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A Phase I trial of Non-invasive Ventilation and seizure prophylaxis with levetiracetam In Children with Cerebral Malaria Trial (NOVICE-M Trial)

Background African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert ‘spikes’ of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation. Methods A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days. Conclusions This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria. Registration ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021).

Dexmedetomidine use during orthotopic liver transplantation surgery on early allograft dysfunction: A randomized controlled trial.

Previous studies have shown a protective effect of dexmedetomidine use in kidney transplantation. In contrast, it is not known whether intraoperative administration of dexmedetomidine can reduce early allograft dysfunction incidence following liver transplantation. To investigate the effect of dexmedetomidine use during surgery on early allograft dysfunction following orthotopic liver transplantation (OLT). This is a single-center, double-blinded, placebo-controlled randomized clinical trial. 330 adult patients undergoing orthotopic liver transplantation were enrolled from Jan 14th, 2019 to May 22nd, 2022. Patients received dexmedetomidine or normal saline during surgery. 1 year follow-ups were recorded. Patients were randomized to two groups receiving either dexmedetomidine or normal saline intraoperatively. For patients in the dexmedetomidine group, a loading dose (1μg/kg over 10 min) of dexmedetomidine was given after induction of anesthesia followed by a continuous infusion (0.5μg/kg /h) until the end of surgery. For patients in the normal saline group, an equal volume loading dose of 0.9% saline was given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. The primary outcome was early allograft dysfunction. Secondary outcomes included primary graft non-function, acute kidney injury and acute lung injury/ acute respiratory distress syndrome. Of 330 patients included in the intention-to-treat analysis, 165 were in the dexmedetomidine group (mean [SD] age, 49 [10] years; 117 [70.9%] men), and 165 were in the normal saline group (mean SD age, 49 [9] years; 118 [74%] men). 39 (24.4%) patients in the dexmedetomidine group and 31 (19.4%) in normal saline group developed early allograft dysfunction and the difference was statistically insignificant (P=0.28). Secondary outcomes including primary graft non-function and acute kidney injury was similar between the two groups. Intraoperative administration of dexmedetomidine did not reduce early allograft dysfunction rate after orthotopic liver transplantation.

Comparison of Levosimendan Versus Milrinone After the Arterial Switch Operation for Infants ≤3 kg.

Background: Various inotropes and inodilators have been utilized to treat low cardiac output syndrome after the arterial switch operation. The use of levosimendan, a calcium sensitizer has been limited in this setting. This study compares the effects of levosimendan with milrinone in managing low cardiac output after the arterial switch operation. Methods: A retrospective, comparative study was conducted in a tertiary care hospital on patients weighing up to 3 kg undergoing the arterial switch operation between January 2017 and January 2022. Patients received a loading dose followed by continuous infusion of either levosimendan or milrinone. Echocardiographic, hemodynamic and biochemical parameters were compared. Results: Forty-three patients received levosimendan and 42 patients received milrinone as the primary test drug. Cardiac index of less than 2.2 L/min/m2 on postoperative day 1 and 2 was found in 9.3% and 2.3% of patients receiving levosimendan versus 26.2% and 11.9% in those receiving milrinone, respectively (P = .04 and .08, respectively). Early lactate-clearance and better central venous oxygen saturations were noted in the levosimendan group. Prevalence of acute kidney injury was higher in the milrinone group (50% vs 28%; P = .03). Use of peritoneal dialysis in the milrinone group versus levosimendan was 31% and 16.3%, respectively (P = .11). There was no difference in hospital mortality between the groups (milrinone, 3; levosimendan, 2, P = .62). Conclusions: Levosimendan is safe and as effective as milrinone to treat low cardiac output syndrome occurring in neonates after the arterial switch operation. In addition we found that levosimendan was renal protective when compared with milrinone.

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T<0.5ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360mg SC and 180mg IM with a maintenance dose of 360mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

HALF DOSE THROMBOLYSIS IN INTERMEDIATE – HIGH RISK PULMONARY EMBOLISM WITH TRICUSPID VALVE MOBILE MASS: A BAIL OUT STRATEGY

Abstract A 82–year–old previously healthy male was referred to the emergency department complaining sudden onset dyspnea and witnessed syncope complicated by head trauma. Recurrent dizziness occurred previously. No history or drug consumption noted. On admission: heart rate 90 beats/min, blood pressure 110/60 mmHg, respiratory rate 25 breaths/min, oxygen saturation 87% in room air, normal body temperature. No lower extremities tenderness or swelling reported. Consistent with peripheral blood oxygen saturation levels, arterial blood gas analysis showed hypoxemia and respiratory alkalosis. Laboratory exams were significant for thrombocytopenia (89.000 cells/L), elevated cardiac troponin T levels (222 ng/L) and natriuretic peptide (NT pro–BNP 3944 pg/mL). Head CT excluded acute cerebral hemorrhage. At the electrocardiogram, signs of RV strain were present (biphasic T–waves in V1–V3 leads, S1–Q3–T3). Transthoracic echocardiography (TTE) showed dilated RV with hypokinetic free wall, “D–shaped” LV, “60/60” sign and a mobile filiform mass crossing the tricuspid valve plan in the right atrium (fig. 1). The patient did not present structural valvular abnormalities or endocarditis–related risk factors. CT pulmonary angiography detected a “saddle” PE and extensive thrombosis in inferior vena cava. After unfractioned heparin (UFH) bolus, the patient was transferred to our intensive care unit and balancing risks and benefits the chosen treatment option consisted in half dose systemic thrombolysis (50 mg rtPA in 60’’; 10 mg as loading dose in 2’). Because of potential harmful effects in thrombocytopenia and recent head trauma, UFH was temporarily withheld and started again after 1 hour. The day after, a beside TTE showed complete tricuspid thrombus resolution, a significant decrease in RV/LV ratio and systolic pulmonary artery pressure (fig. 2). Apart from small hematomas, no bleedings were reported. The patient was shifted to the ward on the next day and following course was uneventful. On day 4 a direct oral anticoagulant (Dabigatran 110 mg) was started. Abdominal and inferior limb–deep–venous ultrasound were both negative for pathological reports. A total body CT was scheduled to exclude silent malignancies at discharge. Take home message: in intermediate–high risk PE, half dose systemic fibrinolysis strategy is controversial since its potential benefit is counterbalanced by concerns about major bleedings, but increasing data suggest its efficacy with low risk profile.

Intranasal vitamin B12 administration in elderly patients: A randomized controlled comparison of two dosage regimens.

Vitamin B12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B12 dosage regimens in elderly vitamin B12-deficient patients. Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 μg cobalamin. Total vitamin B12, holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90. Both dosage regimens resulted in a rapid increase of vitamin B12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B12 of 1090 pmol/L (reference 350-650 pmol/L) concentration after 14 days. Following weekly administration, B12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B12 of 717 pmol/L after 90 days. Intranasal vitamin B12 administration is an effective and suitable way to replenish and sustain vitamin B12 levels in elderly patients.

Dexmedetomidine Versus Fentanyl on Time to Extubation in Patients with Morbid Obesity Undergoing Laparoscopic Sleeve Gastrectomy

Background: Sleeve gastrectomy (SG) is an effective method for managing obesity. While opioids are used for their hemodynamic stability and their ability to reduce intraoperative stress, they also have reported side effects. Dexmedetomidine (DEX), an α2 adrenergic receptor agonist, is noted for its analgesic and anesthetic-sparing effects, leading to a higher quality of recovery. Objectives: The study aims to compare the effects of fentanyl and dexmedetomidine (DEX) on the recovery of morbidly obese patients following laparoscopic sleeve gastrectomy (SG). Methods: This randomized, double-blind study involved 64 patients, equally divided into two groups. The Dexmedetomidine group (Group D) received an intravenous (IV) loading dose of dexmedetomidine (1 μg/kg) over 15 minutes before anesthesia induction, followed by a 10 ml saline 0.9% infusion over 60 seconds during induction. Post-intubation, dexmedetomidine was administered at 0.5 μg/kg/h. The Fentanyl group (Group F) received a volume-matched saline 0.9% IV over 15 minutes pre-induction and fentanyl (1 μg/kg) diluted in 10 ml saline 0.9% IV over 60 seconds during induction. After intubation, a continuous fentanyl infusion was maintained at a rate of 1 μg/kg/hr. Results: Extubation time was significantly shorter in the Dexmedetomidine group (Group D) at 8.25 ± 2.7 minutes compared to the Fentanyl group (Group F) at 10.47 ± 2.17 minutes, with a P value of 0.001. Intraoperative heart rate and mean arterial blood pressure were also significantly lower in Group D than in Group F. Visual analogue scale (VAS) pain scores were significantly lower in Group D compared to Group F upon arrival at the post-anesthesia care unit and at 2 hours postoperatively (P-value &lt; 0.05). Additionally, the morphine dose consumed in the first 12 hours after surgery was significantly lower in Group D (5.75 ± 2.20 mg) compared to Group F (8 ± 2.38 mg), with a P-value of 0.001. Conclusions: For morbidly obese patients undergoing laparoscopic sleeve gastrectomy, dexmedetomidine (DEX) proves to be an effective anesthetic choice. It not only reduces extubation time but also lowers early postoperative visual analogue scale (VAS) pain scores and opioid consumption within the first 12 hours following surgery.

Early Therapeutic Drug Monitoring Optimizes Teicoplanin Use in Febrile Neutropenic Patients with Hematological Malignancies.

A target trough concentration (Cmin) of teicoplanin ≥ 15-20mg/L between the fourth and sixth day has been suggested for severe infections or management of febrile neutropenia (FN). Owing to no reports discussing the impact of early target attainment on treatment outcomes, this study aimed to evaluate the dose-Cmin relationship and clinical outcome and estimate the optimal early target Cmin for FN in patients with hematological malignancies. This single-center, prospective study enrolled patients with hematological malignancies who were treated with teicoplanin either as an empirical antibiotic for FN or as targeted treatment for Gram-positive bacteria. Blood samples were collected on day three (48h) post-loading doses, day5 (96h), and day8 (when applicable) and determined by ultrahigh-pressure liquid chromatography-triple quadruple mass spectrometry. A total of 117 samples from 47 patients with FN (27 men, 20 women) were consecutively analyzed. A two-tailed αvalue of 0.05 was considered statistically significant. The mean Cmin values at 48h, 96h, and on day8 were 23.4, 21.4, and 27.8mg/L, respectively. The patients achieving Cmin ≥ 20mg/L at 48h had a higher likelihood of treatment success. The areas under the receiver operating characteristic curves were 0.71 for clinical efficacy and the cutoff value of Cmin at 48h was 18.85mg/L (95% confidence interval 0.55-0.87; P = 0.018). The Cmin of teicoplanin after completion of loading doses could predict the treatment response, with a target concentration ≥ 18.85mg/L.

The 90% effective dose (ED90) of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP

BackgroundCompared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, this study aims to determine the 90% effective dose (ED90) of remimazolam to inhibit responses to insertion of a duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP).MethodsA dose-response study was carried out undergoing ERCP who received remimazolam-alfentanil anesthesia using 10 µg/kg of alfentanil between September 2021 and November 2021. The initial dose of remimazolam was 0.2 mg/kg. The dose was then decided based on the responses of earlier patients by exploiting the sequential ascend and descend according to a 9: 1 biased coin design. Upon failure, the dose of remimazolam was increased by 0.025 mg/kg in the next patient. When the insertion was successful, the succeeding patient was randomized to an identical dose or a dose that was lower by 0.025 mg/kg.The ED90 of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP was calculated. Adverse events and complications of remimazolam were recorded.ResultsA total of 55 elderly patients (age > 65) were included in the study. 45 successfully anesthetized patients, and 10 unsuccessfully. The ED90 of remimazolam was 0.300 mg/kg (95% CI = 0.287–0.320). ED95 was 0.315 (95% CI = 0.312–0.323) and ED99 was 0.323 (95% CI = 0.323–0.325). Among the patients, 9 patients developed hypotension, 2 patients developed bradycardia and 1 patient developed tachycardia, and hypoxia occurred in 2 patients.ConclusionsA loading dose of 0.300 mg / kg of remimazolam for elderly patients undergoing ERCP can safely, effectively, and quickly induce patients to fall asleep and inhibit responses to the insertion of a duodenoscope.Trial registrationThe study protocol was registered at the website ClinicalTrials.gov on 22/09/2021(NCT05053763).

Efficacy of lebrikizumab in adolescent patients with moderate-to-severe atopic dermatitis: 16-week results from three randomized phase 3 clinical trials

Background Lebrikizumab, a high-affinity monoclonal antibody targeting IL-13, previously demonstrated clinical efficacy in three randomized, double-blind, placebo-controlled Phase 3 trials that included adults and adolescents with moderate-to-severe atopic dermatitis (AD): ADvocate1, ADvocate2, and ADhere. Aim This subset analysis evaluated 16-week physician- and patient-reported outcomes of lebrikizumab in the adolescent patients enrolled in these three trials. Methods Eligible adolescents (≥12 to <18 years weighing ≥40kg) were randomized 2:1 to subcutaneous lebrikizumab (500 mg loading doses at baseline and Week 2 followed by 250 mg every 2 weeks) or placebo as monotherapy in ADvocate1&2, and in combination with topical corticosteroids (TCS) in the ADhere study. Week 16 analyses included clinical efficacy outcomes (IGA (0,1) with ≥2-point improvement, EASI 75, EASI 90), patient-reported Pruritus NRS ≥4-point improvement and Sleep-Loss Scale ≥2-point improvement. Results Pooled ADvocate1&2 16-week results in lebrikizumab (N = 67) vs placebo (N = 35) were: IGA (0,1) 46.6% vs 14.3% (p < 0.01), EASI 75 62.0% vs 17.3% (p < 0.001), EASI 90 40.7% vs 11.5% (p < 0.01), Pruritus NRS 48.9% vs 13.1% (p < 0.01), and Sleep-Loss Scale 26.9% vs 6.9% (p = 0.137). Corresponding results for ADhere, (lebrikizumab + TCS, N = 32; placebo + TCS, N = 14), were consistent. Conclusions Lebrikizumab treatment demonstrated efficacy in improving the signs and symptoms of AD in adolescent patients, consistent with the ADvocate and ADhere overall population results.

Safety and Efficacy of Levetiracetam for Prevention of Epileptic Seizures in Acute Phase of Intracerebral Bleeding

Background: Epilepsy, characterized by recurrent, unprovoked seizures due to anomalous brain activity, is a significant complication for patients with intracerebral hemorrhage (ICH). The onset of epileptic convulsions during the acute phase of ICH can worsen the patient's prognosis and survival chances, making it crucial to identify a safe and effective method to prevent these seizures. Levetiracetam, a pyrrolidone derivative, is noted for its unique mechanism of action, exceptional tolerability, and advantageous pharmacokinetics, making it efficacious against various types of seizures. Objective: This study aims to evaluate the safety and efficacy of levetiracetam in preventing epileptic seizures during the acute phase of ICH and to determine its impact on neurological outcomes in this patient population. Methods: A cross-sectional investigation was conducted between October 2022 and June 2023 at Pak Emirates Military Hospital in Rawalpindi, Pakistan, involving 85 patients with spontaneous ICH confirmed by CT or MRI within 24 hours of symptom onset. Inclusion criteria included adult patients aged 18 or older, with various forms of ICH, excluding isolated subarachnoid hemorrhage, penetrating wound injury, depressed skull fracture, or early posttraumatic seizure. Patients with a Glasgow Coma Scale (GCS) score of less than 6, serum creatinine level &gt;1.7 mg/dL, history of psychosis, unprovoked seizures, cerebrovascular accidents, traumatic brain injuries, or encephalitis within the previous three years were excluded. Patients were administered an initial loading dose of levetiracetam (1,000 to 1,500 mg), followed by a maintenance dose (500 to 1,500 mg every 12 hours) based on renal function. Continuous electroencephalography (cEEG) monitoring was used to detect seizures for at least the first 72 hours of hospital admission. The primary outcome was the incidence of epileptic seizures during hospitalization, while the secondary outcome was the patient's neurological status at discharge, assessed using the Modified Rankin Scale (mRS). Data were analyzed using descriptive statistics and the Chi-square test, with a p-value of ≤0.05 considered statistically significant. Analyses were conducted using SPSS version 25. Results: The mean age of the patients was 47.89 years (SD=7.46), with 62.35% male and 37.65% female. The mean GCS score at admission was 10.52 (SD=2.13), and the mean volume of ICH was 17.5 ml (SD=3.4). At baseline, 2.35% of patients had GCS scores of 3-5, which improved to 0% after treatment. The percentage of patients with GCS scores of 13-15 increased from 65.88% to 83.52% (p=0.3730). Seizures within the first 7 days occurred in 10.58% of patients, and the overall seizure incidence during hospitalization was 20%. At discharge, 9.41% of patients had an mRS score of 0, and the percentage of patients with an mRS score of 2 increased significantly from 18.18% to 37.64% (p=0.4086*). The percentage of patients with severe disability (mRS score of 5) significantly decreased from 22.72% to 5.68% (p=0.0094*). Conclusion: Levetiracetam is effective in improving neurological outcomes and reducing the incidence of seizures in patients with acute intracerebral hemorrhage, with a manageable safety profile. These findings suggest that levetiracetam can be a valuable addition to therapeutic strategies for managing ICH-related seizures, potentially enhancing patient care and improving health outcomes.

Injection burden and treatment intervals of aflibercept in observe-and-plan regimen for neovascular age-related macular degeneration.

The Observe-and-Plan (O&P) regimen allows for individualised treatment. In this study, we evaluated injection burden and intervals using aflibercept in an O&P regimen for eyes with neovascular age-related macular degeneration (AMD). This was a retrospective registry-based study of treatment-naïve eyes with neovascular AMD. Treatment data were compiled for 3 years after commencement of intravitreal aflibercept therapy. We evaluated clinical consequences at the first follow-up after loading dose, the proportion of patients who obtained and kept dry macula after loading dose, number of injections and intervals between injections. Data were obtained for 1103 eyes. After loading dose, 0.4% were lost to follow-up, 7.5% discontinued, 50.9% booked for further injections and 41.3% booked for monthly observations. After loading dose, the macula remained dry in 49.2% at 3 months, 34.0% at 6 months, 23.7% at 12 months and 15.2% at 24 months. For the entire population, median cumulative total number of injections was 7, 12 and 15, after 1, 2 and 3 years, respectively. After the 3rd year, the proportion of eyes in the short 4-6 weeks treatment interval was 51.1%, 8 weeks interval was kept in 14.4% and the extended treatment intervals of 10 and 12 weeks was possible in 34.4%. After loading dose, one in two eyes required further injections. A large proportion required therapy with shorter intervals than the label-recommended 8 weeks. The large majority of those who obtained a dry macula after loading dose turned exudative again, mostly within the first 3 months.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

A clinical case of atopic dermatitis with a rapid positive effect from the use of a genetically engineered biological drug in a teenager

Introduction. The instructions for the drug dupilumab indicate that the administration of a single loading dose on the first day leads to the rapid achievement of clinically effective concentrations within 2 weeks, which we saw in the example of our patient and her real clinical response to the first injection. Presentation of a clinical case. Under our medical supervision was a 17-year-old patient with severe atopic dermatitis, resistant to traditional therapy. Heredity for allergic pathology is burdened: the girl’s mother suffers from pollen allergy. Initially before the start of therapy: SCORAD — 88 points, EASI — 48.8 points, IGA — 4, blood eosinophils — 11 % (1188 cells/ml), total IgE — 1102.0 IU/ml; the content of nitric oxide in exhaled air (FeNO) is 30 ppb. On April 28, 2021, the patient was administered dupilumab at a dose of 600 mg. Assessment of atopic dermatitis control in points upon admission to the hospital 2 weeks after the first administration of dupilumab: on the SCORAD scale — 44.5 points; EASI — 13.8 points; IGA — 2 points, eosinophils — 9 % (1070 cells/ml); total IgE — 840 IU/ml; FeNO — 5 ppb. Conclusion. This clinical observation clearly illustrates the fact that patients with severe atopic dermatitis who don’t respond to first-line therapy can achieve positive clinical results after the first use of a recombinant human monoclonal antibody (IgG4).

Successful Use of Lidocaine in the Management of Severe Flécaïne Poisoning Refractory to Conventional Treatment

Introduction: Intoxications with class Ic antiarrhythmics, such as flécaïne, are rare but potentially life-threatening. We report a case of severe flécaïne poisoning where the use of lidocaine, a class Ib antiarrhythmic, enabled effective management of refractory rhythm disturbances. Methods: A 22-year-old female patient was admitted for voluntary flécaïne poisoning after ingesting 2 g. She presented with shock, ventricular fibrillation, and torsades de pointes refractory to conventional treatment (cardioversion, magnesium sulfate, bicarbonates, amiodarone). Results: After initial treatment failure, a lidocaine loading dose successfully resolved refractory ventricular rhythm disturbances. Continuous administration of lidocaine subsequently stabilized the patient's hemodynamic status and reduced the need for vasopressors. Discussion: While the use of lidocaine is traditionally contraindicated in poisoning with class Ic antiarrhythmics due to the risk of drug interactions, this case demonstrates its potential value in refractory situations. Lidocaine may have a competitive effect on sodium channels, thereby reversing the toxicity of potent inhibitors such as flécaïne. Conclusion: In severe flécaïne poisoning refractory to conventional treatment, the use of lidocaine can be a life-saving therapeutic option when extracorporeal clearance techniques are not available.

Load and go: Assessing safety outcomes of patients discharged from the emergency department after receiving phenobarbital for alcohol withdrawal.

Phenobarbital (PB) is a long-acting GABA A-agonist with favorable pharmacokinetics (long half-life and duration of effect) that allows effective treatment of alcohol withdrawal (AW) after administration of a single loading dose. Current evidence suggests that in the setting of AW, PB administration may be associated with decreased hospital admissions and hospital length of stay. The aim of this study was to evaluate the safety outcomes of AW patients who were treated and discharged from the emergency department (ED) after receiving PB for AW. This retrospective chart review included a convenience sample of 33 AW patients who presented to four EDs within an 18-month span. Descriptive statistics (frequencies and percentages) were used to describe demographics, distribution of resources and referrals, and the safety outcomes of PB administration for low-risk AW patients. Patients were selected for inclusion in consultation with a medical toxicologist, treated with PB, and discharged from the ED. Electronic medical records were utilized to gather information on the patient cohort. All patients were treated with at least a single loading dose of 5‒10mg/kg (ideal body weight) of intravenous or per os PB during their ED stay. Only one patient had an unanticipated event after discharge, which was related to driving against advice. Two additional patients had ED revisits for recurrent alcohol use within 72h, and 16 patients had recurrent alcohol use within 30 days. All 33 patients were provided with resources for linkage to treatment. None required hospital admission. ED PB "load and go" may be a safe, effective AW treatment that could help treat AW, facilitate linkage to specific rehabilitation treatments, and decrease hospital admissions.

To Study Perioperative Changes in Plasma Phenytoin Levels in Patients with Brain Tumor Undergoing Craniotomy and Its Correlation with Postoperative Seizures

Abstract Introduction Phenytoin, although commonly used for postoperative seizure prophylaxis, exhibits variable results in mitigating seizure frequency following craniotomy. These discrepancies may be linked to a reduction in plasma phenytoin levels subsequent to the surgical intervention. Aims This prospective study aims to characterize changes in plasma phenytoin levels after craniotomy and their relationship with intraoperative blood loss. Methods Fifty consecutive patients were enrolled in this study after obtaining written informed consent. These patients had either been on oral phenytoin for at least 7 days or had received an intravenous loading dose before undergoing craniotomy. Serum phenytoin levels were measured 24 hours preoperatively, immediately before craniotomy (prior to skin incision), postcraniotomy (after skin closure), and 24 hours postcraniotomy. Additionally, intraoperative blood loss was calculated using a modified Gross formula. Results Immediately following craniotomy, there was a statistically significant mean decline of 28.16% in serum phenytoin levels. Furthermore, the analysis revealed a robust positive correlation between the decrease in phenytoin concentration level and several factors, including blood loss during surgery, the duration of the surgical procedure, intravenous fluids administered during surgery, and the occurrence of postoperative seizures. Conclusion This study underscores the potential utility of routinely measuring perioperative serum phenytoin levels in high-risk patients to prevent postcraniotomy seizures. Moreover, it suggests that patients with substantial intraoperative blood loss may benefit from an additional bolus dose of phenytoin toward the end of the surgical procedure.

Abstract PO5-19-08: Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial

Abstract Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: Patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer are being randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K. After enrollment of 22 pts to arm C, a prespecified interim efficacy analysis was conducted, and enrollment to this arm was subsequently terminated. Enrollment to the other arms continues with 32/58 pts enrolled to arm A and 33/58 pts enrolled to arm B as of 2/14/2023. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion per local clinical standard. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Funding sources: BCRF, Merck NCT03747120 Citation Format: Heather McArthur, Jorge Henrique Santos Leal, Isaac Chan, Nisha Unni, Stephen Shiao, Joshua Gruber, Samira Syed, Namrata Peswani, Navid Sadeghi, Glenda Delgado, Dawn Klemow, Reva Basho, Meredith Carter, Mai Badran, Nasir Qureshi, Jessica Curtin, Joshua Weese, Stephanie Rice, Michelle Phillips, David Chan, Hugo Hool, Dorothy Park, Mary El-Masry, Philomena McAndrew, Swati Sikaria, Laura Spring, Aditya Bardia, Mourad Tighiouart, Farnaz Dadmanesh, Armando Giuliano, Katherine Sanchez, David Page. Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-08.

Abstract PO1-01-02: Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study

Abstract Background: The optimal neoadjuvant treatment regimen for HER2-positive breast cancer remains unclear, especially regarding the use of anthracycline. We conducted a prospective phase II study to evaluate sequential neoadjuvant chemotherapy with pegylated liposomal doxorubicin (PLD)/cyclophosphamide followed by taxanes in the presence of full-course trastuzumab/pertuzumab in HER2-positive early breast cancer patients. Methods: In this single-arm, open-label, multicenter, phase II study, eligible patients with confirmed HER2-positive early breast cancer were recruited from four independent hospitals. Patients received four cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (ypT0/is ypN0, tpCR). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, the proportion of patients requiring breast-conserving surgery, and safety. For biomarkers analysis, tumor tissues were collected at baseline and evaluated for Topoisomerase 2 Alpha (TOP2A) expression assessed prospectively with immunohistochemistry (IHC) assay by independent pathologists. Results: Between May 27, 2020 and May 11, 2022, 78 eligible patients were treated and underwent surgery, of whom 42 (53.8%) patients underwent breast-conserving surgery. After neoadjuvant therapy, 47 (60.3%, 95% CI, 48.5%-71.2%) patients achieved a tpCR in the breast and axilla. The bpCR was observed in 49 (62.8%) patients. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. All (100%) patients achieved disease control since the end of the first cycle. No correlations between clinicopathological variables and pathological response were observed. Grade 3 or worse AEs occurred in 35 (44.9%) patients. Nine (11.5%) patients experienced asymptomatic LVEF reduction (≥10% from baseline), but all with a minimum value of &amp;gt;55%. No treatment-related surgical delay or death occurred. For biomarkers analysis, the status of TOP2A was not found to be associated with pCR or 4th-cycle ORR. Conclusions: This dual HER2-blockade plus polychemotherapy as sequential neoadjuvant regimen demonstrates promising anti-tumor activity and acceptable tolerability for patients with HER2-positive breast cancer. Citation Format: Yaping Yang, Liang Jin, Yudong li, Fengxia Gan, Nanyan Rao, Jun Zhang, Ruifa Feng, Zhenzhen Liu, Qiang Liu. Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-02.

Abstract PO1-27-05: De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab in HER2-positive early breast cancer (HELEN-006):a randomized,phase 3 trial

Abstract Background: Chemotherapy de-escalation is currently under investigation as a treatment approach for HER2-positive early-stage breast cancer(EBC). We conducted a phase 3 clinical trial to evaluate the effectiveness of a weekly regimen of nab-paclitaxel monotherapy in combination with dual HER2 blockade for HER2-positive EBC. Methods: We conducted a multicenter, randomized, open-label Phase 3 trial at six hospitals in China. Eligible participants were women aged 18-70 with locally confirmed, HER2-positive, stage II-III, invasive, operable breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. Participants were randomly assigned (1:1) using central block randomization, with block sizes of four, stratified by hormone receptor status, tumor stage, and node status. They were assigned to receive either intravenous nab-paclitaxel (125mg/m2 on days 1, 8, and 15) for six 3-week cycles (group A), or intravenous docetaxel (75mg/m² on day 1) and carboplatin (area under the concentration-time curve 6mg/mL per min on day 1) for six 3-week cycles (group B). Both groups received concurrent trastuzumab (8mg/m2 loading dose, 6mg/m2 maintenance dose on day 1) and pertuzumab (intravenous 840mg loading dose, 420mg maintenance dose on day 1). The primary endpoint was the proportion of patients achieving a pathological complete response(pCR) in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery, assessed using a modified intention-to-treat analysis. To test for non-inferiority, we used a closed test procedure, considering the nab-paclitaxel group non-inferior to the docetaxel plus carboplatin group if the lower 95% confidence interval(CI) for the odds ratio (OR) was above 0.802, which accounted for a 5.5% non-inferiority margin (10% of the 55% pCR rate for docetaxel plus carboplatin and dual HER2 blockade regimen). We planned to test for superiority only if the non-inferiority test was positive, using an alpha value of 0.05. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, with the registration number NCT04547907. Findings: Between September 10, 2020, and March 1, 2023, we randomly assigned 689 women, of whom 669 started treatment (332 with nab-paclitaxel and 337 with docetaxel plus carboplatin). The nab-paclitaxel group had a higher proportion of patients achieving a pCR (220 [66.3%, 95% CI 61.2-71.4]) compared to the docetaxel plus carboplatin group (194 [57.6%, 52.3-62.9]). The OR for pCR was 1.448 (95% CI 1.058-1.981), indicating a statistically significant difference (unadjusted p=0.021). Overall, 228 (34.1%) patients were noted to have at least one grade 3 or 4 event, 100(30.1%) in the nab-paclitaxel group and 128 (38.0%) in the docetaxel plus carboplatin group (P=0·032). The most common grade 3 or 4 events overall were nausea (98[14.6%] of 669 patients), diarrhea (80 [12.0%]), and neuropathy (51 [7.6%]).However, no treatment-associated deaths were identified. Conclusions: In neoadjuvant treatment of HER2-positive EBC, 18 weeks of nab-paclitaxel monotherapy combined with dual HER2 blockade has shown significantly higher pCR rates and improved tolerability compared to the standard docetaxel plus carboplatin and dual HER2 blockade regimen. These findings could potentially reshape preferences for neoadjuvant therapy in HER2-positive EBC. Patient Characteristics pCR by clinical-pathological variables Abbreviation:Nab-PHP,nanoparticle albumin-bound paclitaxel plus trastuzumab and pertuzumab; TCbHP,docetaxel plus carboplatin ,trastuzumab and pertuzumab; HR,hormone receptor; IHC,immunohistochemistry. *estrogen and/or progesterone receptor positive is classified as hormone receptor positive;estrogen and progesterone receptor negative is classified as hormone receptor negative Adverse events Abbreviation:Nab-PHP,nanoparticle albumin-bound paclitaxel plus trastuzumab and pertuzumab; TCbHP,docetaxel plus carboplatin ,trastuzumab and pertuzumab;ALT,alanine aminotransferase;AST,aspartate transaminase. Citation Format: Zhenzhen Liu, Xiuchun Chen, Jianghua Qiao, Jiao Dechuang, Chengzheng Wang, Xianfu Sun, Zhenduo Lu, Lianfang Li, Chongjian Zhang, Min Yan, Ya Wei, Chen Bo, Yueqing Feng, Miao Deng, Mingde Ma. De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab in HER2-positive early breast cancer (HELEN-006):a randomized,phase 3 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-05.