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Antimicrobial and Wound Treatment Aspects of Micro- and Nanoformulations of Carboxymethyl, Dialdehyde, and TEMPO-Oxidized Derivatives of Cellulose: Recent Advances.
Alavi, M, Nokhodchi, A
Macromolecular bioscience. 2020;(4):e1900362
Abstract
The remedy for infected chronic wounds such as diabetic foot ulcers is more complicated particularly in the case of patients with an inefficient immune system. Also, fighting against microbial infections in the wound site by available antibiotics may not be effective because of emerging antibiotic resistance properties among pathogenic bacteria and fungi. Recently, applications of micro- and nanoformulations of biomaterials have demonstrated improved therapeutic abilities for wound dressings. In this way, carboxymethyl, dialdehyde, and 2,2,6,6-tetramethylpiperidine-1-oxyl-oxidized celluloses are common biomaterials having outstanding physicochemical and therapeutic properties compared to unmodified cellulose. Therefore, in this review, recent progress in the field of wound healing and antimicrobial activities of these derivatives are presented and discussed.
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Effects of curcumin-piperine co-supplementation on clinical signs, duration, severity, and inflammatory factors in patients with COVID-19: a structured summary of a study protocol for a randomised controlled trial.
Miryan, M, Bagherniya, M, Sahebkar, A, Soleimani, D, Rouhani, MH, Iraj, B, Askari, G
Trials. 2020;(1):1027
Abstract
OBJECTIVES This study aims to investigate the efficacy of curcumin-piperine co-supplementation on disease duration, severity and clinical symptoms, and inflammatory mediators in patients with coronavirus (COVID-19). TRIAL DESIGN This is a randomized, placebo-controlled, double-blind, parallel arm clinical trial. PARTICIPANTS All patients aged 20-75 years with the diagnosis of Covid-19 based on the PCR test. The exclusion criteria will include an age less than 20 and more than 75 years, current use of warfarin or other anticoagulant drugs, and the presence of sensitivity to herbal products such as turmeric and pepper. This study will be conducted in academic hospitals affiliated to Isfahan University of Medical Sciences, Isfahan, Iran. INTERVENTION AND COMPARATOR Fifty outpatients will be randomly allocated in a ratio of 1:1 to receive a capsule of curcumin-piperine containing 500 mg curcumin plus 5 mg piperine or matching placebo containing 505 mg maltodextrin twice a daily, after lunch and dinner, over a period of 2 weeks. Similarly, 50 inpatients who are admitted to hospital wards excluding intensive care unit (ICU) will be randomly assigned in a ratio of 1:1 to receive a capsule curcumin-piperine or matching placebo (provided by the Sami Labs company) twice a daily, after lunch and dinner, over a period of 2 weeks. MAIN OUTCOMES The main outcomes of this study are the efficacy of curcumin-piperine on coronavirus disease's clinical symptoms, duration, severity, and inflammatory mediators after 2 weeks of curcumin-piperine co-supplementation. RANDOMISATION Randomization sequences will be generated with the use of a random-number table with a permuted block design (block size of 4) and stratification according to the gender variable (male vs. female). These sequences will be prepared by an independent statistician and will be kept in opaque, sealed, numbered envelopes which will be opened only at the time of enrollment. The allocation ratio in intervention and control groups is 1:1. Researchers and all patients will be unaware of the study-group assignment until the completion of data analyses. BLINDING (MASKING): This study is a double-blind clinical trial (participant, researcher). The curcumin-piperine and placebo supplements are packaged in similar numbered drug containers, and the researcher and all patients will be unaware of the study assignment until the end of the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 100 patients, with 25 patients in each group. TRIAL STATUS The protocol is Version 2.0, May 24, 2020. Recruitment began May 4, 2020, and is anticipated to be completed by April 19, 2021. TRIAL REGISTRATION This trial has been registered by the title of "Effect of curcumin-piperine co-supplementation on disease duration, severity and clinical signs, and inflammatory factors in patients with coronavirus (COVID-19): A randomized, double-blind, placebo-controlled clinical trial study" in the Iranian Registry of Clinical Trials (IRCT) with code "IRCT20121216011763N46", https://www.irct.ir/trial/47529 . The registration date is May 4, 2020. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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Comparison of the Efficacy of Repaglinide Versus the Combination of Mitiglinide and Voglibose on Glycemic Variability in Japanese Patients with Type 2 Diabetes.
Okada, H, Tanaka, M, Hasegawa, G, Nakajima, H, Kadono, M, Okada, Y, Hirata, A, Oyamada, H, Yamane, T, Fukui, M
Current pharmaceutical design. 2020;(43):4600-4605
Abstract
BACKGROUND Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia. OBJECTIVE We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes. METHODS We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability. was assessed using a continuous glucose monitoring system. RESULTS The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase. CONCLUSION Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability.
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Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis.
Ho Lee, Y, Gyu Song, G
Journal of clinical pharmacy and therapeutics. 2020;(4):674-681
Abstract
WHAT IS KNOWN AND OBJECTIVE Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed. METHODS We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA. RESULTS AND DISCUSSION Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo. WHAT IS NEW AND CONCLUSION All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.
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5.
[Advances in treatment of narcolepsy].
Xu, Q, Lou, G, Wang, T, Zhang, L
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. 2020;(4):419-424
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Abstract
Narcolepsy is the most common cause of excessive daytime sleepiness (EDS) following obstructive sleep apnea. Its treatment aims to reduce EDS and cataplexy, improve nighttime sleep disturbance, sleep paralysis and sleep-related hallucinations. Pitolisant (a histamine H3 receptor antagonist) and solriamfetol (a norepinephrine reuptake inhibitor) have recently been approved effective for narcolepsy in the United States and the European Union. Pitolisant has proved to be effective for both EDS and cataplexy. Besides being effective on EDS, solriamfetol seems to have advantages in abuse potential and withdrawal syndrome. As potential treatments for EDS and cataplexy associated with narcolepsy, several new drugs are being developed and tested. These new drugs include new hydroxybutyrate preparations (controlled release sodium hydroxybutyrate FT218, low sodium hydroxybutyrate JZP-258), selective norepinephrine reuptake inhibitor (AXS-12), and modafinil combined with astroglial junction protein inhibitor (THN102). This paper reviews the recently approved drugs and potential treatments for narcolepsy.
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Allosteric mechanism of an oximino-piperidino-piperidine antagonist for the CCR5 chemokine receptor.
Zhang, Y, Chen, HF
Chemical biology & drug design. 2020;(1):113-123
Abstract
The first step for the HIV-1 virus infecting host cell is bound with the CCR5 chemokine receptor. A set of allosteric inhibitors of oximino-piperidino-piperidine antagonists for CCR5 chemokine receptor was discovered. However, the allosteric mechanism of these inhibitors is still unsolved. Therefore, residue-level dynamics correlation network combining with on molecular dynamics simulation was used to investigate the allosteric mechanism. The dynamics correlation network of bound CCR5 is significantly different from that of free CCR5. The community of the most active complex suggests that the allosteric information can freely transfer from the allosteric site to the effector site of the second extracellular loop, while the information transfers bottleneck for the less active one. Here, a hypothesis was proposed that "binding-induced allosteric mechanism" was used to reveal the allosteric regulation of antagonists and the network perturbation confirmed it. Finally, the shortest path algorithm was used to identify the possible allosteric pathway with Gly173-Lys171-Thr177-Tyr89-LIG which was evaluated by the network perturbation of key residue. Furthermore, the efficiency of allostery for the most active system is the highest among these antagonist complexes. The strategy targeting the allosteric pathway can be used to design novel inhibitors of HIV-1 virus.
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Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study.
Kim, JM, Kim, SS, Kim, JH, Kim, MK, Kim, TN, Lee, SH, Lee, CW, Park, JY, Kim, ES, Lee, KJ, et al
Diabetes & metabolism journal. 2020;(1):67-77
Abstract
BACKGROUND There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM. METHODS This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement. RESULTS Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: -0.81%, P<0.001; glimepiride: -1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001). CONCLUSION Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.
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Flavonoids as anticancer therapies: A systematic review of clinical trials.
Bisol, Â, de Campos, PS, Lamers, ML
Phytotherapy research : PTR. 2020;(3):568-582
Abstract
Flavonoids have been proposed as potential chemotherapeutic agents because they are toxic against cancer cells but not harmful to healthy cells. This systematic review analyzed flavonoid effectiveness in human cancer chemotherapy. Overall, 22 phase II and 1 phase III clinical trials (PubMed, Scopus, and Web of Science) that used flavonoids as a single agent or combined with other therapeutics against hematopoietic/lymphoid or solid cancer published by January 2019 were selected for analysis. Flavopiridol was the most commonly used flavonoid (at a dose of 50-mg/m2 IV) for all tumor types. Aside from the relatively low rate of complete response (CR) or partial response (PR) with any administration protocol, flavonoids showed higher positive outcomes for hematopoietic and lymphoid tissues (140 patients with CR and 88 with PR among 615 patients in 11 trials) than for solid tumors (4 patients with CR and 21 with PR among 525 patients in 12 trials). However, because of the high variety in administration schedule, more studies are needed to further understand how flavonoids can promote positive outcomes for cancer patients.
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Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities.
Syed-Abdul, MM, Parks, EJ, Gaballah, AH, Bingham, K, Hammoud, GM, Kemble, G, Buckley, D, McCulloch, W, Manrique-Acevedo, C
Hepatology (Baltimore, Md.). 2020;(1):103-118
Abstract
BACKGROUND AND AIMS Elevated hepatic de novo lipogenesis (DNL) is a key distinguishing characteristic of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. In rodent models of NAFLD, treatment with a surrogate of TVB-2640, a pharmacological fatty acid synthase inhibitor, has been shown to reduce hepatic fat and other biomarkers of DNL. The purpose of this phase I clinical study was to test the effect of the TVB-2640 in obese men with certain metabolic abnormalities that put them at risk for NAFLD. APPROACH AND RESULTS Twelve subjects (mean ± SEM, 42 ± 2 years, body mass index 37.4 ± 1.2 kg/m2 , glucose 103 ± 2 mg/dL, triacylglycerols 196 ± 27 mg/dL, and elevated liver enzymes) underwent 10 days of treatment with TVB-2640 at doses ranging from 50-150 mg/day. Food intake was controlled throughout the study. Hepatic DNL was measured before and after an oral fructose/glucose bolus using isotopic labeling with 1-13 C1 -acetate intravenous infusion, followed by measurement of labeled very low-density lipoprotein palmitate via gas chromatography mass spectometry. Substrate oxidation was measured by indirect calorimetry. Across the range of doses, fasting DNL was reduced by up to 90% (P = 0.003). Increasing plasma concentrations of TVB-2640 were associated with progressive reductions in the percent of fructose-stimulated peak fractional DNL (R2 = -0.749, P = 0.0003) and absolute DNL area under the curve 6 hours following fructose/glucose bolus (R2 = -0.554, P = 0.005). For all subjects combined, alanine aminotransferase was reduced by 15.8 ± 8.4% (P = 0.05). Substrate oxidation was unchanged, and safety monitoring revealed that the drug was well tolerated, without an increase in plasma triglycerides. Alopecia occurred in 2 subjects (reversed after stopping the drug), but otherwise no changes were observed in fasting glucose, insulin, ketones, and renal function. CONCLUSION These data support the therapeutic potential of a fatty acid synthase inhibitor, TVB-2640 in particular, in patients with NAFLD and nonalcoholic steatohepatitis.
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Tofacitinib for ulcerative colitis: results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry.
Biemans, VBC, Sleutjes, JAM, de Vries, AC, Bodelier, AGL, Dijkstra, G, Oldenburg, B, Löwenberg, M, van Bodegraven, AA, van der Meulen-de Jong, AE, de Boer, NKH, et al
Alimentary pharmacology & therapeutics. 2020;(9):880-888
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Abstract
BACKGROUND Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). AIM: To evaluate effectiveness, safety and use of tofacitinib in daily practice. METHODS UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. RESULTS In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. CONCLUSION Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.