Keywords: 2-Aminobenzothiazole / Dibenzothiazolyltetraazathiapentalene / Electrophilic and nucleophilic sulfur atoms Reactions between CS 2 and the exocyclic amino groups of 2-aminobenzothiazoles gave series of molecules bearing thiourea, isothiourea, dithiocarbamate, dithiocarboimine, dimethyldithiocarbamate, methyldithiocarbamate, S-CH 3 and O-alkyl thiocarbamic ester, and guanidine groups. Preferred tautomers and conformers were determined. Most compounds present coordinative bonds between the endocyclic sulfur atom, which behaves as a Lewis acid, and oxygen, ni-

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BackgroundA promising novel cell-free bioactive formulation for articular cartilage regeneration, called BIOF2, has recently been tested in pre-clinical trials. The aim of the present study was to evaluate the efficacy and safety of BIOF2 for intra-articular application in patients with severe osteoarthritis of the knee.MethodsA prospective, randomized, 3-arm, parallel group clinical trial was conducted. It included 24 patients with severe osteoarthritis of the knee (WOMAC score 65.9 ± 17). Before they entered the study, all the patients were under osteoarthritis control through the standard treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), prescribed by their family physician. Patients were distributed into three groups of 8 patients each (intra-articular BIOF2, total joint arthroplasty, or conservative treatment with NSAIDs alone). The WOMAC score, RAPID3 score, and Rasmussen clinical score were evaluated before treatment and at months 3, 6, and 12. BIOF2 was applied at months 0, 3, and 6. Complete blood count and blood chemistry parameters were determined in the BIOF2 group before treatment, at 72 h, and at months 1, 3, 6, and 12. In addition, articular cartilage volume was evaluated (according to MRI) at the beginning of the study and at month 12.ResultsThe NSAID group showed no improvement at follow-up. Arthroplasty and BIOF2 treatments showed significant improvement in all the scoring scales starting at month 3. There were no statistically significant differences between the BIOF2 group and the arthroplasty group at month 6 (WOMAC score: 19.3 ± 18 vs 4.3 ± 5; P = 0.24) or month 12 (WOMAC score: 15.6 ± 15 vs 15.7 ± 17; P = 1.0). Arthroplasty and BIOF2 were successful at month 12 (according to a WOMAC score: ≤ 16) in 75% of the patients and the daily use of NSAIDs was reduced, compared with the group treated exclusively with NSAIDs (RR = 0.33, 95% CI 0.12–0.87, P = 0.02. This result was the same for BIOF2 vs NSAIDs and arthroplasty vs NSAIDs). BIOF2 significantly increased the articular cartilage by 22% (26.1 ± 10 vs 31.9 ± 10 cm2, P < 0.001) and produced a significant reduction in serum lipids. BIOF2 was well tolerated, causing slight-to-moderate pain only upon application.ConclusionsThe intra-articular application of the new bioactive cell-free formulation (BIOF2) was well tolerated and showed no significative differences with arthroplasty for the treatment of severe osteoarthritis of the knee. BIOF2 can regenerate articular cartilage and is an easily implemented alternative therapy for the treatment of osteoarthritis.Trial registration Cuban Public Registry of Clinical Trials (RPCEC) Database RPCEC00000250. Registered 08/15/2017—Retrospectively registered, http://rpcec.sld.cu/en/trials/RPCEC00000250-En.Electronic supplementary materialThe online version of this article (10.1186/s40001-018-0349-2) contains supplementary material, which is available to authorized users.

Background: Coronavirus disease (COVID-19) is currently the main public health problem worldwide. The administration of neutral electrolyzed saline, a solution that contains reactive species of chlorine and oxygen (ROS), may be an effective therapeutic alternative due to its immunomodulating characteristics, in systemic inflammation control, as well as in immune response improvement, promoting control of the viral infection. The present study evaluated the efficacy of treatment with intravenous and/or nebulized neutral electrolyzed saline combined with usual medical care versus usual medical care alone, in ambulatory patients with COVID-19.Methods: A prospective, 2-arm, parallel group, randomized, open-label, phase I-II clinical trial included 39 patients in the control group (usual medical care alone) and 45 patients in the experimental group (usual medical care + intravenous and/or nebulized electrolyzed saline, with dose escalation). Two aspects were evaluated during the twenty-day follow-up: i) the number of patients with disease progression (hospitalization or death); and ii) the Patient Acceptable Symptom State (PASS), a single-question outcome that determines patient well-being thresholds for pain and function. Biochemical and hematologic parameters, as well as adverse effects, were evaluated in the experimental group. Results: The experimental treatment decreased the risk for hospitalization by 92% (adjusted RR=0.08, 95% CI: 0.01-0.50, P=0.007), with a 43-fold increase in the probability of achieving an acceptable symptom state on day 5 (adjusted RR= 42.96, 95% CI: 9.22-200.0, P<0.001). Intravenous + nebulized administration was better than nebulized administration alone, but nebulized administration was better than usual medical care alone. Clinical improvement correlated with a decrease in C-reactive protein, and aberrant monocytes and an increase of lymphocytes, and platelets. Cortisol and testosterone levels were also evaluated, observing a decrease in cortisol levels and an increment of testosterone-cortisol ratio, on days 2 and 4. Conclusions: The experimental treatment produced no serious adverse effects. In conclusion, intravenous and/or nebulized neutral electrolyzed saline importantly reduced the symptomatology and risk of progression (hospitalization and death), in ambulatory patients with COVID-19.Trial registration: Cuban Public Registry of Clinical Trials (RPCEC) Database RPCEC00000309. Registered: 05. May 2020. https://rpcec.sld.cu/en/trials/RPCEC00000309-En

Reactions of the tetranuclear (Cp*RuCl) 4 (1) with the corresponding butadienesulfinate salts Li[SO 2 CHdCR 0 CHdCHR] [R=R 0 =H, (2a); R=H, R 0 =Me, (2b); R=R 0 =Me, (2c)] in THF result in the formation of tetrameric [Cp*Ru(1,2,5-η-SO 2 CHdCR 0 CHdCHR)LiCl] 4 [R = R 0 = H, (3); R=H, R 0 =Me, (4); R=R 0 =Me, (5)] complexes. Compound 5 has been isolated in two pseudopolymorphic crystal forms as 5 in space group P42 1 c and as 5 3 3THF, where there are three molecules of solvated THF per tetramer, in space group I4. Both tetramers occupied a crystallographic 4-foldroto inversion axis. In both structures the tetramer symmetry is S 4 , and these distorted cubane-like kernel structures are similar to the one found in compound 1. If potassium butadienesulfinates are used in the reaction with 1 instead of lithium salts 2a-c, mononuclear allylsulfene ruthenium compounds 6); R = H, R 0 = Me, ( 7)] are isolated. The analogous compound 8 [R=R 0 =Me] was prepared directly from addition of water to 5. Compounds 6-8 are the first complexes to contain a dioxo-η 5 -thiapentadienyl or 1-5-η-butadienesulfonyl ligand, as confirmed by the determination of the structure of 7 by X-ray crystallography. Tetrameric 3-5 and monomeric 6-8 easily interconvert into each other in the presence of H 2 O and LiCl, respectively. A comparative study of the dissociation of tetramers 1 and 3, in the presence of THF, via dynamic light scattering measurements shows a tendency of 1 to dissociate and favor polydisperse aggregates in THF, whereas in 3 the tetranuclear structure remains essentially preserved. Furthermore, when the mononuclear 6 was studied and compared to 3, only one welldefined peak was observed in each case, with the average aggregate 4:1 radius ratio. This implies that 3 has aggregates 4 times larger than those formed by 6. Cyclic voltammetry confirms the formation of the ion pair [Cp*Ru(1,2,5-η-SO 2 CHdCHCHdCH 2 )(5-η-S(O 2 -K þ )CHdCHCHdCH 2 )] (12a-K) from 6 and 2a-K under stoichiometric ratio or directly from 1 and excess of 2a-K. Selective exchange of the counterion occurs for 12a-K in the presence of AgBF 4 and n-Bu 4 NBF 4 in THF to afford 12a-Ag and 12a-(n-Bu 4 N). Compound 6 reacts with a high excess of 2a-Li, under reflux in THF, to yieldThe equilibrium reaction between analogous 13a-K and 12a-K was studied in solution by means of 1 H NMR spectroscopy. HRMS provided evidence of the capacity of the SO 2 fragment, in the butadienesulfinate complexes, to afford new aggregation states according to the cations employed.