruments in three cancer randomized clinical trials

Qual Life Res. 2021 Apr 2. doi: 10.1007/s11136-021-02818-0. Online ahead of print.

ABSTRACT

PURPOSE: Missing patient-reported outcome (PRO) data can seriously threaten the validity of randomized clinical trials (RCTs). Identifying which factors predict missing instruments may help researchers develop strategies to prevent it from happening. This study examined the association of factors with time to the first missing instrument after randomization in three cooperative group RCTs.

METHODS: We performed descriptive analyses and Cox proportional hazards regressions for three RCTs selected from the Canadian Cancer Trials Group: MA17 (breast cancer), PR7 (prostate cancer), and LY12 (non-Hodgkin’s lymphoma). The outcome was the time from randomization to the first missing instrument. Variables for 15 factors were used as covariates based on availability and previously-reported putative associations with missing PRO data.

RESULTS: Nine percent of 1352 subjects on MA17, 37% of 923 subjects on PR7, and 59% of 477 subjects on LY12 had a missing instrument. Twenty-five percent of subjects on MA17 had first missing instrument within 4.6 years. The median time to first missing instrument was: not observed for MA17, 7.3 years for PR7, 0.12 years for LY12. Cox regression revealed statistically significant independent associations with outcome for only five factors: baseline age (PR7) and level of well-being (LY12), and centre level of activity (LY12), presence of post-graduate residency training program (MA17, PR7), and centre geographic location (PR7, LY12).

CONCLUSION: Many factors reported to have association with missing instruments do not seem to predict time to the first missing instrument after randomization in RCTs. Context is important in understanding the few that may.

PMID:33797688 | DOI:10.1007/s11136-021-02818-0

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A thermoluminescent method for the evaluation of the 131I effective half-life in the thyroid when treating Graves’ disease

Radiat Environ Biophys. 2021 Apr 2. doi: 10.1007/s00411-021-00907-9. Online ahead of print.

ABSTRACT

When planning treatment for Graves’ disease with 131I, the effective half-life (Teff) should be estimated individually as it depends on biological characteristics such as iodine uptake and excretion, which differ from an individual to another (Berg et al. 1996). All the methods to quantify Teff described in the literature are quite complex and are difficult to be used in clinical routine. With the aim of optimizing this process, a simplified method is proposed here to evaluate Teff of 131I during treatment of Graves’ disease. The present study suggests improving the method of determining Teff based on thermoluminescence dosimetry. This involves implementing a new method and includes reduction of TLD (Thermoluminescent Dosimeter) measurements. The proposed method was validated on patients with Graves’ disease. The radiation dose delivered to the patients was determined using the MIRD (Medical Internal Radiation Dosimetry) formalism. The relative difference between Teff obtained based on seven measurement intervals at [0-24 h, 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h] and based on three measurement intervals at [0-24 h, 72-96 h, 144-168 h] and [0-24 h, 120-144 h, 144-168 h] was 1.9% and 3.81%, respectively. Comparison of doses obtained based on a general Teff and on a personalized Teff gave a statistically significant difference with a correlation coefficient R2of 0.44. The Teff obtained from just three measurements was found to be sufficiently accurate and easily applicable. The results obtained demonstrate the need to determine and use personalized Teff values instead of using a fixed value of 7 days.

PMID:33797646 | DOI:10.1007/s00411-021-00907-9