The study aimed to analyze the efficacy and safety of rituximab in the treatment of 23 cases of lupus nephritis and explore the prospect of half-dose rituximab in lupus nephritis treatment. Twenty-three patients with lupus nephritis hospitalized in the Department of Rheumatology and Immunology at the First Medical Center of the PLA General Hospital from May 2013 to December 2021 were selected. Eighteen patients received rituximab 375 mg/m2 on the first and 14th days, 5 patients received 500 mg of rituximab on the first and 14th days, and rituximab was used as needed 6 months later. Methylprednisolone (80-120 mg) was given together with rituximab. Afterward, 1 mg/kg prednisone was used for 4 weeks, which was progressively tapered to maintenance doses or discontinued. B lymphocyte level, renal function, 24-h urine protein level, and systemic lupus erythematosus (SLE) disease activity index 2000 (SLEDAI2K) score before and after treatment were recorded. The efficacy and adverse reactions were analyzed. The results showed that 11 patients suffered from renal insufficiency [creatinine (162.7±58.6) μmol/L ] at baseline, while the creatinine level of 9 patients returned to normal 12 months after the treatment [ (66.3±10.1)μmol/L ]. Normal renal function of the other 12 patients was maintained during treatment. After 12 months, the 24-h urine protein level decreased from 4.00 (2.00,6.80) g in the baseline period to 0.10 (0.08,0.40) g. SLEDAI2K score decreased from 22 (18,26) in the baseline period to 3 (0,6) 12 months after the treatment. The B lymphocyte level reached 0.00 (0.00,0.01)% at 3 months. Of 23 patients, 13 patients achieved complete remission, and 7 patients achieved partial remission after 6 months of rituximab treatment. Five patients experienced adverse reactions related to rituximab, including 1 case of transfusion reaction, 1 case of perioral herpes with pulmonary infection, and 3 cases of decreased IgG levels. Therefore, rituximab regimen used in this study can be an effective treatment strategy for lupus nephritis.

Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host's eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018-2022) and identified twenty two eligible cases, restricted only to human patients' experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (Lactobacillus and Bifidobacterium), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via 19Fluorine magnetic resonance spectroscopy (19F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver 19F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development.

Olanzapine(OLZ)is a multi-acting receptor-targeted antipsychotic drug approved in Japan in December 2017 for the treatment of anticancer drug-induced nausea and vomiting. However, the recommended doses and administration periods of OLZ in the literature and guidelines are varied. Reports on the efficacy and safety of OLZ combined with perioperative chemotherapy for breast cancer in Japanese patients are few. Moreover, the risk of nausea and vomiting during treatment with anticancer drugs in young and women patients remains to be high. In this study, we conducted an exploratory survey on the optimal duration of OLZ administration(days 1-4: 5 mg, before sleep)during perioperative breast cancer 5-fluorouracil, epirubicin, cyclophosphamide(FEC)therapy. We found that treatment with OLZ showed efficacy in improving nausea grade and maintaining relative dose intensity. Moreover, it could be used safely without interruption due to side effects, such as weight gain, elevation in blood glucose, somnolence, and insomnia. Prophylactic antiemetic therapy with OLZ administration (days 1-4: 5 mg)prior to sleep was effective in patients having FEC therapy-induced nausea and vomiting.

The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the PANORAMA-1 trial which investigated this triplet in early relapse. In routine clinical care, PanBorDex is used primarily in later relapses and is commonly administered in attenuated dosing schedules to mitigate the treatment-related toxicity. We set out to evaluate efficacy and safety outcomes with PanBorDex later in the disease course and evaluate the role of attenuated dosing schedules. This was a retrospective evaluation of patients treated in routine clinical practice between 2016-2019 across seven heamatology centres in the UK; patients who received at least one dose of PanBorDex were eligible for inclusion. The dosing schedule of panobinostat (10mg, 15mg or 20mg, twice or three times a week) and bortezomib (0.7mg/m2, 1mg/m2 or 1.3mg/m2 once or twice weekly) was as per treating physician choice. Patients received treatment until disease progression or unacceptable toxicity. The primary outcome is response rates according to IMWG criteria. Key secondary endpoints include progression-free survival (PFS) and overall survival (OS). Other secondary endpoints include rates of adverse events according to CTCAE criteria. In total, 61 patients were eligible for inclusion and received PanBorDex primarily as ≥5th line of treatment. One third of patients received PanBorDex at full dose, for the remaining two thirds, treatment was given in reduced dose intensities. The overall response rate was 44.2%, including 14.7% very good partial response (VGPR) rates; 68.8% of patients derived clinical benefit with stable disease or better. The median PFS was 3.4 months; non-refractory patients and those who achieved VGPR benefited from prolonged PFS of 11.4 months and 17.7 months, respectively. The median OS was 9.5 months. The triplet was associated with 45% and 18% incidence of grade 3-4 thrombocytopenia and diarrhea, respectively.

A variety of corticosteroids are available as an alternative to reduce inflammatory complications after mandibular third molar surgery (3MS). However, it is unclear which are the best preoperative drugs, doses, and routes of administration. A frequentist network meta-analysis was performed to assess the comparative effectiveness of corticosteroids to reduce inflammatory complications after 3MS. We searched Embase, PubMed, and the Cochrane Library without language restrictions. Only randomised clinical trials (RCTs) were included. We obtained the relative effectiveness using network meta-analysis and an estimate of the relative ranking of interventions according to their effects. Our search yielded 2427 results, from which 61 studies involving 3561 subjects fulfilled our inclusion criteria. Five corticosteroids (dexamethasone, betamethasone, methylprednisolone, prednisolone, and triamcinolone) were compared. Dexamethasone 8mg via submucosal injection (-3.58[-6.98; -0.17]) and via pterygomandibular injection (-3.56[-6.30; -0.82]) were significantly more effective than placebo to reduce oedema after 3MS. The ranking analysis showed that dexamethasone 8mg via submucosal injection and via oral tablets were the interventions with the highest probability of being the most effective methods to reduce oedema after 3MS (p values = 0.71 and 0.75, respectively). Compared with placebo, only dexamethasone 8mg via submucosal injection effectively reduced pain in the first and second days after 3MS (-30.95[-43.41; -18.49]) and (-15.25[-23.27; -7.22]), respectively. Overall, corticosteroids reduced inflammatory complications after 3MS and did not show any serious adverse effects. Among the corticosteroids reviewed, dexamethasone 8mg was the best preoperative option to control inflammatory complications after 3MS. Further RCTs are needed to confirm the optimal route of administration.

Intravenous patient controlled analgesia (PCA) with opioids to provide perioperative analgesia is commonly used after orthopedic surgery, but have side-effects. Addition of adjutant drugs results in reducing the side-effects and the dosage of opioids. The aim of current study was to evaluation the analgesic efficacy of combination of fentanyl and dexamethasone (8 and 16 mg) in compared with fentanyl alone in patients undergoing orthopedic surgery of the lower extremity. In a double-blind clinical trial, 102 patients were randomly allocated to receive PCA, which included: F+S group (fentanyl 1 mcg/ml + isotonic saline), F+8mD group (fentanyl 1 mcg/ml + dexamethasone 8 mg/ml), and F+16mD group (fentanyl 1 mcg/ml + dexamethasone 16 mg/ml). Anesthesia technique and rescue analgesia regimen were standardized. Postoperatively, pain was assessed based on visual analog scale (VAS). In addition, we evaluated the postoperative nausea and vomiting (POVN) in different groups. In over the post-operative period, the mean VAS-score was significantly lower in the F+16mD group than the F+S and the F+8mD groups (p<0.001 and p<0.01, respectively). In addition, the incidence of PONV significantly was lower in the F+18mD group than the F+S group (p<0.05). We conclude that the addition of preoperative intravenous high dose of dexamethasone (16 mg) to fentanyl was effective in reducing postoperative pain and PONV after orthopedic surgery of the lower extremity.

Therapeutic strategies that target novel pathways are urgently needed for patients with relapsed/refractory multiple myeloma (RRMM). Ibrutinib is an oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in MM cells. This phase 1 dose-escalation study examined various doses of ibrutinib in combination with standard doses of lenalidomide (25 mg) and dexamethasone (40 mg) using a standard 3 + 3 design in RRMM patients. The primary objective was to determine the maximum tolerated dose (MTD) of ibrutinib in combination with lenalidomide and dexamethasone. Patients (n = 15) had received a median of 4 prior regimens, 53% were triple-class exposed, 33% were penta-exposed, and 54% were lenalidomide-refractory. The MTD of ibrutinib was 840 mg (n = 6) and only 1 dose-limiting toxicity; a grade 3 rash possibly related to ibrutinib was noted. The most common ≥ grade 3 adverse events were rash in 2 (13%), lymphopenia in 2 (13%), leukopenia, neutropenia, thrombocytopenia, and anemia all occurring in 3 (20%) patients each. One patient achieved a partial response for an overall response rate of 7%. The clinical benefit rate was 80%. The median time to progression was 3.8 months. Ibrutinib, lenalidomide and dexamethasone appears to be a safe and well-tolerated regimen with reasonable efficacy in heavily pretreated RRMM patients.

Transferrin receptor 1 (TfR1) is a universal cancer marker and a meaningful target for antibody-based immunotherapy. We previously developed a mouse/human chimeric antibody (ch128.1/IgG1) specific for the human TfR1 and reported that treatment of SCID-Beige mice bearing disseminated human multiple myeloma (MM) cells with ch128.1/IgG1 results in significant antitumor activity in early-stage and late-stage disease. Both bortezomib and lenalidomide are Food and Drug Administration (FDA) approved therapeutics used to treat MM in combination with other agents. Since combining treatments with different mechanisms of action is an effective antitumor strategy and given the relevance of bortezomib and lenalidomide in MM therapy, we decided to explore, for the first time, the combination of bortezomib or lenalidomide treatment with ch128.1/IgG1 within the context of late-stage MM disease. We found that treatment with a single dose of ch128.1/IgG1, or multiple doses of bortezomib or lenalidomide, used as single agents, results in significant antitumor activity in SCID-Beige mice bearing late-stage disseminated human MM.1S tumors. However, this antitumor activity is superior when ch128.1/IgG1 is combined with either bortezomib or lenalidomide, showing significantly longer survival compared with any therapy used alone. These novel results suggest that the combinations of ch128.1/IgG1 and bortezomib or lenalidomide are promising strategies against MM.

Identifying effective combination regimens is a high priority in multiple myeloma (MM), as most patients eventually become refractory to their current treatments. In this study, we investigated whether the proteasome inhibitor (PI) ixazomib could delay disease progression among patients who failed regimens containing another PI, bortezomib or carfilzomib. This phase 1/2, multicenter, open-label, nonrandomized study enrolled patients who were refractory to a previous regimen containing bortezomib or carfilzomib. Patients continued the other anti-MM drugs in the regimen at the same doses and frequencies. Patients with combination regimens with unknown maximum tolerated dose (MTD) of ixazomib were enrolled in phase 1, with ixazomib starting at 3 mg and then dose escalated to 4 mg. Patients on regimens with a known ixazomib MTD were enrolled in phase 2. Primary endpoints were overall response rate (ORR), clinical benefit rate (CBR), adverse events (AEs), and determination of maximum tolerated dose (MTD). Of the 46 patients enrolled, 39 were evaluable for efficacy. ORR and CBR were 12.8% and 17.9%, respectively. Ixazomib appeared to be well tolerated as a replacement for carfilzomib and bortezomib, with 23.9% of patients experiencing at least one grade ≥3 serious adverse event (SAE) and 37.0% experiencing at least one grade ≥3 AE. The most common grade ≥3 AEs were hyponatremia (8.7%), anemia (8.7%), dyspnea (8.7%), thrombocytopenia (6.5%), dehydration (4.3%), and pneumonia (4.3%). The results indicate that ixazomib is not an effective replacement for bortezomib or carfilzomib for patients with MM who have previously relapsed on other bortezomib/carfilzomib-containing regimens.

Selinexor is a first in class selective inhibitor of nuclear export (SINE), blocks exportin 1 (XPO1), a protein transporter, that among other actions, shuttles cargo proteins such as tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and oncoprotein messenger RNAs (mRNAs) across the nuclear membrane to cytoplasm. By blocking XPO1, selinexor facilitates nuclear preservation and activation of TSPs, and prevents mRNA translation of the oncoproteins leading to induction of apoptosis. The therapeutic value of selinexor in combination with dexamethasone has been successfully demonstrated in treating relapsed and/or refractory myeloma (RRMM), leading to the Food and Drug Administration (FDA) approval of selinexor in combination with dexamethasone in 2019 for the treatment of adult patients with RRMM who received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (mAb) - a pentarefractory myeloma. More recently, selinexor in combination with bortezomib and dexamethasone was approved by the FDA in December 2020, based on the BOSTON study among RRMM patients who had received at least one prior line of therapy. With more available safety and efficacy data supporting the increased interval between dosing of selinexor (and lesser cumulative weekly dosing) and schedule, contrary to the originally approved dose of 160 mg per week, the supportive care guidelines needed to be revisited. The current manuscript summarizes the supportive care solutions with weekly dosing of selinexor and identifies the ideal potential patient for selinexor treatment.

Isatuximab is an approved anti-CD38 monoclonal antibody with multiple antitumor modes of action. An exposure-response (E-R) analysis using data from patients with relapsed/refractory multiple myeloma (RRMM) enrolled in a phase Ib clinical study who received isatuximab at doses from 5 to 20 mg/kg weekly for 1 cycle (4 weeks) followed by every 2 weeks thereafter (qw/q2w) in combination with pomalidomide/dexamethasone (n = 44) was first used to determine the optimal dose/schedule for the phase III ICARIA-MM study. It was complemented by an E-R analysis from a second phase Ib study of patients who received isatuximab at doses from 3 to 10 mg/kg q2w or 10 or 20 mg/kg qw/q2w in combination with lenalidomide/dexamethasone (n = 52). Plasma trough concentration at week 4 (CT4W) was the best predictor for response, and the benefit of the initial 4-weekly administration was confirmed. Although the predicted overall response rate (ORR) was higher at 20 mg/kg vs. 10 mg/kg, the 95% confidence intervals were overlapping. Considering the high probability of success to reach the targeted ORR of greater than or equal to 60%, 10 mg/kg qw/q2w was selected. Results of the E-R analysis from the lenalidomide/dexamethasone study and published disease modeling using data from both phase Ib clinical studies reinforced 10 mg/kg qw/q2w as the optimal dose/schedule for the phase III ICARIA-MM study. E-R analysis showed that higher CT4W was associated with higher ORR. Developed models supported the phase III isatuximab dosing regimen selection/confirmation of 10 mg/kg qw/q2w for use in combination with pomalidomide/dexamethasone in patients with RRMM.