Continuous Administration Research Articles

Varicella-associated disseminated intravascular coagulation secondary to Henoch-Schönlein purpura with renal and gastrointestinal system involvement in a child: A case report.

Immunocompromised patients who developed varicella-zoster virus (VZV)-associated disseminated intravascular coagulation (DIC) previously included recipients of bone marrow, hematopoietic stem cell, or organ transplantations, patients with primary nephropathy receiving corticosteroid therapy, cancer patients receiving chemotherapy, and patients with human immune deficiency virus infection. The case reported here is novel because, to our knowledge, there has been no report of VZV-associated DIC after the onset of Henoch-Schönlein purpura (HSP). To report the successful treatment of a novel pediatric case with VZV-associated DIC secondary to HSP. An 8-year-old girl developed VZV-associated DIC 24 days after diagnosis of HSP with renal and gastrointestinal involvement. She was treated with methylprednisolone at a local hospital for 19 days, and suddenly developed fever starting from day 4 in our hospital. Her fever persisted with vesicular skin rashes on her back, strong abdominal and lower back pain, epistaxis, hematochezia, erosion and bleeding on her lips, in her mouth and at puncture sites on day 5. She was diagnosed with DIC with the laboratory evidence of dramatically decreased platelet count and fibrinogen, prolonged activated partial thromboplastin time and prothrombin time, and increased fibrin degradation products including d-dimers. She also developed multiple organ dysfunction syndrome. On day 7, the patient VZV nucleic acid result turned out to be positive. Methylprednisolone treatment was discontinued, and she was given a multi-modality therapy including medications of acyclovir and antibiotics, intravenous gamma-immunoglobulin, various blood product transfusions, continuous renal replacement therapy, plasma exchange, and administration of liver and gastrointestinal system protection drugs. The patient multi-organ function damage gradually recovered. After VZV control, the patient was treated with oral methylprednisolone again for HSP with nephritis. Urine analysis was normal 1 year later, and oral hormone was discontinued. No complication or relapse occurred during 2 years of follow-up. This case report, for the first time, adds HSP treated with corticosteroids to the spectrum of clinical conditions that progressed to life-threatening secondary varicella-associated DIC. Early identification of varicella infection and DIC, combined with timely antiviral, immunoglobulin transfusion, plasma exchange, and other combined therapies are essential for saving patients' lives.

Postoperative clinical outcomes with and without short-term intravenous tranexamic acid after posterior lumbar interbody fusion: A prospective cohort study.

The use of tranexamic acid (TXA) in posterior lumbar interbody fusion (PLIF) surgery is believed to be beneficial for reducing intraoperative blood loss, postoperative drainage volume (PDV), and length of hospital stay (LOS). However, whether continued administration of intravenous TXA within 24 hours after surgery is more beneficial to patients has not yet been studied. This study prospectively analyzed the perioperative outcomes of patients who received and did not receive intravenous TXA within 24 hours after PLIF (≥2 segments) surgery from January 2018 to December 2021. A total of 78 and 69 patients were included in the TXA (receive intravenous TXA intraoperatively and within 24 hours postoperatively) and non-TXA (only receive intravenous TXA intraoperatively) groups, respectively. No significant differences were observed in the intraoperative blood loss and operative time between the 2 groups. The postoperative drainage volume, postoperative drainage time, and length of hospital stay in the TXA group were significantly lower than those in the non-TXA group. The rates and volumes of postoperative blood and albumin transfusions were significantly lower in the TXA group than those in the non-TXA group. No significant differences were observed in the perioperative complication rates between the 2 groups. No increase in thrombosis-related complications was observed with postoperative TXA administration. Short-term TXA use after PLIF (≥2 segments) surgery is safe. In addition to intraoperative use of TXA, additionally administration of intravenous TXA within 24 hours postoperatively can improve the perioperative clinical outcomes of patients without increasing the risk of thrombotic events.

Fe-doped carbon dots: a novel biocompatible nanoplatform for multi-level cancer therapy

BackgroundTumor treatment still remains a clinical challenge, requiring the development of biocompatible and efficient anti-tumor nanodrugs. Carbon dots (CDs) has become promising nanomedicines for cancer therapy due to its low cytotoxicity and easy customization.ResultsHerein, we introduced a novel type of “green” nanodrug for multi-level cancer therapy utilizing Fe-doped carbon dots (Fe-CDs) derived from iron nutrient supplement. With no requirement for target moieties or external stimuli, the sole intravenous administration of Fe-CDs demonstrated unexpected anti-tumor activity, completely suppressing tumor growth in mice. Continuous administration of Fe-CDs for several weeks showed no toxic effects in vivo, highlighting its exceptional biocompatibility. The as-synthesized Fe-CDs could selectively induce tumor cells apoptosis by BAX/Caspase 9/Caspase 3/PARP signal pathways and activate antitumoral macrophages by inhibiting the IL-10/Arg-1 axis, contributing to its significant tumor immunotherapy effect. Additionally, the epithelial-mesenchymal transition (EMT) process was inhibited under the treatment of Fe-CDs by MAPK/Snail pathways, indicating the capacity of Fe-CDs to inhibit tumor recurrence and metastasis.ConclusionsA three-level tumor treatment strategy from direct killing to activating immunity to inhibiting metastasis was achieved based on “green” Fe-CDs. Our findings reveal the broad clinical potential of Fe-CDs as a novel candidate for anti-tumor nanodrugs and nanoplatform.

Transvenous Radiofrequency Catheter Ablation for an Aldosterone-Producing Tumor of the Left Adrenal Gland: A First in Human Case Report

PurposeTo describe a novel technique of transvenous radiofrequency catheter ablation of an aldosterone-producing adenoma (APA) of the left adrenal gland using the GOS System (Japan Lifeline, Tokyo, Japan). Using the GOS system, a flexible radiofrequency tip catheter can be inserted into the adrenal central and tributary veins, the drainers for functional tumors.Materials and methodsAn APA at the left adrenal gland, which was diagnosed by segmental adrenal venous sampling following administration of 0.25 mg cosyntropin, was ablated using the GOS catheter inserted into adrenal tributary veins via a right femoral vein 7-Fr sheath. The effect of radiofrequency ablation on APA was assessed using the international consensus on surgical outcomes for unilateral primary aldosteronism (PA).ResultsNo device-related complications were observed. The patient was deeply sedated under blood pressure and heart rate control with continuous administration of β-blockers. Then, the tumor and surrounding adrenal gland were cauterized at 7000 J two times each in sequence. The output time was 7−11 min for each ablation and 80 min in total. For blood pressure and pulse rate control, esmolol hydrochloride and phentolamine mesylate were used. The contrast enhancement of APA disappeared on dynamic CT immediately after the procedure. PA was biochemically cured until 12 months after the procedure.ConclusionUsing the radiofrequency device with the GOS catheter and system is a method for cauterizing adrenal tumors from blood vessels. This approach resulted in a marked reduction in aldosterone concentrations and a complete biochemical cure of PA over the observation period.Graphical

Efficacy, safety, and pharmacokinetics of MR13A11A, a generic of remifentanil, for pain management of Japanese patients in the intensive care unit: a double-blinded, fentanyl-controlled, randomized, non-inferiority phase 3 study

BackgroundThe aims of this study were to evaluate the efficacy, safety, and pharmacokinetics (PK) of continuous intravenous administration of remifentanil in mechanically ventilated patients in the intensive care unit (ICU).MethodsThis was a multicenter, randomized, double-blinded, fentanyl-controlled, non-inferiority phase 3 study. Patients aged ≥ 20 years requiring 6 h to 10 days mechanical ventilation in an ICU and requiring pain relief were randomly assigned in a 1:1 ratio to receive either remifentanil (n = 98) or fentanyl (n = 98). Dose was titrated from an infusion rate of 1 mL/h (remifentanil: 0.025 µg/kg/min, fentanyl: 0.1 µg/kg/h) until the target level of analgesia (behavioral pain scale [BPS] ≤ 5 or numerical rating score [NRS] ≤ 3) was achieved by escalating the dose in 1 mL/h increasing. Administration was then adjusted to maintain the target level of analgesia until weaning from the ventilator. The primary endpoint was the proportion of patients who did not require rescue fentanyl. Safety was assessed according to standard procedures. PK of remifentanil in the arterial blood was assessed in 24 patients.ResultsThe proportion of patients achieving the primary endpoint in the remifentanil and fentanyl groups was 100% (92/92) and 97.8% (88/90), respectively. The difference between the groups was 2.2% (95% confidence interval, − 0.8–5.3) and non-inferiority of remifentanil to fentanyl was verified (p < 0.0001). The incidences of any adverse events in the remifentanil and fentanyl groups was 34 of 92 patients (37.0%) and 34 of 90 patients (37.8%), respectively. Adverse drug reactions was 12 in 92 patients (13.0%) and 15 in 90 patients (16.7%), respectively. In the PK analysis, blood remifentanil concentration decreased within 10 min to almost 50% of the end of administration, suggesting rapid offset of action following discontinuation of remifentanil.ConclusionsRemifentanil can be used safely for pain management in mechanically ventilated Japanese patients in the ICU.Trial registration: Japan Registry of Clinical Trials, jRCT2080224954. Registered 20 November 2019, https://jrct.niph.go.jp/latest-detail/jRCT2080224954.

Preclinical Hemotoxicological Profile Investigations of an Ayurvedic Medication Following Long-Term Adminidration to Male Sprague-Dawley Rats

Kutajarista (KTJ) is an Ayurvedic preparation used as a traditional medicine in ulcerative colitis in the rural population. A self-made alcoholic preparation derived from the Indian Medical System known as Kutajarishta. The main ingredient in this polyherbal combination is Holarrhena antidysenterica Wall. Ex DC (Family: Apocynaceae). It is used to treat gastrointestinal disorders, diarrhea, and amebic dysentery. Ayurvedic practitioners have been using Kutaja formulations for centuries, as they have been found to be quite helpful clinically in certain diseases. This study was conducted using mainly old literature as a basis method. At a dose of 40 milliliters per kilogram, KTJ was given chronically to male Sprague-Dawley rats in order to determine its toxicological characteristics. Following a continuous 28-day KTJ preparation administration, the following toxicological alterations were observed. Several erythrocytic parameters were found in this experiment. The anemia panel studies' findings are as follows: The total amount of red blood cells in the male rat has decreased by [7.98%]. This drop was noticeable (p=0.083) even if it was not statistically significant. There is a [8.08 %] decrease in the Hemoglobin content of the blood of the male rat, the decrease though not significant yet it was prominent (p=0.097). There is a [8.03 %] decrease in the Hematocrit level of the blood of the male rat, the decrease though not significant yet it was prominent (p=0.072). There is a statistically insignificant (p=0.882) [0.19 %] increase in the Mean corpuscular volume, a red cell index of the male rat. There is a statistically insignificant (p=0.420) [3.02 %] decrease in the Mean corpuscular hemoglobin, a red cell index of the male rat. A statistically insignificant (p=0.203) [8.50 %] increase in the red cell volume distribution width, a red cell index of the male rat, is observed, along with a negligible [3.01 %] decrease in the Mean corpuscular hemoglobin concentration, a red cell index of the male rat, which was statistically not at all significant (p=0.561).

Updated Results from a Phase I Dose Escalation Study of the Rapidly-Switchable Universal CAR-T Therapy UniCAR-T-CD123 in Relapsed/Refractory AML

Introduction CAR-T efficacy in AML has been limited by a lack of ideal target antigens as well as the aggressive and resistant nature of disease. CD123 expression on leukemic blasts has been observed in about 80% of AML patients. However, the antigen is also expressed on non-malignant hematopoietic cells including neutrophils and endothelial cells. As consequence, targeting of CD123 with conventional CAR-T has been shown to result in persistent cytopenias, capillary leakage syndrome, CRS, and ICANS. AVC-101 (UniCAR02-T-CD123) is an adapter CAR-T, consisting of a universal CAR-T cell (UniCAR-T) and a CD123 targeting module (TM). The TM binds to the CAR-T cell via a peptide tag and induces T cell activity against CD123 bearing cells. Due to the short half-life of the TM, interruption of its continuous IV administration will rapidly switch T cell activity off, and mitigate toxicities as shown previously. Since the presentation of initial results, the study was amended to include a stricter and prolonged schedule of TM consolidation cycles. Given the excellent safety enabled by the switchable mechanism, additional dose levels (DL) of TM were added. Methods Key inclusion criteria included rrAML patients with ECOG ≤ 1, CD123 expression in ≥ 20% of blasts, and no suitable approved treatment option available or MRD positive AML patients. Initial dosing was applied using an adaptive Bayesian optimal interval design for drug-combination trials, escalating either cell dose or TM concentration based on posterior probability calculation of AEs. Dose escalation for the two additional dose levels was guided by a classical 3+3 design. Patients received standard Flu/Cy lymphodepletion (LD) for 3 days and TM was administered as continuous infusion, whereas UniCAR-T cells were given as one-time infusion on cycle 1 day 1. After completion of the initial 20-day induction cycle, responding patients were allowed to receive up to 3 consolidation cycles of 12 days continuous TM infusion with 7-14 days treatment free intervals in between cycles. Results As of this time 19 patients have received the induction cycle, 8 patients have also received at least one consolidation cycle (1-3, total 13 cycles). Patients were heavily pretreated with a median of 4 (2-7) prior treatment lines. Twelve of these patients had received a prior allogeneic (Allo) stem cell transplantation (SCT). Most of the patients (60%) were in adverse risk category according to ELN classification. In the initial escalation phase, 19 patients were treated in 16 dose cohorts. We observed a single DLT at DL 8 (reversible drop in fibrinogen levels, reported earlier) but no DLTs occurred in 11 patients treated in the yet highest dose cohort of 4 mg/day TM and 500 million UniCAR-T. Treatment was generally well tolerated irrespective of age and prior treatments. CRS was observed in 12 patients, mostly grade 1 or 2. Three grade 3 CRS and 1 grade 2 ICANS were reported, all resolving within 24 hrs from interruption of TM administration. Treatment-related AEs were most frequent in cycle 1, none were reported in cycles 3 and 4. No treatment-induced lasting myelosuppression was observed, and no patient required SCT support for WBC reconstitution. ORR in the first 19 patients was 53% (8/15) for the rrAML population and 75% (3/4) for the MRD population. Since the last presentation, extended administration of TM (20-day induction followed by three 12-day consolidation cycles 1-2 weeks apart) initiated by protocol amendment resulted in durable, ongoing responses approaching 5 months, longer than any prior. A 64-year-old MRD+ patient (#19) with 4 prior lines of therapy experienced a 3-log reduction in MRD levels (NPM1 mutation by qPCR) in both bone marrow and blood (Figure 1) and became transplant eligible. Re-administration of TM resulted in a significant re-expansion of UniCAR-T (Figure 2) without further cell dosing or LD. Another patient (#20) with overt hematological relapse after AlloSCT achieved a CR, ongoing at 5 months. Full safety and efficacy results of the additional 2 dose cohorts with prolonged TM consolidation will be presented at the meeting. Conclusions AVC-101 continues to be safe and tolerable. Repeated dosing of TM in consolidation cycles resulted in robust re-expansion of UniCAR-T with deeper remissions of extended durability. The switchable mechanism provides proven rapid reversal of safety events, enabling higher dose levels.

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 &amp;lt;200 was the only risk factor (AUTC 14-28&amp;lt;200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 &amp;lt;200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 &amp;lt;200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 &amp;lt;200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

An Open-Label, Multicenter, Single-Arm, Phase I Dose Escalation Study of OP-2100, an Orally Bioavailable Prodrug of Decitabine, for Patients with Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

CONCLUSIONS Hypomethylating agents (HMA) are commonly used to treat high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Decitabine (DEC), one of the HMAs, is S phase-specifically incorporated into DNA to exert its effect, and sustained plasma concentration may increase its efficacy (Saunthararajah et al. J Clin Invest. 2015). Therefore, we developed OP-2100, an orally bioavailable prodrug of DEC. It showed equal efficacy to conventional HMAs in various blood cancer mouse models and exhibited a favorable safety profile in healthy mice (Watanabe et al. Blood. 2020; Ureshino et al. Mol Cancer Ther. 2021). In addition, it exhibited a sustained-release pharmacokinetic (PK) profile when orally administered to monkeys. In a phase I study, OP-2100 monotherapy showed the expected PK profile on patients with relapsed or refractory higher-risk MDS and CMML, and we reported the preliminary result. We designed a single-arm, multicenter phase I study for Japanese patients with MDS or CMML with intermediate-risk, high-risk, or very high-risk by Revised International Prognostic Scoring System (IPSS-R) and relapsed, refractory, or intolerant to standard therapy. The primary objective was to determine the maximum tolerated dose following the incidence of dose-limiting toxicity (DLT) in the first cycle, whereas the secondary objectives were to evaluate the safety, PK, and efficacy. Treatment-emergent adverse events (TEAEs) and response to therapy were assessed per NCI CTCAE v5.0 and IWG 2018 response criteria, respectively. Oral administration of OP-2100 as a single agent was continued for the patients daily on days 1-5 of each 28-day cycle until meeting discontinuation criteria, including disease progression. The dose level was defined as 30, 50, 80, and 120 mg/day. The initial dose of 50 mg/day was determined based on the highest non-severely toxic dose of OP-2100 in monkeys and the PK of DACOGEN TM in humans. This study was implemented in the 3+3 design according to DLT incidence. The plasma concentration of DEC and OP-2100 was measured on days 1 and 5. Furthermore, the LINE-1 methylation, a common HMA pharmacodynamics marker, was measured. This study is registered in the Japan Registry for Clinical Trials (jRCT2071220035). In total 3 patients with a history of azacitidine treatment for MDS were registered in the 50-mg initial cohort. These patients had been categorized as intermediate to high-risk in the IPSS-R, respectively. Table 1 shows patient characteristics. Out of 3, 2 patients did not experience DLT, while the 3rd one suffered from Grade 4 neutropenia, which was confirmed as DLT. As of April 30, the most common TEAEs were cytopenia of leukopenia, neutropenia, and thrombocytopenia, all of which were Grade 3 or 4. Other adverse events of Grade 3 or 4 include anemia, lymphopenia, COVID-19, and fall. In terms of efficacy, 2 patients had stable disease, while one had progressive, according to the IWG2018 response criteria. However, the 2 patients with stable disease still received administration up to 9 and 5 cycles, respectively (Figure 1). The PK profile of DEC after OP-2100 administration indicated sustained release, with an area under the curve (AUC) similar to that of DACOGEN TM (5-day regimen, 1-h continuous intravenous administration at 20 mg/m 2) and C max approximately 1/5. The LINE-1 methylation exhibited the similar behavior as conventional HMAs. The PK profile of DEC released from the prodrug after 50 mg of OP-2100 oral administration in 3 patients showed a similar AUC to that of the 5-day regimen of DACOGEN TM, and then C max showed a low with sustained plasma concentration. Among the 3 patients, OP-2100 could be administered for at least 5 cycles in 2 patients. To determine maximum tolerated dose, enrollment for this study is ongoing.

Intra-soft tissue and intramedullary antibiotic perfusion in combination with negative pressure wound therapy.

Intra-soft tissue and intramedullary antibiotic perfusion (iSAP and iMAP), which combine continuous administration of antibiotic solution to the wound and negative pressure wound therapy (NPWT), have been reported to be a useful management approach for hard-to-heal ulcers in the field of orthopaedic surgery. We report the efficacy of this treatment and discuss the key points. The recipients of this treatment had contaminated fresh severe trauma with a high risk of infection, or hard-to-heal ulcers which were expected to be difficult to manage with conventional NPWT alone. Continuous administration of 1200µg/ml of gentamicin (GM) solution to the wound was performed along with NPWT. The GM solution was administered subcutaneously using a small catheter for iSAP, while intramedullary administration used a bone marrow needle for iMAP. iSAP was employed in all 10 patients who took part, and iMAP in three of these patients. The average treatment time was 13.6 days with iSAP and 9.3 days with iMAP. The mean serum GM level during the therapy was 1.02µg/ml. Moderate GM-induced acute kidney injury was suspected in one case, but resolved spontaneously after GM administration was stopped. Favourable wound bed preparation was achieved in all cases without recurrence of infection. Combination with continuous suction by NPWT is able to keep the local concentration of antibiotic above the minimum inhibitory concentration of biofilm-coated bacteria within the wound. We have referred to this treatment as continuous local antibiotic perfusion. Further investigation of local pharmacodynamics in the wound and side-effects of this treatment are warranted.

Oral Furosemide and Hydrochlorothiazide/Amiloride versus Intravenous Furosemide for the Treatment of Resistant Nephrotic Syndrome

Background: Data on diuretic treatment in nephrotic syndrome (NS) are scarce. Our goal was to assess the non-inferiority of the combined oral diuretics (furosemide/hydrochlorothiazide/amiloride) compared to intravenous (i.v.) furosemide in patients with NS and resistant edema. Methods: We conducted a prospective randomized trial on 22 patients with resistant nephrotic edema (RNE), defined as hypervolemia and a FENa &lt; 0.2%. Based on a computer-generated 1:1 randomization, we assigned patients to receive either intravenous furosemide (40 mg bolus and then continuous administration of 5 mg/h) or oral furosemide (40 mg/day) and hydrochlorothiazide/amiloride (50/5 mg/day) for a period of 5 days. Clinical and laboratory measurements were performed daily. Hydration status was assessed by bioimpedance on day 1 and at the end of day 5 after treatment initiation. The primary endpoint was weight change from baseline to day 5. Secondary endpoints were hydration status change measured by bioimpedance and safety outcomes (low blood pressure, severe electrolyte disturbances, acute kidney injury and worsening hypervolemia). Results: Primary endpoint analysis showed that after 5 days of treatment, there was a significant difference in weight change from baseline between groups [adjusted mean difference: −3.33 kg (95% CI: −6.34 to −0.31), p = 0.03], with a higher mean weight change in the oral diuretic treatment group [−7.10 kg (95% CI: −18.30 to −4.30) vs. −4.55 kg (95%CI: −6.73 to −2.36)]. Secondary endpoint analysis showed that there was no significant difference between groups regarding hydration status change [adjusted mean difference: −0.05 L (95% CI: −2.6 to 2.6), p = 0.96], with a mean hydration status change in the oral diuretic treatment group of −4.71 L (95% CI: −6.87 to −2.54) and −3.91 L (95% CI: −5.69 to −2.13) in the i.v. diuretic treatment group. We observed a significant decrease in adjusted mean serum sodium of −2.15 mmol/L [(95% CI: −4.25 to −0.05), p = 0.04]), favored by the combined oral diuretic treatment [−2.70 mmol/L (95% CI: −4.89 to −0.50) vs. −0.10 mmol/L (95%CI: −1.30 to 1.10)]. No statistically significant difference was observed between the two groups in terms of adverse events. Conclusions: A combination of oral diuretics based on furosemide, amiloride and hydrochlorothiazide is non-inferior to i.v. furosemide in weight control of patients with RNE and a similar safety profile.

Metronomic chemotherapy in ovarian cancer

Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer over the last decade. However, recurrent ovarian cancer continues to pose formidable challenges to therapeutic interventions, necessitating innovative strategies to optimize treatment outcomes. Current research focuses on the development of pharmaceuticals that target potential resistance pathways to DNA repair pathways. However, the cost and toxicity of some of these therapies are prohibitive and majority of patients lack access to clinical trials. Metronomic chemotherapy, characterized by the continuous administration of low doses of chemotherapeutic agents without long treatment breaks, has emerged as a promising approach with potential implications beyond recurrent setting. It acts primarily by inhibition of angiogenesis and activation of host immune system. We here review the mechanism of action of metronomic chemotherapy, as well as its current role, limitations, and avenues for further research in the management of epithelial ovarian cancer.

Protective effect of Liujing Toutong Tablets on rats with permanent cerebral ischemia via NF-κB signaling pathway

This study investigated the neuroprotective effects and underlying mechanism of Liujing Toutong Tablets(LJTT) on a rat model of permanent middle cerebral artery occlusion(pMCAO). The pMCAO model was established using the suture method. Eighty-four male SPF-grade SD rats were randomly divided into a sham operation group, a model group, a nimodipine group(0.020 g·kg~(-1)), and high-, medium-, and low-dose LJTT groups(2.8, 1.4, and 0.7 g·kg~(-1)). The Longa score, adhesive removal test and laser speckle contrast imaging technique were used to evaluate the degree of neurological functional impairment and changes in local cerebral blood flow. The survival and mortality of rats in each group were recorded daily. After seven days of continuous administration following the model induction, the rats in each group were euthanized, and brain tissue and blood samples were collected for corresponding parameter measurements. Nissl staining was used to examine pathological changes in brain tissue neurons. The levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), IL-1β, vascular endothelial growth factor(VEGF), calcitonin gene-related peptide(CGRP), beta-endorphin(β-EP), and endogenous nitric oxide(NO) in rat serum were measured using specific assay kits. The entropy weight method was used to analyze the weights of various indicators. The protein expression levels of nuclear factor kappa-B(NF-κB), inhibitor kappaB alpha(IκBα), phosphorylated IκBα(p-IκBα), and phosphorylated inhibitor of NF-κB kinase alpha(p-IKKα) in brain tissue were determined using Western blot. Immunohistochemistry was used to detect the protein expression of chemokine-like factor 1(CKLF1) and C-C chemokine receptor 5(CCR5) in rat brain tissue. Compared with the sham operation group, the model group showed significantly higher neurological functional impairment scores, prolonged adhesive removal time, decreased cerebral blood flow, increased neuronal damage, reduced survival rate, significantly increased levels of TNF-α, IL-1β, IL-6, CGRP, and NO in serum, significantly decreased levels of VEGF and β-EP, significantly increased expression levels of NF-κB p65, p-IκBα/IκBα, and p-IKKα in rat brain tissue, and significantly upregulated protein expression of CKLF1 and CCR5. Compared with the model group, the high-dose LJTT group significantly improved the neurological functional score of pMCAO rats after oral administration for 7 days. LJTT at all doses significantly reduced adhesive removal time and restored cerebral blood flow. The high-and medium-dose LJTT groups significantly improved neuronal damage. The LJTT groups at all doses showed reduced levels of TNF-α, IL-1β, IL-6, CGRP, and NO in rat serum, increased VEGF and β-EP levels, and significantly decreased expression levels of NF-κB p65, p-IκBα/IκBα, p-IKKα, and CCR5 protein in rat brain tissue. The entropy weight analysis revealed that CGRP and β-EP were significantly affected during the model induction, and LJTT exhibited a strong effect in reducing the release of inflammatory factors such as TNF-α and IL-1β. LJTT may exert a neuroprotective effect on rats with permanent cerebral ischemia by reducing neuroinflammatory damage, and its mechanism may be related to the inhibition of the NF-κB signaling pathway and the regulation of the CKLF1/CCR5 axis. Additionally, LJTT may exert certain analgesic effects by reducing CGRP and NO levels and increasing β-EP levels.

Mercury species analysis and tissue distribution in rats after continuous administration of Cinnabaris

Cinnabaris is a traditional Chinese medicine(TCM) commonly used for sedation and tranquilization in clinics, and its safety has always been a concern. This study intends to investigate the species and tissue distribution of mercury in rats after continuous administration of Cinnabaris. In the experiment, 30 rats were randomly divided into the control group(equivalent to 0.5% carboxy-methyl cellulose sodium), low-dose Cinnabaris group(0.2 g·kg~(-1)), high-dose Cinnabaris group(2 g·kg~(-1)), pseudogerm-free control group(equivalent to 0.5% sodium carboxymethyl cellulose), and pseudogerm-free Cinnabaris group(2 g·kg~(-1)). They were orally administered for 30 consecutive days. Ultrasound-assisted acid extraction method combined with high performance liquid chromatography and inductively coupled plasma-mass spectrometry(HPLC-ICP-MS) was adopted to determine inorganic mercury [Hg(Ⅱ)], methylmercury(MeHg), and ethylmercury(EtHg) in different tissue, plasma, urine, and feces of rats. The optimal detection conditions and extraction methods were optimized, and the linearity(R~2&gt;0.999 3), precision(RSD&lt;7.0%), and accuracy(spike recoveries ranged from 73.05% to 109.5%) of all the mercury species were satisfied, meeting the requirements of analysis. The results of mercury species detection showed that Hg(Ⅱ) was detected in all the tissue of the five experimental groups, and the main accumulating organs were the intestinal tract, stomach, and kidney. MeHg existed at a low concentration in most tissue, and EtHg was not detected in all groups. In addition, pathological examination results showed that hepatocyte vacuolar degeneration, loose cytoplasm, light staining, and mononuclear cell infiltration were observed in the high-dose Cinnabaris group, low-dose Cinnabaris group, and pseudogerm-free Cinnabaris group, with slightly milder lesions in the low-dose Cinnabaris group. Hydrous degeneration of renal tubular epithelium could be seen in the high-dose Cinnabaris group and pseudogerm-free Cinnabaris group, but there was no significant difference between the other groups and the control group. No abnormal changes were found in the brain tissue of rats in each group. This paper studied the different mercury species and tissue distribution in normal and pseudogerm-free rats after continuous administration of Cinnabaris for 30 days and clarified its effects on the tissue structure of the liver, kidney, and brain, which provided supporting evidence for the safety evaluation of Cinnabaris.

Estimation of the physiochemical characteristics of an antibiotic drug using M-polynomial indices

Antibiotics are more effective against intracellular bacterial infections. However, with continuous administration of antibiotics, cells acquire drug resistance. The bioconjugated Geranyl and farnesyl penicillin G is the best antibiotic to reduce the replication of bacteria inside the cells as compared to untreated cells. Topological index is a technique used for understanding the fundamental topology of chemical compounds investigated by the quantitative structure-properties relationship (QSPR). Özge Çolakoğlu Havare [43] developed the QSPR relation between M-polynomial indices and physiochemical characteristics. In this article, we have calculated the degree-based M-polynomial indices for the geranyl and farnesyl penicillin G bioconjugate structure. Based on the results of Özge Çolakoğlu Havare article, we can say that our computed results for antibiotic drug are helpful for predicting the physiochemical characteristics.

Application of surface-layer matrix-assisted laser desorption/ionization mass spectrometry imaging to pharmaceutical-loaded poly(ester urea) films

Polymer thin films are often used in transdermal patches as a method of continuous drug administration for patients with chronic illness. Understanding the drug segregation and distribution within these films is important for monitoring proper drug release over time. Surface-layer matrix-assisted laser desorption/ionization mass spectrometry imaging (SL-MALDI-MSI) is a unique analytical technique that provides an optical representation of chemical compositions that exist at the surface of polymeric materials. Solvent-free sublimation is employed for application of matrix to the sample surface, so that only molecules in direct contact with the matrix layer are detected. Here, these methodologies are utilized to visualize variations in drug concentration at both the air and substrate interface in pharmaceutical-loaded polymer films.

Acute cholecystitis with sepsis due to Edwardsiella tarda: a case report

BackgroundEdwardsiella tarda (E. tarda) is a Gram-negative facultative anaerobe belonging to Enterobacteriales and is commonly isolated from fishes and reptiles. Infection due to E. tarda is uncommon among humans, with a reported human retention rate of 0.001%. It can cause sepsis in the elderly or those with pre-existing conditions such as liver failure, autoimmune disease, or malignancy. E. tarda is susceptible to many antibiotics; however, a high mortality rate (approximately 40%) has been reported with sepsis.Case presentationA 65-year-old woman presented to our hospital with a chief complaint of fever and abdominal pain for 2 days. Her blood tests showed elevated inflammatory markers, and contrast-enhanced computed tomography showed distention and wall thickening of the gallbladder and inflammation of peri-gallbladder fat. Subsequently, a diagnosis of cholecystitis with systemic inflammatory response syndrome was made. Laparoscopic cholecystectomy was performed after starting antimicrobial therapy. Blood culture of samples obtained on admission were positive for E. tarda, which was also detected in bile juice culture. Therefore, she was diagnosed with bacteremia caused by E. tarda, and postoperative antimicrobial therapy was continued. The patient improved, and there were no complications.ConclusionsWe experienced an extremely rare case of acute cholecystitis caused by E. tarda. Only a few cases of acute cholecystitis due to E. tarda have been reported. Furthermore, similar to this case, no previous study has reported the detection of E. tarda in both blood and bile cultures in acute cholecystitis cases. In addition to appropriate surgical intervention, continuous administration of antibiotics based on culture results resulted in a favorable outcome.

Aqueous extracts of Ocimum gratissimum mitigate colitis and protect against AOM/DSS-induced colorectal cancer in mice.

In this study, we explored the in vivo effects of Ocimum gratissimum aqueous extracts (OGE) on colorectal cancer (CRC) development provoked by azoxymethane/dextran sodium sulfate (AOM/DSS). The results showed a significant reduction in the tumor load and tumor number for the OGEH group that received continued administration of OGE compared to the AOM/DSS group, with P values of <0.01, but this was not observed in the OGEHs group that received separated administration of OGE. All groups except the control group exhibited aberrant crypt foci (ACF) and adenocarcinoma of lesion pathology in colon, and both conditions were significantly reduced in the OGEH group (P < 0.01) as compared to the AOM/DSS group. Subsequent investigation into whether OGE exhibits eliminative effects on DSS-induced severe colitis (SC) in mice showed that the disease activity index score was significantly reduced in the OGE-treated groups (P < 0.01), also colon colitis histological score was reversed. These data suggest that OGE may be potentially effective in preventing CRC when administered throughout the promotional stages of carcinogenesis by inhibiting inflammatory SC.

Personalized application of antimicrobial drugs in pediatric patients with augmented renal clearance: a review of literature.

ARC impacts antimicrobial drugs in pediatric patients. • ARC is inextricably linked to the failure of antimicrobial therapy, recurrence of infection, and subtherapeutic concentrations of drugs. • This study provides an updated overview of the influence of ARC on medication use and clinical outcomes in pediatric patients. • In this context, there are several recommendations for using antibiotics in pediatric patients with ARC: 1) increase the dose administered; 2) prolonged or continuous infusion administration; 3) use of TDM; and 4) use alternative drugs that do not undergo renal elimination.

Lack of benefit from premedication for pegylated asparaginase during pediatric acute lymphoblastic leukemia/lymphoma therapy: A side-by-side comparison.

Pegylated l-asparaginase (PEG) is integral to treatment regimens for acute lymphoblastic leukemia (ALL) and lymphoma. Hypersensitivity reactions (HSRs) to PEG are common and can preclude continued administration. Data supporting recommendations for universal premedication (UPM) prior to PEG infusion to reduce incidence of HSRs are limited; UPM has become common practice. Two free-standing children's hospitals independently implemented UPM prior to PEG infusions in 2016 and 2019, respectively. In a side-by-side retrospective analysis, incidence and severity of HSRs were analyzed pre- and postimplementation of UPM in youth ≥1 years old treated with frontline PEG-containing ALL regimens (2015-2018, 2016-2020). All HSRs were centrally reviewed within each institution to confirm and grade the HSR (Common Terminology Criteria for Adverse Events, v5). Planned analyses of subsets at potentially greater risk for HSRs included intensive PEG regimens (≥5 doses), adolescent and young adults (AYA), Hispanic/Latinx ethnicity, and obesity. In 410 patients (by institution, n=282 and n=128), the overall incidence of Grade≥3 HSRs was 20% (56 out of 282) and 18% (23 out of 128), respectively. No difference in incidence of Grade≥3 HSRs in patients with versus without UPM was found at either institution (23vs. 19%, p=.487 and 19vs. 17%, p=.845). UPM also did not reduce the severity of HSRs, nor influence HSR risk within any patient subset. UPM prior to PEG infusion did not alter incidence or severity of HSRs at either institution. HSR remains a common complication of PEG therapy, impacting the patient experience. Alternative strategies to reduce HSRs are urgently required.