Abstract Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a non-surgical alternative. This systematic review and meta-analysis aims to assess the ...efficacy and safety of chemonucleolytic enzymes for LDH. The primary objective is to evaluate efficacy through “treatment success” (i.e., pain reduction) and severe adverse events (SAEs) rates. Additionally, differences in efficacy and safety trends among chemonucleolytic enzymes are explored. Following our PROSPERO registered protocol (CRD42023451546) and PRISMA guidelines, a systematic search of PubMed and Web of Science databases was conducted up to July 18, 2023. Inclusion criteria involved human LDH treatment with enzymatic chemonucleolysis reagents, assessing pain alleviation, imaging changes, and reporting on SAEs, with focus on allergic reactions. Quality assessment employed the Cochrane Source of Bias and MINORS tools. Meta-analysis utilized odds ratios (OR) with 95% confidence intervals (CI). Among 62 included studies (12,368 patients), chemonucleolysis demonstrated an 79% treatment success rate and significantly outperformed placebo controls (OR 3.35, 95% CI 2.41–4.65) and scored similar to surgical interventions (OR 0.65, 95% CI 0.20–2.10). SAEs occurred in 1.4% of cases, with slightly higher rates in chymopapain cohorts. No significant differences in “proceeding to surgery” rates were observed between chemonucleolysis and control cohorts. Limitations include dated and heterogeneous studies, emphasizing the need for higher-quality trials. Further optimization through careful patient selection and advances in therapy implementation may further enhance outcomes. The observed benefits call for wider clinical exploration and adoption. No funding was received for this review.
An 11-year-old neutered male Domestic Shorthair cat presented with a 3-month history of hypoglycemia, two episodes of seizure, and intermittent tick-like signs. Serum biochemistry revealed severe ...hypoglycemia associated with high insulin concentrations. Dynamic abdominal computed tomography (CT) indicated two pancreatic masses, which were enhanced most during the late arterial phase but had different degrees and variations of attenuation. Partial pancreatectomy was performed. Histopathology and immunohistochemistry confirmed that one mass was an insulinoma and the other was an ectopic splenic tissue, consistent with the differences in imaging findings. When an intrapancreatic lesion with hyper-attenuation on dynamic abdominal CT is detected, not only insulinoma or metastasis of malignancies but also intrapancreatic accessory spleen (IPAS) should be considered as differential diagnoses.
To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA).
Of 346 patients who received 24 weeks of double-blind ...treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks.
The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity 28-joint Disease Activity Score (DAS28) ≤ 3.2, or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy.
TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.
We have studied the water durability of ZrO2 containing FeO–Fe2O3–P2O5 glasses for the immobilization of nuclear waste including Zr isotope. ZrP2O7 crystals with 1–2 micrometer in diameter were ...precipitated in the glass matrix incorporated with ≥1 mol % ZrO2. The molecular structure of phosphate network including ZrP2O7 precipitates was analyzed by micro-Raman spectroscopy. Formations of Q1 and Q0 phosphate units contributing to better water durability are ascribed to preferential precipitation of ZrP2O7 crystals with Q1 units and the compensation of phosphate component in residual glass matrix.
ObjectiveTo investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).MethodsPatients with TAK who had relapsed within the ...previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms.ResultsThe intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr’s definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths.ConclusionAlthough the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK.Trial registration numberJapicCTI-142616.
Enzyme-immobilized magnetic microparticles (EMMP) have been prepared for use as a microreactor in flow injection analysis (FI). The microparticles were directly injected into the FI system. Their ...retention occurred within the flow line by small permanent magnets located near the detector. The analytical utility of this concept was illustrated by the assay of glucose using glucose oxidase (GOx), immobilized microparticles, and amperometric detection of liberated hydrogen peroxide. The microparticles were derived from silica gel (nominal pore diameter, 15−80 nm) by impregnation with a citric acid/ethanol solution and a ferric nitrate/ethanol solution and then by calcination in a nitrogen atmosphere to produce ferrimagnetic fine particles of spinel-type iron oxide (γ-Fe2O3) inside the pore. They were characterized by X-ray diffraction. The calibration curve of the glucose sample (2 μL injected) was linear between 2.5 × 10-6 and 5 × 10-4 mol/L (R = 0.9995), and the detection limit was 1.0 × 10-6 mol/L or 0.36 ng of injected glucose (S/N = 3). The repeatability for a 5 × 10-4 mol/L glucose solution was RSD = 1.5% (n = 6). Application to the assay of glucose in a fermentation broth is illustrated. The GOx MMP were stable and active for more than eight months when kept at 10 °C.
Purity assay of high-purity materials (HPMs) of phthalic acid esters (PAEs) was carried out by means of a mass balance method. In this method, chromatographic methods such as gas chromatography-flame ...ionization detector (GC-FID) and/or high-performance liquid chromatography (HPLC) in combination with other methods such as Karl-Fischer (KF) titration and vacuum evaporation (VE) were applied. The sum of the impurities estimated by these methods allowed the estimation of the purity of the main component by difference. Seven PAEs with varying side chain structures and levels of impurities were analysed on a systematic way in which impurities were classified into several groups in terms of their abundance, availability of qualitative information and availability of authentic compounds, etc. The absolute quantity of each impurity was determined by GC-FID and/or HPLC based on the calibration made by the authentic compounds of impurities whenever available. The purities in mass fraction of these PAEs were certified at the National Metrology Institute of Japan (NMIJ), and the PAEs were registered as primary reference materials playing an essential role in linking the metrological traceability of the Japan Calibration Service System (JCSS) to the International System of Units (SI).
INTRODUCTION:
Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII and is currently indicated for routine prophylaxis of bleeds in patients with congenital ...hemophilia A (CHA) regardless of factor VIII (FVIII) inhibitor status. Nonclinical investigations suggest that emicizumab would be efficacious for preventing bleeds also in patients with acquired hemophilia A (AHA) (J Thromb Haemost 2020;18:825-33). However, no dedicated investigations have been performed to explore the optimal dosing algorithm of emicizumab for AHA. We present herein a proposed dosing algorithm of emicizumab potentially appropriate for AHA.
METHODS:
The dose selection for AHA aimed to achieve trough levels of plasma emicizumab concentration (Ctrough) of >30 μg/mL in most patients, at which the effect of emicizumab for preventing bleeds is expected to be almost maximized as in patients with CHA (Res Pract Thromb Haemost 2019;3Suppl 1:315). Because the time spent with a high risk of bleeding in AHA is much shorter than in CHA due to the immunosuppressive therapy (IST) given to eradicate FVIII inhibitors (a reported median is 31 days Blood 2015;125:1091-7), and because bleeding symptoms in AHA can be severer than in CHA, the loading dose duration of 4 weeks for the current approved subcutaneous dosing regimens of emicizumab for CHA (i.e., 3 mg/kg once weekly QW for first 4 weeks loading dose followed by 1.5 mg/kg QW, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks from the 5th week onwards maintenance dose) was considered too long to maximize the effect of emicizumab in AHA. In addition, the potential risk of hypercoagulation associated with coexistence of emicizumab and FVIII restored as a consequence of successful IST was concerning. Modification of the loading dose together with definition of an appropriate timing for the dosing completion of emicizumab were therefore considered necessary.
Exploration of a modified dosing regimen was performed by pharmacokinetic (PK) simulations using a population PK model developed in patients with CHA (Clin Pharmacokinet 2020 Jun 5) with the covariates adjusted for patients with AHA. The given dose per administration was capped at the maximum one approved for CHA. The dosing frequency of the maintenance dose was set to QW, aiming to keep the maximum plasma emicizumab concentration at steady state low for minimizing the potential risk of hypercoagulation after FVIII activity is restored. Development of the dosing completion criteria for emicizumab was addressed by a literature review.
RESULTS:
A modified subcutaneous dosing regimen of 6 mg/kg and 3 mg/kg on the 1st and 2nd days of the 1st week, respectively (loading dose), followed by 1.5 mg/kg QW from the 2nd week onwards (maintenance dose) was found to meet the defined requirements for AHA. With the modified dosing regimen, the median Ctrough was predicted to achieve >30 μg/mL by the 2nd week and to reach steady state by the 3rd week, which would allow for rapider maximization and stabilization of the effect of emicizumab than with the current approved QW dosing regimen (Figure). However, there remained uncertainty in the PK predictions in association with the older age and severer disease conditions in AHA than in CHA, which may require further adaptation of the dosing regimen in case of insufficient exposure or efficacy.
In reference to the lower limit of the normal range of FVIII activity and the definitions of partial remission employed in previous researches, an endogenous FVIII activity of >50 IU/dL measured in the absence of interference by emicizumab was selected for a criterion for guiding the dosing completion of emicizumab. In addition, taking into account a standardized definition of a bleeding event (J Thromb Haemost 2014;12:1935-9) together with the bleeds in AHA possibly occurring even if FVIII is restored, absence of using coagulation factor products for >72 hours after the last episodic use of coagulation factor products was considered as another dosing completion criterion to be met.
CONCLUSIONS:
A dosing algorithm of emicizumab potentially appropriate for prophylaxis in AHA was proposed leveraging literature information and PK simulations. The appropriateness of the selected dosing regimen together with the developed dosing completion criteria is currently under investigation with possibility of data-driven adaptations in a clinical study (AGEHA; JapicCTI-205151).
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Shima:Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity’s Board of Directors or advisory committees; Chugai Pharmaceutical Co.: Consultancy; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Honoraria. Nagami:Chugai Pharmaceutical Co., Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Yoneyama:Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Nomura:Chugai Pharmaceutical Co., Ltd.: Current Employment. Ogawa:Chugai Pharmaceutical Co., Ltd.: Consultancy; Bayer AG: Research Funding. Amano:Pfizer Inc.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; F. Hoffmann-La Roche Ltd.: Research Funding; CSL Behring: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Sanofi S.A.: Speakers Bureau; Bayer AG: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau. Nogami:Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shire Plc: Research Funding, Speakers Bureau; Bioverativ Inc.: Research Funding, Speakers Bureau; Novo Nordisk A/S: Research Funding, Speakers Bureau; Bayer AG: Research Funding, Speakers Bureau.
Emicizumab for acquired hemophilia A
Rationale
The long-term effectiveness of olanzapine and aripiprazole in real clinical conditions at flexible doses in patients after hospital discharge has not been evaluated yet.
Objectives
This ...study was a multicenter retrospective cohort study. Patients with schizophrenia (
n
= 398) were prescribed olanzapine (
n
= 303) or aripiprazole (
n
= 95) at hospital discharge. The continuation of olanzapine or aripiprazole at 26, 52, or 104 weeks after the hospital discharge were compared using a Cox proportional hazards model and adjusted for possible confounders.
Results
The Kaplan–Meier survival curves revealed that the continuation of olanzapine at 26 (
P
= 0.001) and 52 weeks (
P
= 0.018) was significantly higher than that of aripiprazole but not at 104 weeks. Olanzapine was better than aripiprazole in efficacy at 26 (hazard ratio: 0.321, 95% confidence interval: 0.159–0.645,
P
= 0.001), 52 (hazard ratio: 0.405, 95% confidence interval: 0.209–0.786,
P
= 0.008), and 104 weeks (hazard ratio: 0.438, 95% confidence interval: 0.246–0.780,
P
= 0.005). Aripiprazole was better than olanzapine in tolerability at 104 weeks (hazard ratio: 4.574, 95% confidence interval: 1.415–14.787,
P
= 0.011). Rates after two years continuation of olanzapine and aripiprazole were not significantly different in patients with less than five years' duration of illness, but olanzapine was more commonly maintained for more than two years in those patients who had been ill for over five years' due to its greater efficacy.
Conclusion
Olanzapine treatment showed better continuation rates at 26 and 52 after hospital discharge than aripiprazole, whereas maintenance with the two antipsychotics did not differ significantly at 104 weeks, due reduced tolerability of long-term olanzapine treatment.
Malignant hyperthermia (MH) is a rare but potentially fatal complication that may develop under general anesthesia (GA) and is rarely reported in elderly patients. We encountered a case of mild-onset ...MH in a 70-year-old patient who was receiving an elective thoracoscopic pulmorrhaphy and had a history of several GA procedures. Anesthesia was induced with propofol, fentanyl, and rocuronium and maintained with sevoflurane and remifentanil. His body temperature (BT) was 37.9°C after induction. During the procedure, the end-tidal CO2 (ETCO2) increased steadily to 47–50 mmHg, presumably in response to the single lung ventilation. At the end, BT was 38.1°C and ETCO2 was 47 mmHg under spontaneous breathing. After extubation, the patient wheezed on inspiration and expiration, and his trachea was reintubated. Sixty minutes after surgery, BT increased to 40.5°C and the arterial blood gas analysis showed severe metabolic acidosis. Based on these findings, MH was suspected and a bolus dose of dantrolene was administered. He responded to the dantrolene, and no complications or recurrence of MH was observed postoperatively. In this patient, the initial signs of MH were so subtle that making the diagnosis of MH was difficult. A high degree of suspicion is necessary to prevent a fulminant MH crisis.
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