Gradual Dose Research Articles

Glucocorticoids in myocarditis therapy after COVID-19

Abstract The aim of the study - to evaluate the efficacy of glucocorticoids (GC) in patients with acute myocarditis (AM) after COVID-19 infection. Material and methods We included 60 pts with severe AM and heart failure (HF) with reduced (<40%) left ventricular (LV) ejection fraction (EF) who had COVID-19 infection 1–2 months before the enrollment. According to the results of cardiac magnetic resonance (CMR) included pts had ≥2 Lake Louise criteria for myocarditis. All pts on the background of HF therapy (β-blockers, ACE-inhibitors, MRA antagonists, diuretics) were prescribed GC: 0.25 mg/kg per day methylprednisolone for 3 months, followed by a gradual dose reduction of 1–2 mg per week until complete discontinuation after 6 months. Evaluation before the start of GC therapy and after 6 months included CMR, 2D- and speckle-tracking echocardiography. Results After 6 months according to the results of CMR the number of LV segments with inflammatory lesions decreased to (3,58±0,42) from (6,32±0,77) segments in average (p=0,001). This was followed by improvement of LV systolic function: increase of LV EF in average to (43,5±2,6) from (32,2±2,4) % (p=0,003), longitudinal global systolic strain (LGSS) absolute value to (11,3±1,1) from (7,9±0,5) % (p=0,012) and circumferential global systolic strain (CGSS) to (12,1±1,0) from (8,9±0,6) % (p=0,023). Also we observed LV volume reduction: decrease of LV end-diastolic (from 118,9±8,6 to 95,3±7,2 ml/m2, p=0,033) and LV end-systolic (from 80,1±5,1 to 59,1±4,4 ml/m2, p=0,027) volume indexes. Wherein in 24 of 60 pts (41,6%) on the background of significant decrease in the number of LV segments with inflammatory lesions (to 1,34±0,21 from 6,12±0,73 segments, p=0,0001) after 6 months we observed the recovery of LV EF ≥50%, followed by an improvement of LGSS and CGSS on 42,1 and 39,4% respectively (p=0,001). According to multivariate regression analysis, predictors of LV EF recovery (≥50%) after 6 months of GC treatment were established: presence of inflammatory lesions in ≤5,0 LV segments, values of LGSS and CGSS ≥9.0% and ≥9.5% respectively before the start of GC. Conclusions The use of GC in pts with severe AM after COVID-19 was followed by the decrease of LV segments number affected by inflammation, improvement of LV systolic function and reduction of LV volume indexes. In 41,6% of pts GC therapy was associated with LV EF recovery after 6 months and predictors of its effectiveness were found: presence of inflammatory lesions in ≤5,0 LV segments, values of LGSS and CGSS ≥9.0% and ≥9.5% respectively before the start of GC. Funding Acknowledgement Type of funding sources: None.

Addressing Medications Definitively By Avoiding “Medication Management”

Addressing Medications Definitively By Avoiding “Medication Management”

Changes in fatty acid profile of Holothuria forskali muscle following acute mercury exposure

The present study aimed to document the interaction between mercury (Hg), as a model chemical stressor to an aquatic organism, and Fatty acid (FA) profile in the longitudinal muscle of the sea cucumber Holothuria forskali. To assess the sensitivity of this species to the toxic effects of Hg, young H. forskali were exposed to gradual doses of Hg (40, 80 and160 µg·L-1) for 96 h. The results showed that following Hg exposure, the FA profile of H. forskali corresponded to an increase in the level of saturated fatty acids, and the decrease in the level of monounsaturated and polyunsaturated fatty acids. The most prominent changes in the FA composition were recorded at the lowest dose with noticeable decreases in linoleic, arachidonic and eicosapentaenoic acid levels and an increase of docosahexaenoic acid. The occurrence of a state of oxidative stress induced by Hg contamination was evidenced by the enhanced levels of malondialdehyde, hydrogen peroxide and lipid hydroperoxide. Overall, the low concentration of mercury exerted the most obvious effects on lipid metabolism, suggesting that changes in fatty acid composition may be act as an early biomarker to assess mercury toxicity in this ecologically and economically important species.

Idiopathic hypertrophic cranial pachymeningitis successfully treated with dexamethasone – a case report

Introduction : Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare pathological entity which is diagnosed after the exclusion of secondary reasons. Most frequently, IHCP is related to rheumatological diseases such as rheumatic arthritis, sarcoidosis, anti-neutrophil cytoplasmic antibody-associated vasculitis, and IgG4-related disorders. The inflammatory process concerns dura mater and manifests with symptoms of cranial nerve damage or compression. Case description : A 59-year-old Caucasian man presented with transitional episodes of tinnitus and an unspecific headache. Imaging studies (magnetic resonance imaging – MRI) demonstrated a thickened dura mater. Lymphoma was suspected due to an abnormal flow cytometric analysis of a cerebrospinal fluid (CSF) sample. Hematological diagnostics including bone marrow biopsy, whole body computed tomography (CT) and digestion tract examination were performed leading to the exclusion of hematological malignancy. The patient underwent surgery, and a specimen from the lesion was obtained. On this basis, intracranial idiopathic hypertrophic pachymeningitis was diagnosed. First line treatment strategy was introduced with corticosteroids with a gradual dose reduction. After the 48-month follow-up, we observed an alleviation of symptoms with a gradual significant decrease in the thickening of dura matter with almost complete resolution. Conclusions : Idiopathic hypertrophic pachymeningitis should be considered in the differential diagnosis of a thickened dura mater. Administration of steroids appears reasonable as a first line treatment of IHCP.

COVID-19-асоційований міокардит: власний досвід патогенетичного лікування

The aim – to evaluate the effectiveness of glucocorticoid therapy in patients with myocarditis with reduced left ventricular ejection fraction that developed after COVID-19 infection. Materials and methods. The results of glucocorticoid therapy in 32 patients aged (35.2±2.3) years with acute myocarditis after COVID-19 infection and left ventricular ejection fraction <40 % are presented. All patients were prescribed a 3-month course of methylprednisolone at a daily dose of 0.25 mg/kg, followed by a gradual dose reduction of 1 mg per week until complete withdrawal 6 months after the start of treatment. Results and discussion. The analysis of the results of the examinations was performed in the 1st month from the onset of myocarditis to the appointment of glucocorticoids and after 6 months of observation. Six months later, the end-diastolic volume index decreased by 18.5 %, the left ventricular ejection fraction increased by 23.8 %, and the longitudinal global systolic straine increased by 39.8 %. On cardiac MRI, the number of left ventricular segments affected by inflammatory changes decreased from 6.22±0.77 to 2.89±0.45 segments, and the number of segments with fibrotic changes did not change significantly. After 6 months of treatment, there was a significant decrease in the concentrations of proinflammatory cytokines and cardiospecific antibodies. Conclusions. The use of a 6-month course of glucocorticoid therapy in patients with myocarditis that developed after COVID-19 infection improved the contractility of the left ventricle against the background of a significant reduction in inflammatory lesions of the left ventricle and reduced concentrations of proinflammatory cytokines and cardiospecific antibodies.

Acute Ischemic Priapism: An AUA/SMSNA Guideline.

Priapism is a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation and results in a prolonged and uncontrolled erection. Given its time-dependent and progressive nature, priapism is a situation that both urologists and emergency medicine practitioners must be familiar with and comfortable managing. Acute ischemic priapism, characterized by little or no cavernous blood flow and abnormal cavernous blood gases (ie, hypoxic, hypercarbic, acidotic) represents a medical emergency and may lead to cavernosal fibrosis and subsequent erectile dysfunction. A comprehensive search of the literature was performed by Emergency Care Research Institute for articles published between January 1, 1960 and May 1, 2020. Searches identified 2948 potentially relevant articles, and 2516 of these were excluded at the title or abstract level for not meeting inclusion criteria for any key question. Full texts for the remaining 432 articles were reviewed, and ultimately 137 unique articles were included in the report. This Guideline was developed to inform clinicians on the proper diagnosis and surgical and non-surgical treatment of patients with acute ischemic priapism. This Guideline addresses the role of imaging, adjunctive laboratory testing, early involvement of urologists when presenting to the emergency room, discussion of conservative therapies, enhanced data for patient counseling on risks of erectile dysfunction and surgical complications, specific recommendations on intracavernosal phenylephrine with or without irrigation, the inclusion of novel surgical techniques (eg, tunneling), and early penile prosthesis placement. All patients with priapism should be evaluated emergently to identify the sub-type of priapism (acute ischemic versus non-ischemic) and those with an acute ischemic event should be provided early intervention. Treatment of the acute ischemic patient must be based on patient objectives, available resources, and clinician experience. As such, a single pathway for managing the condition is oversimplified and no longer appropriate. Using a diversified approach, some men may be treated with intracavernosal injections of phenylephrine alone, others with aspiration/irrigation or distal shunting, and some may undergo non-emergent placement of a penile prosthesis.

Modulation of growth, photosynthetic efficiency, leaf biochemistry, cell viability and yield of Indian mustard by the application of trehalose

Trehalose (Tre) is a nonreducing glucose disaccharide. It modulates diverse physio-biochemical processes in crop plants. A randomized pot experiment was designed to investigate whether the leaf-applied Tre could improve the growth, photosynthesis, leaf biochemistry, cell viability and yield of Indian mustard. Uniform surface sterilized seeds of mustard were sown in earthen pots. The plants were sprayed with four graded doses of Tre, viz. 0, 10, 20 or 30 mM using a hand sprayer twice at 50 and 70 days after sowing (DAS). The crop performance was assessed in terms of morpho-physiological, biochemical, microscopical and histochemical parameters at 80 DAS and yield attributes at harvest (120 DAS). The spray concentration of 10 mM Tre proved efficacious for all parameters studied, i.e. growth traits, relative water content, gas exchange parameters, enzyme activities, leaf glycine betaine and proline content, stomatal size and width, carbohydrate and mineral content, root cell viability and yield parameters. Moreover, foliar feeding of 10 mM Tre also reduced the generation of superoxide anion and hydrogen peroxide in mustard leaves, which were further confirmed with the fluorescence microscopy and histochemical localization examinations. The spray concentrations higher than 10 mM Tre were either equally or less effective. The foliar spray of 10 mM Tre increased shoot dry mass by 15.81%, chlorophyll content by 17.64%, photosynthetic rate by 17.04%, carbohydrate content by 22.40% and seed yield by 21.85% over the water-sprayed control. The data revealed the overall superiority of 10 mM Tre for improving the performance of Indian mustard.

Factors influencing engagement and utilisation of opium tincture-assisted treatment for opioid use disorder: A qualitative study in Tehran, Iran.

In response to a high burden of opioid use disorder (OUD), Iran established a network of opioid agonist treatment (OAT) centres beginning in 2002. To increase treatment diversity, particularly for patients who use opium as their drug of choice, opium tincture (OT)-assisted treatment was introduced to the network. This study aimed to explore factors influencing OT-assisted treatment selection for OUD in Tehran, Iran. We conducted 54 in-depth interviews with patients with OUD (n= 33), family members of patients (n= 9) and drug treatment providers (n= 12). Participants were recruited from 12 drug treatment centres across Tehran, between September and November 2019. All interviews were audio-recorded, transcribed and coded in OpenCode 4.02 software and analysed using thematic analysis. Study participants more commonly reported individual-level factors as facilitators (e.g. to reduce harms associated with illicit opioid use, achieve recovery through a gradual dose reduction regimen combined with Congress 60 recovery program) and structural level factors (e.g. low adoption by OAT system and lack of familiarity of treatment providers) as barriers for utilisation of OT-assisted treatment regimens. OT was perceived to produce lower levels of physiological dependence than methadone, but the requirement for twice supervised dosing was restrictive. Low familial and community acceptance were also seen as barriers to access. This research identified a range of perceived benefits for OT-assisted treatment ranging from harm reduction to an intermediate step to achieve recovery. However, several structural-, individual-, familial- and community-level barriers impede its availability and acceptability.

A brief review on efficacy and safety of brivaracetam in the management of partial onset epilepsy

Brivaracetam, a propyl analog of levetiracetam is a new Antiepileptic Drug (AED), and the first selective ligand that binds to synaptic vesicle protein 2A (SV2A). Brivaracetam has 15–30 times greater affinity for SV2A and faster Blood-Brain Barrier permeability. This review examines the use of brivaracetam as add-on (50–200 mg/day) therapy for partial onset epilepsy with particular emphasis on its early onset of action, long-term efficacy, and safety profile. When initiating treatment with brivaracetam, gradual dose escalation is not required, and right therapeutic dose can be administered on first day itself. In pooled analysis of three phase-3 studies, early ≥50% responder rate (on day 1) was found across all brivaracetam treatment groups i.e. 15.5%, 18.1%, 19.4%, for 50, 100, 200 mg/day, respectively. In 11-year, follow-up trial, brivaracetam showed 50% responder rate as 55.6% which increased by exposure through 3 years and remained consistent through 9 years. Seizure freedom rates were 30.3% at 6 months and 20.3% at 12 months. Another long-term follow-up study involving 2,051 patients also reported increased ≥50% seizure reduction with brivaracetam in partial onset seizure from baseline over 5 years, 71.0% (at 58–60 months). In addition, brivaracetam demonstrated a favorable safety profile with minimal drug-drug interactions, lesser incidence of behavioral and psychiatric adverse effects. Brivaracetam also demonstrates improvement in cognitive profile and executive functions with reduced anxiety and improvement in quality of life in patient with epilepsy.

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease constitutes the most prevalent hereditary kidney disease, associated with high rates of morbidity leading eventually to end-stage renal disease. Tolvaptan is a selective vasopressin antagonist and has emerged as a promising therapeutic option for patients with autosomal dominant polycystic kidney disease. The present review summarized current evidence regarding the safety profile of tolvaptan in patients with the disease. Consistent with its pharmacological action, aquaretic adverse events represent the most common side effects of tolvaptan, consisting of polyuria, pollakiuria and polydipsia. Gradual dose titration based on urinary osmolality, as well as dietary interventions aiming to reduce solute excretion, have been proposed as potential strategies to mitigate polyuria. In addition, tolvaptan administration may be complicated by liver injury, characterized by alanine aminotransferase and bilirubin elevations. Hepatotoxicity has been suggested to be triggered by impaired biliary clearance, activation of innate immunity and increased oxidative stress. Frequent monitoring of liver function tests has been shown to be effective in preventing Hy’s Law and liver failure cases. Uric acid elevation due to reduced renal excretion may lead to hyperuricemia and gout, although no drug discontinuations have been linked to these events. Future studies should confirm the safety profile of tolvaptan in large-scale real-world studies, clarify the pathogenetic pathways leading to hepatotoxicity and define its role in special populations, especially pediatric patients.

Targeting innate immunity with BXCL701 in combination with pembrolizumab in patients with advanced solid cancers: Phase 2 basket study.

2558 Background: BXCL701 is an oral competitive inhibitor of dipeptidyl peptidases (DPPs), primarily DPP8/9, which triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß. BXCL701 therefore, can induce an innate immune reaction and tumor inflammation, bridging between innate and adaptive immunity, potentially leading to synergistic anticancer activity when combined with PD-1 antibody pembrolizumab. Methods: This is a phase 2, open-label, single-center study (NCT04171219) of oral BXCL701 0.3 mg BID on days 1-14 and intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle with a safety lead-in to evaluate RECIST/iRECIST response rate in patients with advanced solid cancers. After confirming safety and dose limiting toxicities (DLT) in the first 6 patients, additional patients are being enrolled to an immune checkpoint inhibitors (iCPI) naïve cohort and iCPI pretreated cohort. Each cohort is planned to enroll 9 patients in the first stage, and if a partial (PR) or complete response (CR) is observed the cohort is expanded to a total of 17 patients in the second stage. The treatment is considered promising if at least 3 PRs or CRs are observed in a cohort of 17 patients. Results: As of February 11, 2021, 16 patients were treated; 5 patients (prostate cancer, endometrial cancer, liposarcoma, basal cell carcinoma, squamous cell carcinoma of unknown primary) were enrolled in the iCPI naïve cohort and 11 patients (leiomyosarcoma [2], squamous cell carcinoma of unknown primary, triple negative breast cancer, uveal melanoma, melanoma, uterine myxoid sarcoma, pleomorphic sarcoma, colorectal cancer, anaplastic astrocytoma, prostate cancer) were enrolled to iCPI pretreated cohort. Among all 16 patients, there was 1 episode of grade 4 hypotension (recovered) and 1 episode of grade 5 hypotension attributed to BXCL701, which resulted in implementation of risk-mitigation strategies such as gradual dose escalation and blood pressure monitoring. In the CPI naïve cohort, of 4 patients with available imaging, 1 had a PR (microsatellite stable endometrial cancer [-62%]) and 1 durable stable disease (SD -10%, basal cell carcinoma on therapy for 6+ months). In the CPI pretreated cohort, of 9 patients with available imaging, 1 had a PR (-31%, uveal melanoma) and 3 durable SD (-22%, pleomorphic sarcoma on therapy for 8+ months; +4%, squamous cell carcinoma of unknown primary on therapy for 6 months; +5%, uterine myxoid sarcoma on therapy for 6 months). Conclusions: BXCL701 in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers. Prespecified efficacy endpoints were met in the first stage and both cohorts will proceed to second-stage of the study Clinical trial information: NCT04171219.

Efficacy and Safety of TLANDO, A Novel Oral Easy to Prescribe and Use TRT Option

Most widely used testosterone replacement therapy (TRT) products can be inconvenient and cumbersome topical and invasive injectable requiring dose adjustments to attain efficacy. In a pivotal study, a recently approved oral TRT only 26% of patients did not require any dose adjustment. Typically, patients start on a sub-therapeutic dose with gradual dose increases to attain efficacy resulting in additional visit(s) to clinic and pharmacy. Physician research data (N=402) suggested it typically takes 3-6 months of titrations to reach an efficacious dose for majority of patients, a significant barrier in effecting a switch without a period of “efficacy gap”. The requirement of additional visit(s) presents significant challenges for new and current patients desiring to start and to switch to a convenient TRT option, especially in the current COVID-19 pandemic. Recent reports suggest increase of disease severity/mortality in men with low testosterone is possibly due to underlying co-morbidities commonly associated with male hypogonadism. There remains a need for an effective, safe, and easy to use and prescribe product that does not require dose titration. TLANDO is a “triglyceride-free” oral single strength TRT with single dose designed to lymphatically deliver effective and safe levels of testosterone regardless of meal fat content. Moreover, dose titration is prone to some inherent titration decision errors and requires understanding of often complex titration rules. The objective is to assess whether TLANDO, an oral TRT without requiring dose titration, safely restores effective testosterone (T) levels in hypogonadal men. An open-label, single-arm, multicenter study (NCT03242590) was performed with TLANDO in hypogonadal males (N=95). Subjects received orally 225 mg twice a day testosterone undecanoate (TU) for 24 days without dose adjustment. Efficacy was evaluated by % of subjects who achieved daily T Cavg within the eugonadal range. Using 450mg daily dose without dose adjustment, 80% of subjects (95% CI of 72% to 88%) achieved a T Cavg in the normal range and safely restored with mean T Cavg of 476±184 ng/dL post steady state. T restoration was comparable to other non-oral TRT products. TLANDO was well tolerated with no deaths, no drug-related severe AEs, and no hepatic AEs. In conclusion, effective T restoration using TLANDO, an easy to use and prescribe oral TRT option, was confirmed. Minimal AEs were reported with no hepatic AEs. Upon approval, TLANDO will be the first convenient TRT option without requiring dose adjustments; therefore, enabling selection of an efficacious dose from the start of therapy. TLANDO is well suited for new or existing TRT patients desiring a convenient oral option.

Design of the ForesiGHt Trial: A Multicenter, Randomized, Placebo- and Active-Controlled Trial to Compare Once-Weekly TransCon hGH (lonapegsomatropin) to Placebo and Daily Somatropin in Adults With Growth Hormone Deficiency (GHD)

BackgroundAdult GHD results from insufficient growth hormone (GH) secretion from the anterior pituitary gland and may represent either a continuation of childhood-onset GHD or GHD acquired during adulthood. Clinically, adult GHD is associated with central adiposity, decreased lean muscle mass, increased fat mass, decreased bone mineral density, and reduced quality of life. Current standard of care consists of GH replacement via daily injections.Lonapegsomatropin is a long-acting prodrug of somatropin (hGH), designed to deliver unmodified hGH with a weekly exposure profile. Lonapegsomatropin consists of somatropin that is transiently bound to a carrier via a proprietary TransCon Linker. The carrier extends the duration of somatropin in the circulation through a shielding effect that minimizes renal excretion and receptor-mediated clearance of the prodrug. At physiologic conditions, lonapegsomatropin releases fully active, unmodified somatropin via autocleavage of the linker in a controlled manner.The safety and efficacy of lonapegsomatropin have previously been evaluated in two phase 3 trials and one long-term extension trial in pediatric GHD. Changes in body composition are an objective and sensitive endpoint that reflects biologic activity of GH and clinical efficacy of GH replacement. Methods: The primary objective of the foresiGHt trial is to evaluate the efficacy of once-weekly lonapegsomatropin compared to placebo at 38 weeks in adults with GHD. The trial will be conducted at approximately 120 sites in North America, Europe, Asia, and Oceania. Approximately 240 subjects will be randomized 1:1:1 to once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin (Norditropin®). Subjects will be treatment-naïve or without GH therapy for at least 12 months. Subjects with well-controlled non-insulin dependent diabetes mellitus (HbA1c ≤ 7.5%) will be eligible. Following screening, the 38-week treatment period will consist of a 12-week gradual dose titration period and 26 weeks of fixed dose maintenance. Fixed dosing will be used to ensure maximal comparability across the treatment arms in the trial. Three dosing groups per arm will be established to allow for differences in age and oral estrogen intake in women.The primary endpoint is change from baseline in trunk percent fat at week 38, as measured by dual energy X-ray absorptiometry (DXA). Secondary efficacy endpoints are change from baseline in trunk fat mass and change in total body lean mass at week 38. Exploratory efficacy endpoints include total body fat mass, trunk lean mass, visceral adipose tissue, and patient-reported outcomes. Conclusion: The ongoing global phase 3 foresiGHt trial is designed to assess the efficacy, safety, and tolerability of lonapegsomatropin by weekly administration, compared to weekly placebo and daily hGH replacement therapy in adults with GHD.

A Study on the Neurotoxicity of Flunitrazepam (Rohypnol) Administration on the Cerebral Cortex of Adult Wistar Rats

Flunitrazepam (Rohypnol) is a benzodiazepine drug medically proscribed in United States whereas it's legally prescribed in over sixty nations where the drug is administered as pre-anesthetic drug and in the treatment of insomnia but not without the loss of cerebral cortex functions which inspired this investigation to establish its neurotoxicity on the cerebral cortex of adult wistar rat. Sixteen adult female wistar rats were randomly divided into four groups with four rats in each group (A, B, C and D). Group A, the control group received distilled water. Groups B, C and D received 1mg/kg, 2mg/kg and 3mg/kg of Flunitrazepam (Rohypnol) respectively. The animals were sacrificed after three weeks of administration and the cerebral cortexes were harvested and fixed in 10% formal saline for histological processing and studies. The anthropometric investigation presented an insignificant increase in the relative body weight of the test groups when compared to the control group and also presented a significant increase in the relative organ weight in the entire test groups when compared to the control group. The cerebral cortex of experimental animals showed; severe lymphocytic infiltration, focal areas of liquefactive necrosis, intracerebral hemorrhage, vacuolation and various degrees of damages to the tissue layers and neuronal cells of the cerebral cortex. This scientific investigation indicates that consumption of Flunitrazepam (Rohypnol) across various graded doses causes changes in the cerebral cortex histoarchitecture which explains the rationale behind the loss of cerebral cortex function in drug addicts and patients placed on prolonged Flunitrazepam (Rohypnol) therapy.

Case Report: Maintenance of Desensitization to Nebulized Colomycin Over 10 Years.

Drug desensitization can be achieved successfully by gradual drug dose increases in different protocols. Most protocols are designed to obtain temporal tolerance. The data on long-term maintenance of drug tolerance is scarce. Based on an IgE-mediated colomycin allergy we describe the maintenance of drug tolerance to nebulized drug for the period of 10 years in a 15-year-old cystic fibrosis patient, proceeded by successful rush intravenous desensitization protocol. The mechanism of drug tolerance is largely speculative; however, long-term maintenance of it seems achievable by continuous local drug application.

THE DIFFERENCE OF HISTOPATHOLOGICAL IMAGE OF THE WISTAR RAT’S KIDNEY ADMINISTERED WITH GRADUAL DOSAGE OF PYRETHROID

Background: Pyrethroid pesticide poisoning cases in developed and developing countries have a high incidence every year. One of the active substances in pyrethroid widely used is cypermethrin. The effects of cypermethrin intoxication on the kidneys, especially in humans, are little to be studied. This study aims to determine the difference in the histopathological image of the Wistar rat’s kidney.Method: The experimental research of the post-test only control group design involved 24 male Wistar rats divided into 4 groups randomly, the control (not given cypermethrin), treatments of 125 mg/kgBW, 250 mg/kgBW, and 500 mg/kgBW. Cypermethrin are given orally for 14 days. After the rats were terminated, the kidney were processed to be paraffin-embedded tissues and stained with HE. Tubular injuries were examined using 400x magnification of light microscope and focused on closure of tubular lumen as well as proteinaceous cast inside the lumens.Results: The results of this study showed that the means of histopathological damage to the kidneys increased from control group to 500 mg/kgBW treatment group. Statistical analysis with One way ANOVA showed significant differences (p<0.001), continued with Post hoc games Howell test, there was a significant differences between control group with 250 mg/kgBW treatment group and 500 mg/kgBW treatment group, and between 125 mg/kgBW treatment group with 250mg/kgBW treatment group and 500 mg/kgBW treatment group. There was no significant difference between the control group with 125 mg/kgBW group and 250 mg/kgBW treatment group with 500 mg/kgBW treatment group.Conclusion: There is a significant difference in renal histopathological image due to exposure to pyrethroid (cypermethrin) in gradual doses. The image of kidney damages can result in tubules injury which include: albuminous degeneration with narrowing of the tubular lumen and hyaline cast. The means of tubular injury rate will increase with increasing dose of pyrethroid.

Is There a Geriatric Mental Health Specialist in the House?

Is There a Geriatric Mental Health Specialist in the House?

18Oxygen Substituted Nucleosides Combined with Proton Beam Therapy: Therapeutic Transmutation In Vitro.

PurposeProton therapy precisely delivers radiation to cancers to cause damaging strand breaks to cellular DNA, kill malignant cells, and stop tumor growth. Therapeutic protons also generate short-lived activated nuclei of carbon, oxygen, and nitrogen atoms in patients as a result of atomic transmutations that are imaged by positron emission tomography (PET). We hypothesized that the transition of 18O to 18F in an 18O-substituted nucleoside irradiated with therapeutic protons may result in the potential for combined diagnosis and treatment for cancer with proton therapy.Materials and MethodsReported here is a feasibility study with a therapeutic proton beam used to irradiate H218O to a dose of 10 Gy produced by an 85 MeV pristine Bragg peak. PET imaging initiated >45 minutes later showed an 18F decay signal with T1/2 of ∼111 minutes.ResultsThe 18O to 18F transmutation effect on cell survival was tested by exposing SQ20B squamous carcinoma cells to physiologic 18O-thymidine concentrations of 5 μM for 48 hours followed by 1- to 9-Gy graded doses of proton radiation given 24 hours later. Survival analyses show radiation sensitization with a dose modification factor (DMF) of 1.2.ConclusionsThese data support the idea of therapeutic transmutation in vitro as a biochemical consequence of proton activation of 18O to 18F in substituted thymidine enabling proton radiation enhancement in a cancer cell. 18O-substituted molecules that incorporate into cancer targets may hold promise for improving the therapeutic window of protons and can be evaluated further for postproton therapy PET imaging.

A single-arm feasibility study of gradual dose de-escalation of antiemetic dexamethasone for older patients receiving chemotherapy

ObjectivesTo investigate whether discontinuation of prophylactic dexamethasone by gradual dose de-escalation is practicable in older patients with cancer undergoing moderately emetogenic chemotherapy. Materials and MethodsThis single-arm, feasibility study prospectively enrolled 40 patients (≥70 years old) with colorectal cancer, who were scheduled to undergo adjuvant FOLFOX chemotherapy, and ten patients ≤60 years old to serve as a control group for pharmacokinetic study. All patients received an antiemetic regimen consisting of intravenous dexamethasone 8 mg and palonosetron at day 1 of the first cycle and underwent phone interviews using symptom questionnaires at day 7 of each cycle. Dexamethasone was tapered off through gradual de-escalation by 2 mg per cycle, when complete response (CR; no emesis and no rescue therapy) was achieved. Primary endpoint was the proportion of patients who discontinued dexamethasone completely. ResultsThe median age of the patient was 74 years, and 50% were male. Of the 40 patients, 36 completed twelve cycles of chemotherapy, and 73% (N = 29) were able to discontinue dexamethasone completely. The mean (±SD) dose of dexamethasone per cycle was 3.0 mg (±2.4 mg), which was reduced to 37.5% of the initial dose level. The severity of patient-reported nausea did not significantly change over chemotherapy cycle. Geriatric assessment revealed no decline in any domain and fasting blood glucose and hemoglobin A1c levels were not elevated after twelve cycles of chemotherapy, compared to the baseline. ConclusionGradual dose de-escalation and discontinuation of prophylactic dexamethasone is feasible without compromising its antiemetic effect in older patients undergoing chemotherapy.

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation

Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. ClinicalTrials.gov Identifier: NCT02723383.