Current Therapeutic Research-clinical and Experimental最新文献

Background

Vitamin D deficiency is a common side effect of imatinib mesylate (IM) therapy. Transporter polypeptides involved in the disposition of IM may be required for maintenance of adequate vitamin D concentrations.

Objective

The aim of the present work is to study the association between the plasma concentrations of IM and plasma 25-hydroxyvitamin (25[OH]) D3 with transporter genotypes in patients with chronic myelogenous leukemia.

Methods

A total of 77 adult patients with chronic myelogenous leukemia treated with IM participated in this study. Peak and trough plasma IM and 25(OH) vitamin D3 concentrations were measured and compared to the results of single nucleotide polymorphisms of the efflux transporting gene ABCB1-1236 C>T and the uptake transporting gene OATP1B3-334 T>G. Multiple linear regressions were used to examine the associations between 25(OH) vitamin D3 concentrations and a number of patient characteristics, including responses to therapy. Binary logistic regression analysis was used to predict odd ratios for the clinical response to IM.

Results

Plasma 25(OH) vitamin D3 concentration quartile values were: 25%, 8.2 ng/mL; 50%, 9.8 ng/mL; and 75%, 12 ng/mL. High IM peak concentration, being OATP1B3-334 T>G (TT), and/ or ABCB1-1236 C>T (CT) are associated with lower concentrations of 25(OH) vitamin D3. Moreover, IM peak concentration, IM trough concentration, and plasma concentration of 25(OH) vitamin D3 were associated with the clinical response to IM.

Conclusions

vitamin D, IM concentration, as well as the genotype of OATP1B3-334 T>G, had an influence on the response of patients with chronic myelogenous leukemia.

Background

Sublingual allergy immunotherapy tablets (SLIT-tablets) provide a well-tolerated and clinically efficacious treatment for allergic disease such as allergic rhinitis and allergic asthma. In SLIT, uptake of allergen by immune-competent cells in the oral mucosa activates the immune system and leads to tolerance toward the sensitizing allergen. The ability to deliver the full allergen content into solution within the recommended sublingual holding time is therefore an essential quality of SLIT-tablets that must be supported by the tablet formulation for all relevant allergen sources. SLIT-tablets based on a fast-dissolving orodispersible freeze-dried formulation (Zydis) are currently available for 5 of the most prevalent allergens: tree (birch and related species from the birch-homologous group), grass, ragweed, Japanese cedar, and house dust mite.

Objectives

The purpose of this study was to examine the allergen release properties of three freeze-dried SLIT-tablets containing tree, ragweed, and Japanese cedar extracts, respectively. The correlation between SLIT-tablet allergen release and the level of allergen-specific T-cell activation was examined for the tree SLIT-tablet.

Methods

Allergen release kinetics and tablet disintegration times for the 3 freeze-dried SLIT-tablets were examined. For all 3 tablets, the magnitude of solubilized major allergen relative to time in solution was compared to external controls to achieve a measure of the total allergen release. Additional assessments of allergen release occurring after the initial timepoint (15 or 30 seconds in solution) were done independently of external controls by linear regression analyses. For the tree SLIT-tablet, the immunological potency of the released major allergen was assessed at each experimental timepoint by a Bet v-specific T-cell activation assay.

Results

All 3 SLIT-tablets disintegrated within 1 second after contact with assay buffer without any detectible residue. Complete release of major allergens (Bet v 1, Amb a 1, and Cry j 1, respectively) was seen at the earliest experimental time points (15 or 30 seconds). For the tree SLIT-tablet, full T-cell activation was achieved at 30 seconds (earliest experimental time point).

Conclusions

The freeze-dried SLIT-tablet formulation consistently provides rapid and complete release of allergen from a wide range of species in a standardized in vitro assay. Full release of the SLIT-tablet allergen content within the sublingual holding time is a prerequisite for maximal exposure of allergens to the sublingual mucosa immune system. The freeze-dried SLIT-tablet formulation examined here supports short sublingual holding times and furthermore offers a convenient administration form of allergy immunotherapy.

Background

Hepatorenal syndrome (HRS) is among the leading causes of hospitalization and mortality in patients with chronic liver disease.

Objective

To assess the HRS patient journey from preadmission to postdischarge to understand patient characteristics, disease progression, treatment patterns, and outcomes.

Methods

We conducted a retrospective study using real-world data from a nationwide electronic health record database (Cerner Health Facts, Kansas City, Missouri). We used ICD-9/10 diagnosis codes to identify patients hospitalized with HRS between January 1, 2009, and January 31, 2018. We assessed patient characteristics and history, clinical presentation, treatment, and outcomes. Regression analysis was conducted to assess the association between patient characteristics and survival while adjusting for demographic and clinical covariates.

Results

The study included 3563 patients (62% men). Precipitants of HRS included gastrointestinal bleeding (18%), diuretics and infections (30%), and paracentesis (26%). Although 21% of patients had liver injury exclusively associated with alcohol use, 20% had hepatitis C, 8% had nonalcoholic steatohepatitis, and the etiology of the remainder (51%) was either some combination of conditions or unknown. A total of 42% of patients received vasopressors, including octreotide and midodrine (10%), other combinations of vasopressors (11%), or another single vasopressor (21%). In-hospital mortality was 34%, and 14% of patients were discharged to hospice. Regression analysis showed patients with acute-on-chronic liver failure had higher mortality in acute-on-chronic liver failure grades 1 (odds ratio = 1.59), 2 (odds ratio = 2.49), and 3 (odds ratio = 4.53) versus no acute-on-chronic liver failure. Among survivor patients, 38% were readmitted within 90 days of discharge; 23% of readmissions were HRS-related.

Conclusions

The HRS patient journey presented in this study highlights inconsistencies in, and provides insight into, associated hospital-based treatment strategies. A mortality rate of 34% along with a readmission rate of 23% associated with HRS-related complications warrant more disease awareness and effective treatment. Further research is needed to examine the interactions between the etiology of cirrhosis, precipitants, treatment, and outcomes. (Curr Ther Res Clin Exp. 2022; 82:XXX–XXX)

Background

In a Phase III study, regdanvimab (CT-P59) reduced the risk of hospitalization or death versus placebo in patients with mild-to-moderate coronavirus disease 2019 (COVID-19).

Purpose

We performed a retrospective cohort study of patients with COVID-19 to examine the effect of regdanvimab versus standard of care (SoC) on oxygen saturation.

Methods

We reviewed patients with mild-to-moderate COVID-19 confirmed by reverse transcription-polymerase chain reaction at a single hospital in the Republic of Korea. The primary efficacy end point was the proportion of patients deteriorating with peripheral capillary oxygen saturation <94% on room air up to day 28.

Results

A total of 127 patients were treated for COVID-19 with regdanvimab, 190 with SoC. The proportion of patients deteriorating with peripheral capillary oxygen saturation <94% on room air up to day 28 was 13.4% with regdanvimab and 39.5% with SoC (P < 0.0001); median time (range) until sustained recovery of fever was 2.0 (0.2–14.8) and 4.2 (0.1–17.1) days, respectively. Supplemental oxygen was required by 23.6% of patients with regdanvimab and 52.1% with SoC (P<0.0001) for a mean of 6.3 and 8.7 days, respectively (P = 0.0113); no patients needed mechanical ventilation. Compared with SoC, hospitalization was shorter with regdanvimab (mean = 11.1 vs 13.6 days; 63.8% vs 31.6% discharged within 11 days; both P values < 0.0001). Fewer regdanvimab-treated patients required remdesivir (14.2% vs 43.2%; P < 0.0001). There were no deaths. Two patients had adverse reactions with regdanvimab.

Conclusions

This real-world study indicates that regdanvimab can prevent deterioration in patients with mild-to-moderate COVID-19. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

Tyrosine kinase inhibitors are anticancer drugs that disrupt signal transduction pathways in protein kinases by different mechanisms. This group of pharmacologic agents has significantly improved the outcome of patients with chronic myeloid leukemia. However, their effect is not limited to cancer cells, and various complications, particularly cutaneous reactions, have been reported. We report a very rare case of a 35-year-old female with a history of chronic myeloid leukemia who presented with elephantine psoriasis after the treatment with nilotinib.

Conclusions: This case highlights a critical side effect of tyrosine kinase inhibitors. Awareness of this subject can be useful for better management of similar patients.

Background

Dasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration-QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes.

Objective

The aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers.

Methods

This double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and an estimated maximum effect (E_max) model.

Results

At the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and E_max models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the E_max model, the E_max of dasiglucagon was 3.6 ms (90% CI, 1.23–5.95 ms), and the amount to produce half the effect of E_max) was 426.0 pmol/L (90% CI, −48.8 to 900.71 pmol/L). The treatment effect-specific intercept was −0.44 ms (90% CI, −2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting.

Conclusions

Dasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

Background

Herbal remedies are used to manage type 2 diabetes mellitus (type 2 DM) as the sole treatment or as a complementary therapy. Limitations of herbal remedies, such as poor stability and limited absorption, impede their development as therapeutic agents, which could be overcome by nanoformulations.

Objectives

This review attempts to summarize the studies reported between 2009 and 2020 in the development of medicinal plant-based nanoformulations for the management of type 2 DM, discuss formulation methods, mechanisms of action, and identify gaps in the literature to conduct future research on nanoparticle-based herbal treatment options targeting type 2 DM.

Methods

To retrieve articles published between January 2009 and December 2020, the electronic databases PubMed, Science Direct, and Google Scholar were searched with the keywords nanoparticle, plant, and diabetes in the entire text. Peer-reviewed research articles on herbal nanoformulations published in English-language based on in vitro and/or in vivo models of type 2 DM and/or its complications were included. The literature search and selection of titles/abstracts were carried out independently by 2 authors. The list of full-text articles was selected considering inclusion and exclusion criteria, with the agreement of all the authors.

Results

Among the reported studies, 68% of the studies were on inorganic herbal nanoformulations, whereas 17% and 8% were of polymer-based and lipid-based herbal nanoformulations, respectively. Some of the important biological properties of nanoformulations included improvement in glycemic control and insulin levels, inhibition of the formation of advanced glycation end products, and regeneration of pancreatic β cells. The aforementioned properties were observed by screening nanoformulations using in vitro cellular and noncellular models, as well as in vivo animal models of type 2 DM studied for acute or subacute durations. Only 2 clinical trials with patients with diabetes were reported, indicating the need for further research on medicinal plant-based nanoformulations as a therapeutic option for the management of type 2 DM.

Conclusions

Medicinal plant extracts and isolated compounds have been nanoformulated using various methods. The properties of the nanoformulations were found superior to those of the corresponding herbal extracts and isolated compounds. At both the preclinical and clinical levels, there are a number of poorly explored research areas in the development and bioactivity assessment of herbal nanoformulations. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX) © 2022 Elsevier HS Journals, Inc.

Background

Spinal surgery is associated with severe pain within the first few days after surgery. Opioids are commonly used to control postoperative pain, but these can lead to postoperative nausea and vomiting (PONV). Therefore, use of more effective and better-tolerated agents would be beneficial for these patients. Serotonin receptor antagonists, such as ramosetron, have been used to reduce PONV in patients receiving anesthesia.

Objective

We conducted a meta-analysis of published randomized controlled trials (RCTs) to compare the efficacy and tolerance of ramosetron to prevent PONV after spinal surgery.

Methods

Medline, Embase, Cochrane Library, and Science Citation Index databases were systematically searched for relevant RCT articles published between January 1979 and November 2020. Full text articles restricted to English language that described RCTs comparing the use of ramosetron with other serotonin antagonists to treat PONV following spinal surgery in adult patients were considered for meta-analysis. Two reviewers independently performed study selection, quality assessment, and data extraction of all articles. Differences were resolved by a third reviewer.

Results

The search identified 88 potentially relevant articles, of which only 3 met our selection criteria. Study drugs were administered at the end of spinal surgery in all 3 included articles. The meta-analysis revealed that ramosetron (0.3 mg) reduced the pain score (mean difference = −0.66; 95% CI −1.02 to −0.30), lowered the risk of PONV (risk ratio = 0.86; 95% CI, 0.76–0.97), and postoperative vomiting (risk ratio = 0.32; 95% CI, 0.17–0.60), and limited the use of rescue antiemetics (risk ratio = 0.66; 95% CI, 0.45–0.96) after spinal surgery. However, there were no significant differences in the incidence of postoperative nausea, the use of rescue pain medications, the number of rescue analgesics required, and the risk of discontinuation of patient-controlled analgesia between ramosetron and palonosetron (0.075 mg) or ondansetron (4 mg). There were no statistically significant differences in the risk of adverse events among the 3 medications.

Conclusions

This meta-analysis of 3 RCTs showed that ramosetron reduced the risk of PONV and POV, limited the use of rescue antiemetics, reduced the postoperative pain score, and did not increase the risk of discontinuing patient-controlled analgesia compared with palonosetron or ondansetron after spinal surgery in 3 RCTs. Therefore, this meta-analysis indicates that ramosetron is an effective and well tolerated antiemetic that can be used to prevent PONV following spinal surgery in adult patients. PROSPERO identifier: CRD42020223596 (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

© 2022 Elsevier HS Journals, Inc.

Background

The β₃-adrenergic agonists vibegron and mirabegron have shown favorable safety profiles and efficacy for the treatment of overactive bladder. However, β-adrenergic receptors are also found outside the bladder, which could lead to off-target activity.

Objective

This study assessed the selectivity of vibegron and mirabegron for β-adrenergic receptors and the maximal effect and potency for β₃-adrenergic receptors.

Methods

Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing β₁-, Chinese hamster ovary cells expressing β₂-, and human embryonic kidney 293 cells expressing β₃-adrenergic receptors. Cells were incubated with vibegron, mirabegron, or control (β₁ and β₃, isoproterenol; β₂, procaterol). Responses were quantified using homogeneous time-resolved fluorescence of cyclic adenosine monophosphate and were normalized to the respective control. Half-maximal effective concentration and maximum response values were determined by nonlinear least-squares regression analysis.

Results

Activation of β₃-adrenergic receptors with vibegron or mirabegron resulted in concentration-dependent β₃-adrenergic receptor responses. Mean (SEM) half-maximal effective concentration values at β₃-adrenergic receptors were 2.13 (0.25) nM for vibegron and 10.0 (0.56) nM for mirabegron. At a concentration of 10 µM, β₃-adrenergic activity relative to isoproterenol was 104% for vibegron and 88% for mirabegron. Maximum response at β₃-adrenergic receptors was 99.2% for vibegron and 80.4% for mirabegron. β₁-adrenergic activity was 0% and 3% for vibegron and mirabegron, respectively; β₂-adrenergic activity was 2% and 15%, respectively.

Conclusions

Vibegron showed no measurable β₁ and low β₂ activity compared with mirabegron, which showed low β₁ and some β₂ activity. Both showed considerable selectivity at β₃-adrenergic receptors; however, vibegron demonstrated near-exclusive β₃ activity and a higher maximum β₃ response.

Background

Overactive bladder (OAB) is a common clinical condition for which current drug treatment comprises drugs blocking the cholinergic nerve supply, or augmenting the adrenergic nerve supply, to the detrusor muscle of the urinary bladder. Current treatments have drawbacks, including lack of efficacy and the development of adverse effects in some patients. Hence, new and better drugs for treating OAB will be clinically useful.

Objective

This review is meant to provide information on drugs currently undergoing preclinical or clinical trials for the treatment of OAB published in journal articles or elsewhere.

Methods

The cited articles were retrieved from PubMed and Google Scholar from January 1, 1990, to December 31, 2021. The search terms used were contraction or contractility, detrusor, inhibition, isolated or in vitro, in vivo, overactive bladder, and relaxant effect or relaxation.

Results

There are 4 classes of new drugs under various stages of development for the treatment of OAB. These are drugs acting on the autonomic nerve supply to the detrusor muscle of the urinary bladder that include the anticholinergics tarafenacin and afacifenacin and the β₃ adrenoceptor agonists solabegron and ritobegron; drugs acting on ion channels in the detrusor muscle (eg, potassium channel openers and calcium channel blockers), drugs acting on cellular enzymes like phosphodiesterase-5 inhibitors and Rho kinase inhibitors, and drugs acting on miscellaneous targets (eg, pregabalin and trimetazidine).

Conclusions

Drugs currently used to treat OAB target only the cholinergic and adrenergic cellular signalling pathways. There are many other drugs under trial targeting other cellular pathways that may be useful for treating OAB. Their approval for clinical use might improve the treatment of patients with OAB. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)