Thermodynamic and kinetic study of palladium(II) complexation with 1-methyl-2-mercaptoimidazole (methimazole) and their importance for structural design of metallodrugs

Article

作者: Hamacek, Josef ; Širůčková, Viktorie ; Lubal, Přemysl ; Kapička, Libor ; Elding, Lars-Ivar

The acidobasic and complexing properties of 1-methyl-2-mercaptoimidazole (Methimazole, an anti-thyroid drug) were investigated. The pK_a 11.49 ± 0.03 was estimated by molecular absorption spectroscopy (I = 0.10 M NaCl, t = 25.0 ± 0.1 °C). This value is in good agreement with the value 11.58 ± 0.05, obtained using the solvent-extraction technique. Theoretical (LFER and quantum chemical calculations) and experimental (¹H/¹³C NMR spectroscopy) methods confirmed that the ligand prefers to be in the thion form, and the proton dissociation takes place on the nitrogen atom. Using glass electrode potentiometry, the complexation of the Pd(II) ion by the methimazole ligand occurs without the participation of protons. The best chemical model considers the [Pd(HL)]²⁺, [Pd(HL)₂]²⁺ and [Pd(HL)₃]²⁺ complex species, whose stability constants were also determined using spectroscopy and capillary zone electrophoretic (CZE) measurements. The metal complexes dissociate at -log [H⁺] > 7, where an uncharged palladium(II) hydroxide is formed. The formation kinetics of the palladium(II) complex with methimazole were studied in perchloric and hydrochloric acids (I = 1.00 M, t = 15-40 °C) and the determined rate constants and activation parameters are consistent with literature values determined for the reactions of the Pd(II) ion with thiourea derivatives. The rate constants decrease by two orders of magnitude in both media, which can be assigned to a lower tendency of the chloride ion to dissociate from the [PdCl₄]^2- complex species than the water molecule from the [Pd(H₂O)₄]²⁺ ion. The presented results can be utilized for the design of new Pd and Pt metallodrugs.

2024-10-01·The Lancet Psychiatry

Clinical symptoms and psychosocial functioning in patients with schizophrenia spectrum disorders testing seropositive for anti-NMDAR antibodies: a case–control comparison with patients testing negative

Article

作者: Waters, Patrick ; de Boer, Nini ; Winter-van Rossum, Inge ; van der Horst, Marte ; Pollak, Thomas A ; Lin, Bochao Danae ; Davidson, Michael ; Hasan, Alkomiet ; Luykx, Jurjen J ; Yeeles, Ksenija ; de Witte, Lot D ; Lennox, Belinda R ; Visscher, Robbert ; Fleischhacker, W Wolfgang

BACKGROUNDAntibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies.METHODSIn this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study.FINDINGSWe collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014).INTERPRETATIONSerum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response.FUNDINGNone.

2024-10-01·International Journal of Pharmaceutics

Hansen solubility parameters and quality-by-design oriented optimized cationic nanoemulsion for transdermal drug delivery of tolterodine tartrate

Article

作者: Shahid, Mudassar ; Usman Mohd Siddique, Mohd ; Khuroo, Tahir ; Ramzan, Mohhammad ; Khan, Tasneem

Tolterodine tartrate (TOT) is a selective anti-muscarinic drug to treat urinary urgency and overactive urinary bladder (OAB) occurring in children, renal disease and elderly patients. Oral delivery is associated with several adverse effects. We addressed HSPiP and QbD (quality by design)-oriented TOT loaded cationic nanoemulsions for transdermal delivery. Hansen solubility parameters (HSP) screened excipients based on theoretical solubility whereas, QbD optimized cationic nanoemulsions (CNE-TOT-6). Formulation characteristic parameters were desirable to execute targeted in vitro drug release and ex vivo permeation profiles. In vitro hemolysis was conducted at varied concentrations whereas, histopathological study supported the safety aspect of CNE-TOT6. A comparative bioavailability was carried out in a rat model. Capmul PG8 (CAP), tween 80, and PEG 400 (polyethylene glycol 400) were screened based on HSP and experimental solubility data. QbD suggested optimized content of CAP, tween 80, and PEG 400 to achieve the lowest value of size (184 nm), maximum % entrapment efficiency (87.2 %), high zeta potential (+32.6 mV), optimum viscosity (47.19 cP), and high extrudability (96 %) as compared to its gel. High gel consistency slowed down the drug release and permeation flux as compared to CNE-TOT6 suspension. Hemocompatible CNE-TOT6 increased pharmacokinetic parameters as compared to the control and gel without causing skin toxicity after application. Thus, HSPiP and QbD oriented cationic nanoemulsions are promising carriers to treat overactive urinary bladder.

项与 Anti-Drug Antibodies (Topas Therapeutics) 相关的新闻（医药）

2024-10-12

·echemi

Contradictions Between FDA and Hengrui Pharmaceuticals: Behind the Launch of a New Paclitaxel Drug, a Sales Puzzle of 4.3 Billion RMB

Recently, Hengrui Medicine officially received a notice from the U.S. Food and Drug Administration (FDA) confirming that its abbreviated New Drug Application (ANDA) for paclitaxel for injection (albumin-binding) has been approved. This milestone marks Hengrui becoming the first pharmaceutical company to successfully obtain generic approval for this product in the United States. According to the statistics of Yaozhi data, since Hengrui Pharmaceutical launched paclitaxel for injection (albumin binding type) in China in 2018, the cumulative sales of the product in domestic public medical institutions has reached 4.334 billion yuan, of which in 2021 it broke the mark of 1 billion yuan. The listing in the United States not only further promoted Hengrui Pharmaceutical's internationalization strategy, but also laid a solid foundation for the company's expansion in the global market, and significantly enhanced the company's international competitiveness and brand image. According to the official channels of Hengrui Medicine, the injectable paclitaxel (albumin-binding type) was approved for sale in China in 2018, mainly for the treatment of metastatic breast cancer that failed combined chemotherapy or breast cancer patients who relapsed within 6 months after adjuvant chemotherapy. In 2024, the product received approval for a second indication, in combination with gemcitabine as a first-line treatment for metastatic pancreatic cancer. In the international market, the product has also performed well and is currently approved in 15 European countries for adult patients with metastatic breast cancer who have failed first-line treatment and are not treated with standard anthracyclines, for adult patients with metastatic adenocarcinoma in combination with gemcitabine, and for adult patients with non-small cell lung cancer in combination with carboplatin. Paclitaxel for injection (albumin-bound), as an anti-microtubule drug, has been widely used in many countries and regions since it was first approved in the United States in 2005. According to statistics, the global sales of this variety in 2023 reached about 2.597 billion US dollars. Hengrui Pharmaceutical continues to make efforts in the process of internationalization, so far, its products have entered more than 40 countries, and in Europe, the United States and Japan and other places to obtain more than 20 registration approvals, including injections, oral preparations and inhalation anesthetics. In particular, since 2024, Hengrai has successfully approved three first imitators in the United States: paclitaxel for injection (albumin-bound), tachlimus sustained-release capsules and bupivacaine liposome injection. Among them, bupivacaine liposome injection is the first imitation drug of this variety in the world. Tacrolimus sustained-release capsule is an important drug to prevent graft rejection after adult kidney transplantation. Its sustained-release capsule dosage form was approved by the US FDA and recognized as the first imitation drug of this variety, and it is also the first imitation product in China. The product was approved for sale in China in June 2022. Bupivacaine liposome injection is another important breakthrough in the field of long-acting sustained-release preparations. The product was first approved for listing in the United States in 2011, but due to high technical barriers, no imitation products have been successfully listed for more than 10 years. With its unique DepoFoam technology, Hengrui Pharmaceutical successfully brought the product to market and achieved the first imitation on the market worldwide. The product has been approved for market in China at the end of 2022 and is regarded as the first ultra-long-acting local anesthetic in China through consistency evaluation.

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