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SummaryChanges in areal bone mineral density (aBMD) and other predictors of bone loss were evaluated in 48 same-sex twin/age-matched sibling pairs discordant for antiepileptic drug (AED) use. AED users had reduced BMD at the hip regions. Prolonged AED users had greater aBMD loss, predicting a higher risk of bone fragility.IntroductionTo investigate the longitudinal associations of bone mineral measures with antiepileptic drug (AED) use, including enzyme-inducing (EIAED) and non-enzyme-inducing (NEIAED) types, and other predictors of bone loss in a study of 48 same-sex twin/age-matched sibling pairs (40 female, 8 male) discordant for AED use.MethodsUsing dual-energy X-ray absorptiometry (DXA), areal bone mineral density (aBMD) and content (BMC) at the hip regions, forearm, lumbar spine, and whole body were measured twice, at least 2 years apart. The mean within-pair difference (MWPD), MWPD%, and mean annual rate of aBMD change were adjusted for age, weight, and height. Predictors of bone loss were evaluated.ResultsAED users, compared to non-users, at baseline and follow-up, respectively, had reduced aBMD at the total hip (MWPD% 3.8, 4.4%), femoral neck (4.7, 4.5%), and trochanter regions (4.1, 4.6%) (p < 0.05). For the whole cohort, the annual rate of change in all aBMD/BMC (p > 0.05) regions did not differ within pairs. Nevertheless, EIAED users had greater aBMD loss than non-users (n = 20 pairs) at the total hip (1.7 vs. 0.3%, p = 0.013) and whole body regions (0.7% loss vs. 0.1% BMD gain, p = 0.019), which was not found in NEIAED-discordant pairs (n = 16). AED use >20 years predicted higher aBMD loss at the forearm (p = 0.028), whole body (p = 0.010), and whole body BMC (p = 0.031).ConclusionsAED users had reduced aBMD at the hip regions. Prolonged users and EIAED users had greater aBMD loss, predicting a higher risk of bone fragility. Further prospective studies of AED effects on bone microarchitecture are needed.

Look-twin sound-twin (LTST)-drug-related problems are a worldwide concern because they are associated with safety among medication users. LTST drugs make up one of four types of potentially inappropriate medications circulating within communities. The present study investigates people's perspectives on characteristics of LTST drugs, their experience of use, and abilities to differentiate LTST drugs. The research was conducted via a survey. The data were collected through interviews with individuals aged between 18 and 75 from 330 households during the period November 2017-February 2019. The majority of the participants, accounting for 97.9% of the interviewees were found to have experienced or used them previously. The essential features that enabled the participants to identify LTST drug pairs were similarities in terms of their appearance (93.6%), packaging (82.7%), medication names (76.1%), and medication labels (70.6%). The majority of the interviewees were unable to differentiate between the drugs in LTST drug pairs. In fact, while the drugs in one LTST drug pairs were distinguished accurately with the rate of 79.4%, 44 pairs of drugs were separated accurately by less than 35%. Furthermore, drugs in eight LTST drug pairs could not be accurately differentiated. LTST-drugs-related problems in communities arise from the lack of a monitoring system and effective law enforcement. In fact, they are associated with people's safety in medication use, for most people are unable to distinguish differences among LTST drugs due to their similarities in terms of packaging, physical appearances, and drug names.

[...]our findings support a genetic factor in the aetiology of SPS but not a clinical benefit of rituximab in its treatment.

Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein’s pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine.

Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy. Graphical Abstract

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC.

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that “higher” levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.

The synthesis of five novel homodimers is reported based on the anilinoisoquinolinequinone scaffold. In these twin-drug derivatives, two units of the anilinoquinone pharmacophores are linked through a methylene spacer. The formation of dimers was achieved by reaction of isoquinolinequinones with 4, 4’-diaminodiphenylmethane via a sequence of two oxidative amination reactions. A preliminary in vitro screening of the homodimers reveals moderate to high cytotoxic activities against MDA-MB-21 breast adenocarcinoma and B16-F10 murine metastatic melanoma cell lines. The asymmetrical homodimer 15 stands out due to its cytotoxic potencies at submicromolar concentrations and high selectivity index (mean IC50 = 0.37 μM; SI = 6.97) compared to those of etoposide (mean IC50 = 3.67; SI = 0.32) and taxol (mean IC50 = 0.35; SI = 0.91) employed as reference anticancer drugs.

Background Hodgkin lymphoma (HL) is the most common hematological malignancy during pregnancy. The first-line treatment for HL in pregnancy is the standard ABVD regimen without any drug and/or dose adjustment. However, data on chemotherapy during twin pregnancies are sparse, and a better understanding of the mechanisms involved in exposure to and the toxic effects of anticancer drugs in the fetuses is needed. Case presentation A 41-year-old dichorionic diamniotic pregnant patient was given ABVD treatment for HL at a gestational age of 28 weeks and 3 days. The patient received 2 cycles of chemotherapy with a 15-day therapeutic window including an actual 25 mg/m 2 dose of doxorubicin per cycle. Unlike the female twin, the male twin presented four days after birth a left cardiac dysfunction. Doxorubicin cardiotoxicity in the male newborn was also supported by high blood levels of troponin. At one month of age, echocardiography findings were normal. We investigated literature data on physiological aspects of pregnancy that may influence doxorubicin pharmacokinetics, and pharmacodynamic and pharmacokinetic data on the use of doxorubicin in pregnancy. We detailed the role of the transporters in doxorubicin placenta distribution, and tried to understand why only one fetus was affected. Conclusions Fetal safety depends at least on maternal doxorubicin pharmacokinetics.Because of drug interactions (i.e. drug metabolism and drug transport), care should always be taken to avoid maternal pharmacokinetic variability. The toxic effects were discrepant between the dizygotic twins, suggesting additional fetus-specific pharmacokinetic/pharmacodynamic factors in doxorubicin toxicity.

In the search for new quinoid compounds endowed with potential anticancer activity, the synthesis of novel heterodimers containing the cytotoxic 7-phenylaminoisoquinolinequinone and 2-phenylaminonaphthoquinone pharmacophores, connected through methylene and ethylene spacers, is reported. The heterodimers were prepared from their respective isoquinoline and naphthoquinones and 4,4′-diaminodiphenyl alkenes. The access to the target heterodimers and their corresponding monomers was performed both through oxidative amination reactions assisted by ultrasound and CeCl3·7H2O catalysis “in water”. This eco-friendly procedure was successfully extended to the one-pot synthesis of homodimers derived from the 7-phenylaminoisoquinolinequinone pharmacophore. The electrochemical properties of the monomers and dimers were determined by cyclic and square wave voltammetry. The number of electrons transferred during the oxidation process, associated to the redox potential EI1/2, was determined by controlled potential coulometry.