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Open Veterinary Journal May 2024The intramuscular (IM) administration of 7.5-10 mg/kg of alfaxalone produces anesthetic effects that enable endotracheal intubation with mild cardiorespiratory...
BACKGROUND
The intramuscular (IM) administration of 7.5-10 mg/kg of alfaxalone produces anesthetic effects that enable endotracheal intubation with mild cardiorespiratory depression in dogs. However, the effects of IM co-administration of medetomidine, butorphanol, and alfaxalone on cardiorespiratory function under inhalation anesthesia have not been studied.
AIM
To assess the cardiorespiratory function following the IM co-administration of 5 μg/kg of medetomidine, 0.3 mg/kg of butorphanol, and 2.5 mg/kg of alfaxalone (MBA) in dogs anesthetized with sevoflurane.
METHODS
Seven intact healthy Beagles (three males and four females, aged 3-6 years old and weighing 10.0-18.1 kg) anesthetized with a predetermined minimum alveolar concentration (MAC) of sevoflurane were included in this study. The baseline cardiorespiratory variable values were recorded using the thermodilution method with a pulmonary artery catheter after stabilization for 15 minutes at 1.3 times their individual sevoflurane MAC. The cardiorespiratory variables were measured again following the IM administration of MBA. Data are expressed as median [interquartile range] and compared with the corresponding baseline values using the Friedman test and Sheff's method. A < 0.05 was considered statistically significant.
RESULTS
The intramuscular administration of MBA transiently decreased the cardiac index [baseline: 3.46 (3.18-3.69), 5 minutes: 1.67 (1.57-1.75) l/minute/m : < 0.001], respiratory frequency, and arterial pH. In contrast, it increased the systemic vascular resistance index [baseline: 5,367 (3,589-6,617), 5 minutes:10,197 (9,955-15,005) dynes second/cm/m : = 0.0092], mean pulmonary arterial pressure, and arterial partial pressure of carbon dioxide.
CONCLUSION
The intramuscular administration of MBA in dogs anesthetized with sevoflurane transiently decreased cardiac output due to vasoconstriction. Although spontaneous breathing was maintained, MBA administration resulted in respiratory acidosis due to hypoventilation. Thus, it is important to administer MBA with caution to dogs with insufficient cardiovascular function. In addition, ventilatory support is recommended.
Topics: Animals; Sevoflurane; Butorphanol; Medetomidine; Dogs; Pregnanediones; Male; Female; Injections, Intramuscular; Anesthetics, Inhalation; Heart Rate; Blood Pressure
PubMed: 38938419
DOI: 10.5455/OVJ.2024.v14.i5.20 -
Clinical Drug Investigation Jun 2024Trastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02, a recombinant...
BACKGROUND AND OBJECTIVE
Trastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02, a recombinant IgG1 kappa humanized monoclonal antibody, is being developed as a trastuzumab biosimilar. The objective of this study was to evaluate the equivalence of BP02 with reference trastuzumab (RT: Herceptin-EU) in patients with HER2-positive metastatic breast cancer.
METHODS
This double-blinded, 1:1 randomized, parallel-group, active-controlled, phase III equivalence trial recruited women aged 18-75 years with histologically/cytologically confirmed HER2- positive, locally recurrent or metastatic breast cancer with systemic metastasis, from 59 sites in India. Patients were randomly allocated 1:1 stratified by estrogen receptor/progesterone receptor status to receive BP02/RT (8-mg/kg loading dose on day 1-cycle 1, 6 mg/kg on day 1-cycles 2-8, of each 3-week cycle) combined with docetaxel (75 mg/m on day 1-cycles 1-8) [induction phase]. Participants with complete or partial response, or stable disease at the end of the induction phase continued the study drug until disease progression/treatment discontinuation [maintenance phase]. The primary efficacy endpoint was the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
RESULTS
Between 23 September, 2020 and 16 September, 2022, 690 patients were recruited (n = 345 each to BP02/RT). At the end of the induction phase (intent-to-treat population), a similar proportion of patients achieved an objective response rate with BP02 (n = 231 [67.0%], 95% confidence interval [CI] 62.0, 71.9) and RT (n = 238 [69.0%], 95% CI 64.1, 73.9). The 95% CI of risk difference (-2.03, 95% CI -9.15, 5.09) and 90% CI of risk ratio (0.97, 90% CI 0.89, 1.06) were within equivalence margins of ± 13% and (0.80, 1.25), respectively. Treatment-emergent adverse events leading to treatment withdrawal were reported in 2.9% and 3.2% patients with BP02 and RT, respectively.
CONCLUSIONS
BP02 showed an equivalent efficacy and similar safety profile to RT at the end of 24 weeks.
CLINICAL TRIAL REGISTRATION
CTRI Number: CTRI/2020/04/024456.
PubMed: 38937403
DOI: 10.1007/s40261-024-01374-y -
The Journal of Obstetrics and... Jun 2024To evaluate the relationship between AMH and ovarian response to controlled ovarian hyperstimulation in women with PCOM and PCOS.
AIM
To evaluate the relationship between AMH and ovarian response to controlled ovarian hyperstimulation in women with PCOM and PCOS.
METHODS
A retrospective study was conducted on 559 patients who underwent the IVF-ET cycle between January 2018 and December 2022 at Gangnam Cha Hospital. Patients were divided into 3 groups matched for age and BMI: the PCOS group (n = 54), based on the new 2023 PCOS guideline; the PCOM group (n = 53); and the control group (n = 452) with normal ovaries. Serum AMH levels were converted to multiples of the median (MoM) for each corresponding age. The ovarian sensitivity index (OSI) was calculated as the number of retrieved oocytes divided by the total dose of recombinant FSH administered (per 1000 IU).
RESULTS
There were significant differences in AMH-MoM value among women with PCOS [2.7 ± 1.3 (95% CI 2.3-3.0)], those with PCOM [2.0 ± 1.0 (95% CI 1.7-2.3)], and controls [0.8 ± 0.7 (95% CI 0.8-0.9)] (p < 0.001). The abortion rates in the normoovulatory, PCOM, and PCOS groups were 18.2%, 21.1%, and 25.0%, respectively. OSI and live birth rate were positively correlated with the AMH-MoM value in normoovulatory women (r = 0.389, p < 0.05, r = 0.122, p < 0.05), while no such correlation was observed in women with PCOM and PCOS.
CONCLUSIONS
Ovarian response and live birth rate are possibly correlated with the AMH-MoM value in normoovulatory women, but not in women with PCOM and PCOS.
PubMed: 38937259
DOI: 10.1111/jog.16009 -
Vaccine Jun 2024The aim of this study is to demonstrate that the freeze-dried human rabies vaccine (Vero cell), administered in a four-dose schedule (2-1-1) to the 10-60 years old...
Randomized, blind, controlled phase III clinical trial: Assessing the immunogenicity and safety of freeze-dried human rabies vaccine (vero cell) with a 4-dose regimen (2-1-1) in a 10-60 year-old demographic.
OBJECTIVE
The aim of this study is to demonstrate that the freeze-dried human rabies vaccine (Vero cell), administered in a four-dose schedule (2-1-1) to the 10-60 years old population, has immunogenicity that is not inferior to the approved five-dose schedule and similar vaccines with a four-dose schedule, and to evaluate its safety.
METHOD
A total of 1800 individuals were enrolled and divided into three groups: four-dose test group, four-dose control group, and five-dose control group. The rabies virus neutralizing antibodies were measured using the Rapid Fluorescent Focus Inhibition Test to assess immunogenicity, and the incidence of adverse events and serious adverse events were statistically analyzed.
RESULTS
The seroconversion rates 14 days after the first dose and 14 days after the complete course of vaccination were 100% in all three groups. The antibody GMC of the four-dose test group was higher than that of the five-dose control group, but slightly lower than the four-dose control group. Seven days after the first dose, both four-dose regimen groups showed higher seroconversion rates and antibody GMCs compared to the five-dose regimen group, proving that the immunogenic effect of the four-dose regimen seven days post-first vaccination is superior to the five-dose regimen. The overall incidence of adverse events showed no significant difference between the four-dose test group and the five-dose control group, but was significantly lower in the four-dose test group compared to the four-dose control group.
CONCLUSION
The vaccine in the four-dose test group is equivalent in immunogenic effect to the four-dose control group vaccine and superior to the five-dose control group vaccine; the safety of the vaccine in the four-dose test group is equivalent to the five-dose control group vaccine and superior to the four-dose control group vaccine.
CLINICALTRIALS
gov number: NCT05549908.
PubMed: 38937182
DOI: 10.1016/j.vaccine.2024.06.026 -
Transplant Immunology Jun 2024Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3...
BACKGROUND
Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases.
METHODS
We evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model.
RESULTS
CS12192, starting at a concentration of 0.5 μM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05).
CONCLUSIONS
CS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.
PubMed: 38936745
DOI: 10.1016/j.trim.2024.102075 -
Clinical Neurology and Neurosurgery May 2024The use of endovascular therapy (EVT) has become a widespread strategy for the clinical management of acute ischemic stroke (AIS). However, the combination of arterial... (Review)
Review
OBJECT
The use of endovascular therapy (EVT) has become a widespread strategy for the clinical management of acute ischemic stroke (AIS). However, the combination of arterial injection of tirofiban with EVT for AIS continues to be a subject of controversy. This meta-analysis was conducted to assess the safety and efficacy of this treatment approach.
METHODS
Relevant studies were identified through a systematic literature search in Pubmed, EMBASE, Web of Science, and Cochrane Library databases, covering articles published from January 2010 to January 2023. The efficacy outcomes included favorable functional outcomes, recanalization rates, and safety outcomes including mortality and symptomatic intracranial hemorrhage (sICH).
RESULTS
The meta-analysis consisted of data from 13 studies, which included 1 randomized controlled trial (RCT), 7 prospective cohort studies, and 5 retrospective cohort studies, encompassing a total of 3477 patients. The study results indicate that the intra-arterial (IA) tirofiban+EVT for AIS is associated with significant improvements in favorable functional outcomes (OR, 1.21; 95%CI, 1.05-1.40; P = 0.009) and recanalization rate (OR, 1.33; 95%CI, 1.06-1.65; P = 0.01), as well as significant reductions in mortality rates (OR, 0.65; 95%CI, 0.53-0.79; P = 0.0001). Subgroup analysis revealed that administering a maintenance dose of intravenous (IV) tirofiban post-EVT was significantly associated with improved functional outcomes and reduced mortality in patients. In addition, there was no increase in the incidence of sICH (OR, 0.92; 95%CI, 0.71-1.20; P = 0.54).
CONCLUSION
The administration of Intra-arterial tirofiban combined with EVT is an effective and safe treatment strategy for AIS, and postoperative maintenance doses of intravenous tirofiban may be more effective than IA only.
PubMed: 38936178
DOI: 10.1016/j.clineuro.2024.108330 -
JCO Precision Oncology Jun 2024The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II...
Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
PURPOSE
The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.
METHODS
As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS).
RESULTS
Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with -altered CNS tumors achieved stable disease >6 months.
CONCLUSION
Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.
Topics: Humans; Adolescent; Child; Female; Male; Young Adult; Child, Preschool; Neoplasms; Infant; United States; Mitogen-Activated Protein Kinases; National Cancer Institute (U.S.); MAP Kinase Signaling System; Aminopyridines; Pyrroles
PubMed: 38935895
DOI: 10.1200/PO.24.00103 -
Hepatology Communications Jul 2024Sodium and water retention is a mainstay of the pathophysiology leading to ascites formation in patients with advanced cirrhosis. Refractory ascites denotes the most... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium and water retention is a mainstay of the pathophysiology leading to ascites formation in patients with advanced cirrhosis. Refractory ascites denotes the most severe ascites status with limited treatment options and a poor prognosis. We investigated the efficacy and safety of the natriuretic peptide ularitide in patients with refractory cirrhotic ascites.
METHODS
We conducted a randomized placebo-controlled trial investigating ularitide to manage refractory ascites. Until trial termination after interim analyses, we randomized 17 participants in a 2:1 ratio between ularitide (n=11) and placebo (n=6). While hospitalized, the participants received treatment for up to 48 hours. The primary efficacy endpoint was a change in renal water excretion, and secondary end points included changes in renal sodium excretion rate and body weight. The starting dose was 30 ng/kg/min, though later reduced to 20 for safety reasons.
RESULTS
In contrast to the study hypothesis, the mean urine production decreased after 24 hours of ularitide treatment compared with the baseline level (22.8 vs. 47.5 mL/h, p=0.04) and decreased more in participants randomized to ularitide than placebo (24.7 vs. -6.2 mL/h, p=0.05). Ularitide did not increase the renal sodium excretion rate or reduce the weight gain. The incidence rate ratio of adverse reactions in ularitide versus placebo was 8.5 (95% CI: 2-35, p=0.003). Participants treated with ularitide developed serious blood pressure reductions, impacting their renal responsiveness.
CONCLUSIONS
Ularitide in doses of 20-30 ng/kg/min did not benefit urine production and renal sodium excretion rate in patients with refractory ascites. The participants randomized to ularitide overall developed more adverse reactions than placebo. EudraCT no. 2019-002268-28.
Topics: Humans; Male; Ascites; Liver Cirrhosis; Female; Middle Aged; Treatment Outcome; Double-Blind Method; Aged; Adult; Sodium
PubMed: 38934679
DOI: 10.1097/HC9.0000000000000481 -
American Journal of Hematology Jun 2024Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label,...
Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.
PubMed: 38934629
DOI: 10.1002/ajh.27424 -
British Journal of Haematology Jun 2024Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed...
The correlation of asparaginase enzyme activity levels after PEG-asparaginase administration with clinical characteristics and adverse effects in Chinese paediatric patients with acute lymphoblastic leukaemia.
Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed with acute lymphoblastic leukaemia (ALL) and treated according to the Chinese Children's Cancer Group study protocols, CCCG-ALL-2015/CCCG-ALL-2020 protocols. We measured the AEA at days 7 ± 1 and 14 ± 1 and analysed their association with patient characteristics and PEG-asparaginase-related adverse effects (AEs). We measured 2147 samples from 329 patients. Mean AEA levels (interquartile range) were 931 iu/L (654-1174 iu/L) at day 7 ± 1 and 664 iu/L (463-860 iu/L) at day 14 ± 1. The AEA levels were higher in younger children and increased with the cumulative dose numbers. PEG-asparaginase inactivation rate was 19.1%, and the silent inactivation (SI) rate was 12.5%. Nine patients were identified with allergic-like reactions. Hypofibrinogenaemia, hypertriglyceridaemia, pancreatitis and thrombosis were associated with older age, whereas hypoglycaemia was associated with younger age. The risk of hypertriglyceridaemia and hypoglycaemia increased with cumulative dose numbers of PEG-asparaginase. Except for hypofibrinogenaemia, elevated AEA levels did not increase the risk of PEG-asparaginase-related AEs. Drug monitoring can be utilized as guidance for treatment decision-making. Individualizing asparaginase doses do not reduce toxicities. The treatment target of PEG-asparaginase remains to achieve sustained and adequate activity.
PubMed: 38934331
DOI: 10.1111/bjh.19605