Imrecoxib: Advances in Pharmacology and Therapeutics.

Imrecoxib, a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), was discovered via the balanced inhibition strategy of COX-1/COX-2. It is indicated for the relief of painful symptoms of osteoarthritis. There have been some pharmacological and therapeutic advances since the approval of imrecoxib in 2011. However, an update review in this aspect is not yet available. Relevant literature until January 2024 was identified by search of PubMed, Web of science, Embase and CNKI. From the perspective of efficacy, imrecoxib provides relief of osteoarthritis symptoms, and potential off-label use for treatment of idiopathic pulmonary fibrosis, perioperative pain, hand-foot syndrome, axial spondyloarthritis, COVID-19, cartilage injury, and malignancies such as lung and colon cancer. From a safety point of view, imrecoxib showed adverse effects common to NSAIDs; however, it has lower incidence of new-onset hypertension than other types of selective COX-2 inhibitors, less gastrointestinal toxicities than non-selective NSAIDs, weaker risk of drug interaction than celecoxib, and more suitable for elderly patients due to balanced inhibition of COX-1/COX-2. From a pharmacoeconomic perspective, imrecoxib is more cost-effective than celecoxib and diclofenac for osteoarthritis patients. With the deepening of the disease pathophysiology study of osteoarthritis, new therapeutic schemes and pharmacological mechanisms are constantly discovered. In the field of osteoarthritis treatment, mechanisms other than the analgesic and anti-inflammatory effects of COX-2 inhibitors are also being explored. Taken together, imrecoxib is a moderate selective COX-2 inhibitor with some advantages, and there would be more clinical applications and research opportunities in the future.

The Global Burden of Diseases attributed to high low-density lipoprotein cholesterol from 1990 to 2019.

Background: To demonstrate the real-word situation of burdens that are attributed to the risk factor of high low-density lipoprotein cholesterol (LDL-C) at the global, regional, national levels, among different age groups and between genders. Methods: We analyzed data from the Global Burden of Disease study 2019 related to global deaths, disability-adjusted life years (DALYs), summary exposure value (SEV), average annual percentage change (AAPC), and observed to expected ratios (O/E ratios) attributable to high LDL-C from 1990 to 2019. Results: Globally, in 2019, the total numbers of deaths and DALYs attributed to high LDL cholesterol were 1.47 and 1.41 times higher than that in 1990. The age-standardized deaths and DALYs rate was 1.45 and 1.70 times in males compared to females, while the age-standardized SEVs rate was 1.10 times in females compared to males. The deaths, DALYs, and SEV rates increased with age. In 2019, the highest age-standardized rates of both deaths and DALYs occurred in Eastern Europe while the lowest occurred in high-income Asia Pacific. High-income North America experienced a dramatic reduction of risk related to high LDL-C. Correlation analysis identified that the age-standardized SEV rate was positively correlated with Socio-demographic Index (SDI; r = 0.7753, P < 0.001). The average annual percentage change (AAPC) of age-standardized SEV rate decreased in the high SDI and high-middle SDI regions but increased in the middle SDI, low-middle SDI, and low SDI regions. High LDL-C mainly contributed to ischemic heart diseases. Conclusion: High LDL-C contributed considerably to health burden worldwide. Males suffered worse health outcomes attributed to high LDL-C when compared to females. The burden attributed to high LDL-C increased with age. Lower SDI regions and countries experienced more health problem challenges attributed to high LDL-C as the result of social development and this should be reflected in policymaking.

Association Between Circulating Copeptin Level and Mortality Risk in Patients with Intracerebral Hemorrhage: a Systemic Review and Meta-Analysis.

Copeptin has been identified as a biomarker of disease severity and is associated with mortality risk in several common diseases. This study sought to determine the association between circulating copeptin level and mortality risk in patients with intracerebral hemorrhage. PubMed, Web of Science, and Wanfang Medicine Database were searched for studies assessing the association between circulating copeptin level and mortality risk in patients with intracerebral hemorrhage. The pooled hazard ratio (HR) of mortality was calculated and presented with 95 % confidence interval (95 % CI). Data from 1332 intracerebral hemorrhage patients were derived from 9 studies. Meta-analysis showed that intracerebral hemorrhage patients with poor prognosis had much higher copeptin levels than those survivors (standardized mean difference = 1.68, 95 % CI 1.26-2.11, P < 0.00001). Meta-analysis of 8 studies with HRs showed that high circulating copeptin level was associated with higher risk of mortality in patients with intracerebral hemorrhage (HR = 2.42, 95 % CI 1.60-3.65, P < 0.0001). Meta-analysis of 6 studies with adjusted HRs showed that high circulating copeptin level was independently associated with higher risk of mortality in patients with intracerebral hemorrhage (HR = 1.67, 95 % CI 1.26-2.22, P = 0.0003). Our study suggests that there is an obvious association between circulating copeptin level and mortality in patients with intracerebral hemorrhage. High circulating copeptin level is independently associated with higher risk of mortality in patients with intracerebral hemorrhage.

Levels of brain natriuretic peptide are associated with peripheral arterial disease in subjects with type-2 diabetes mellitus.

BACKGROUND: The effects of brain natriuretic peptide (BNP) on the risk of cardiovascular disease and atherosclerosis have been studied. However, little information is available regarding peripheral arterial disease (PAD), particularly among subjects with type-2 diabetes mellitus (T2DM). The aim of our study was to assess the potential relationship between BNP levels and PAD among T2DM patients. METHODS: The study cohort was 507 T2DM outpatients in which BNP levels were measured. Cross-sectional associations between BNP levels (in tertiles) and PAD were examined. RESULTS: Compared withT2DM patients without PAD, BNP levels were markedly higher in patients with PAD (p = 0.001). Correlation analyses showed that the BNP level was negatively correlated with the ankle-brachial index (r = -0.453, p = 0.033). At a cutoff value of 78.2 pg/ml, the BNP level showed a sensitivity of 71.9%, a specificity of 68.1%, and a positive predictive value of 84.3% for a diagnosis of PAD. The area under the receiver-operating characteristic curve increased significantly if BNP levels were incorporated into a predictive model of the potential risk factors for PAD (0.85 vs 0.81, p = 0.029). CONCLUSIONS: BNP is a potential and promising biomarker for PAD screening in T2DM patients.

Serum galectin-3: a risk factor for vascular complications in type 2 diabetes mellitus.

BACKGROUND: Plasma galectin-3, a mediator of fibrogenesis and inflammation, its potential to associate with type 2 diabetes (T2DM) is poorly investigated. Here, we explored its interaction with the serum galectin-3 and vascular complications. METHODS: We conducted a population-based cross-sectional survey in Zhejiang, China involving 165 men and 119 women (age range, 43 - 84 years), investigating the relationship between serum galectin-3 and vascular disease in patients with T2DM. RESULTS: Serum galectin-3 was higher in subjects with T2DM than that in control participants (27.4 vs. 17.6 ng/ml, P < 0.001). Compared with subjects with galectin-3 values in the lowest quartile, those with values in the highest quartile had an increased likelihood of vascular complications (4th quartile odds ratio (OR) 2.52, 95% confidence interval (CI), 1.25 - 4.07). Increased risk of micro- or macrovascular complications correlated with serum galectin-3 concentration (ORs 11.4 and 8.5, respectively). An increased number of vascular complications was associated with high serum galectin-3 levels (P < 0.05). Patients with serum galectin-3 levels > 25 ng/ml had an elevated risk of diabetes relative to patients with levels < 10 ng/ml (OR for any vascular complication 2.64, for heart failure 3.97, for nephropathy 4.09, for peripheral arterial disease (PAD) 4.18; all P < 0.05). Complication risk was higher in patients with neurogenic, stroke, or retinopathy complications, but this difference was not significant after risk factor adjustment. Serum galectin-3 levels correlated with diabetes duration, C-reactive protein (CRP) levels, and albuminuria. CONCLUSION: High galectin-3 values were associated with increased odds of developing heart failure, nephropathy, and peripheral arterial disease in patients with T2DM.

A cross-sectional study on cerebrospinal fluid biomarker levels in cognitively normal elderly subjects with or without a family history of Alzheimer's disease.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers reflect changes in the brain, and contribute to early screening. Maternal inheritance is putatively stronger than paternal inheritance for late-onset Alzheimer's disease (LOAD). METHODS: Clinical data of 162 cognitively normal subjects were reviewed. A standard questionnaire was used to identify LOAD family history. Mini-mental state examination (MMSE) was used to evaluate cognition. CSF Aß1-40, Aß1-42, total and phosphorylated tau were measured using ELISA. AIMS: To compare biomarkers in cognitively normal elderly subjects with versus without LOAD family history. RESULTS: Among the 162 subjects, 38 and 60 had LOAD family history on paternal and maternal sides, respectively. The remaining 60 subjects had no family history. No difference was noted in age, gender, education level, MMSE score, and memory impairment complaint in the three groups. Aß42 and the Aß42/40 ratio were lower than in subjects with a maternal history than in subjects with a paternal history or without family history (P < 0.05 in both). Phosphorylated and total tau did not differ among the three groups. CONCLUSION: Offspring with a family history of LOAD on the maternal side have lower Aß42 and Aß42/40 ratio in the CSF, and maybe at higher risk for developing AD.

[The relationship between sleep quality and glucose level, diabetic complications in elderly type 2 diabetes mellitus].

OBJECTIVE: To explore the relationship between sleep quality and glucose level, diabetic complications in elderly type 2 diabetes mellitus. METHODS: A total of 130 hospitalized elderly type 2 diabetes in our hospital were included in the study. Questionnaires and other related clinical data were collected within one week after admission. Patients were divided into two groups: poor-sleeper group and good-sleeper group according to Pittsburgh Sleep Quality Index (PSQI). RESULTS: Sixty percent (78/130) of these patients were poor sleepers. The following parameters differed in the two groups: the duration of diabetes [(7.9 ± 1.8) years vs (7.2 ± 1.5) years, t = 2.318], systolic blood pressure [(148 ± 30) mm Hg (1 mm Hg = 0.133 kPa) vs (138 ± 23) mm Hg, t = 2.037], fasting plasma glucose (FPG) [(10.7 ± 2.2) mmol/L vs (9.8 ± 1.9) mmol/L, t = 2.410], hemoglobin A1c (HbA1c) [(8.6 ± 2.2)% vs (7.8 ± 2.1)%, t = 2.068], high-sensitive C-reactive protein (hs-CRP) [(5.27 ± 2.34) mg/L vs (4.44 ± 1.76) mg/L, t = 2.179], ratio of diabetic complications (61% vs 32%, χ(2) = 4.257), percentage of depression (20% vs 8%, χ(2) = 3.722), score of life quality [(98 ± 19) scores vs (89 ± 13) scores, t = 2.980], and proportion of patients treated with insulin (32% vs 12%, χ(2) = 4.489). All the above parameters were significantly higher in poor-sleeper group than the good-sleeper group (all P value < 0.05). Multiple correlation analysis showed that the factors affecting sleep quality were FPG, HbA1c, duration of diabetes, diabetic complications, depression, life quality and insulin application (r = 0.213, 0.257, 0.223, 0.335, 0.422, 0.3451, 0.231, respectively; all P value < 0.05). By multivariate logistic regression analysis, the followings were found: FPG (ß = 1.29, P < 0.05) and PSQI (ß = 1.07, P < 0.05) were found to be correlated with HbA1c. With increasing of PSQI, FPG, HbA1c, diabetic complications and life quality were changed significantly (all P value < 0.05). The independent risk factors of diabetic complications were duration of diabetes (OR = 1.32, 95%CI 1.01 - 2.01), HbA1c (OR = 2.01, 95%CI 1.63 - 2.67), hs-CRP (OR = 1.12, 95%CI 1.08 - 1.21) and PSQI (OR = 1.71, 95%CI 1.58 - 2.02). CONCLUSIONS: Elderly type 2 diabetes mellitus are usually poor sleepers. Sleep quality probably affects blood glucose regulation, and is closely correlated with the occurrence of complications. In addition, poor sleep quality results in poor life quality.

Predictive value of serum cholinesterase for the prognosis of aged patients with systemic inflammatory response syndrome.

BACKGROUND: Some studies found that cholinesterase (ChE) can be an independent risk factor for patients with multiple organ dysfunction syndrome. To assess aged patients with systemic inflammatory response syndrome (SIRS) early and predict their prognosis, the predictive value of ChE for the prognosis of aged patients with SIRS was analyzed. METHODS: From September 2009 to September 2010, all aged patients with SIRS in the ICU of the Second Affiliated Hospital of Zhejiang University School of Medicine were retrospectively analyzed if they met inclusion criteria: patients aged ≥ 65 years and met American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference criteria for SIRS. Serum ChE, albumin, D-dimer, lactic acid and C-reactive protein (CRP) were measured, and the Acute Physiology and Chronic Health Evaluation (APACHE) II and Glasgow Coma Scale (GCS) scores were evaluated within the first 24 hours in the ICU. Fisher's exact test was used for comparison of the primary disease between the deceased group and surviving group. For comparison of study variables between the two groups, the Student's t test or Mann-Whitney U test was used. Multivariate significance was tested with binary Logistic regression analysis. RESULTS: The clinical data of 124 aged patients with SIRS were collected and analyzed. Sixty-six patients (46 male, 20 female, mean age (78.70 ± 8.08) years) who died were included in the deceased group and 58 patients (34 male, 24 female, mean age (76.02 ± 6.57) years) who survived were included in the surviving group. There were no significant differences in age, gender, APACHE II score and GCS score between the deceased group and surviving group (all P > 0.05), but there were significant differences in lactic acid (P = 0.011), D-dimer (P = 0.011), albumin (P = 0.007), CRP (P = 0.008), and ChE (P < 0.0001). The correlation analysis showed that the APACHE II score and CRP were not correlated with ChE (both P < 0.05). D-dimer and albumin were correlated with ChE (Spearman's rho correlation coefficients were -0.206 and 0.324, the corresponding P values were 0.022 and < 0.0001). Multiple Logistic regression analysis showed that age, gender, lactic acid, D-dimer, albumin, CRP, APACHE II score, and GCS score were not independent risk factors for prognosis of aged patients with SIRS, but that ChE was (P < 0.0001). The receiver operating characteristic curve of ChE had an area under the curve of 0.797 (standard error = 0.04; P < 0.0001), and a ChE of 103.00 U/L was the cut-off value with sensitivity = 0.793, specificity = 0.742. CONCLUSION: Serum ChE might be a predictive marker for the prognosis of aged patients with SIRS, with low serum ChE levels indicating poor prognosis.

[Relationship between plasma total homocysteine and mild cognitive impairment in senile patients with type 2 diabetes].

OBJECTIVE: To explore the relationship between fasting plasma level of total homocysteine (tHcy) and mild cognitive impairment in senile patients with type 2 diabetes mellitus. METHODS: A total of 88 senile type 2 diabetics with mild cognitive impairment treated at our hospital from July 2008 to November 2010 were recruited into the MCI group while 52 senile type 2 diabetics into the DNC group. And the control group was composed of 36 healthy elders. The parameters of tHcy, total glyceride (TG), total cholesterol (TC), low density lipoprotein-C (LDL-C), high density lipoprotein-C (HDL-C), creatinine (Cr), hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), 2 h plasma glucose (2 hPG), fasting insulin (FINS), homeostasis model of insulin resistance (HOMA-IR), folic acid (FA) and vitamin B(12) (VitB(12)) were detected. RESULTS: The patients had a higher level of tHcy in the MCI group than those in the NCM and control groups [(11.3 ± 1.8) vs (9.8 ± 1.5) and (8.1 ± 1.1) µmol/L; P < 0.01]. ROC curve showed that tHcy level had some value of predicting the occurrence of mild cognitive impairment in senile patients with type 2 diabetes mellitus (AUC 0.825, 95%CI 0.758-0.893, P < 0.01). Logistic regression analysis showed that tHcy, SBP, HbA1c, 2 h PG, FINS, LDL-C, HOMA-IR, FA and VitB(12) [OR value: 3.64, 1.68, 1.10, 1.05, 0.81, 1.42, 0.83, 0.74, 0.86 (P < 0.05 or 0.01)] were independent risk factors of mild cognitive impairment in senile diabetic patients. CONCLUSION: Such factors as tHcy, SBP, HbA1c, FPG, 2 hPG, FINS, LDL-C, HOMA-IR, FA and VitB(12) induce senile patients with type 2 diabetes mellitus to suffer mild cognitive impairment. But tHcy level may play an important role in senile diabetic patients with mild cognitive impairment.

[A study of microPET for assessing regional cerebral glucose metabolism and the expression of dopamine receptor type 2 in a rat model of Parkinson's disease].

OBJECTIVE: To employ (18)F-fluoro-2-deoxyglucose ((18)F-FDG) and (3-N-[(11)C] methylspiperone)(11)C-NMSP microPET to assess the changes of regional cerebral glucose metabolism and the expression of dopamine receptor type 2 (DRD(2)) in a rat model of Parkinson's disease (PD). METHODS: A hemiparkinsonian model was established in rats by unilateral pretreatment with 6-hydroxydopamine (6-OHDA). At 2 weeks after 6-OHDA insult, (18)F-FDG and (11)C-NMSP microPET scan were performed to compare the differences of regional cerebral glucose metabolism and the expression of DRD(2) between the PD and control groups respectively. The immunohistochemical staining was used to detect the expression of tyrosine hydroxylase in two groups. RESULTS: In the PD model, the glucose metabolism rates were 88.2% ± 2.2%, 94.5% ± 4.5% and 96.2% ± 5.8% respectively, in right striatum, hippocampus and sensorimotor cortex. And they were significantly lower than those in the control group [92.7% ± 2.8% (P < 0.01), 98.9% ± 3.9% (P < 0.01) & 102.8% ± 2.1% (P < 0.01)]. The expression of DRD(2) in right striatum was significantly higher in the PD group than that in the control group (112.9% ± 9.0% vs 102.3% ± 1.4%, P < 0.01). CONCLUSION: In the PD rats, glucose metabolism decreases in injured side striatum, hippocampus and sensorimotor cortex while and the expression of DRD(2) increases in injured side striatum.(18)F-FDG and (11)C-NMSP microPET can effectively assess the regional cerebral glucose metabolism and the expression of DRD(2) in PD. They may serve as effective molecular imaging tools for an early diagnosis of PD.

K(ATP)-dependent neurotransmitter release in the neuronal network of the rat caudate nucleus.

K(ATP) channels can couple the bioenergetic metabolism of the cell to membrane excitability. Here, we show gamma-aminobutyric acid (GABA) mediated inhibition of dopamine outflow from slices of the rat caudate nucleus that is regulated by extracellular glucose via high- and low-affinity K(ATP) channels. During glucose reduction, a biphasic dopamine effect could be observed with first a dopamine increase followed by a decline at low glucose concentrations. Both phases were inhibited by glibenclamide. Pinacidil decreased DA outflow without an effect of glucose reduction implying an overall activation of K(ATP) channels. The first phase with dopamine increase was related to reduced GABAergic activity and could be blocked by bicuculline. Our results may be explained by different types of K(ATP) channels with low affinity of ATP and glibenclamide on inhibitory GABAergic and high-affinity on excitatory DAergic neurons. This led us to suggest a biological principle through which neuronal networks are functioning.

Modulation of a neuronal network by electrical high frequency stimulation in striatal slices of the rat in vitro.

The effects of the GABA(A) receptor antagonist bicuculline, the D2-like receptor antagonist sulpiride and the D1-like receptor antagonist SCH-23390 on the electrical high frequency stimulation (HFS)-evoked gamma-aminobutyric acid (GABA) and dopamine (DA) release were measured from slices of the rat striatum by means of HPLC method with electrochemical detection. HFS with 130Hz stimulated veratridine-activated GABAergic neurons resulting in an increased GABA outflow while DA outflow decreased. In the presence of the GABA(A) receptor antagonist bicuculline extracellular GABA and DA outflow were enhanced. When the competitive dopamine D2-like receptor antagonist S-(-)-sulpiride was added to incubation medium, the HFS-evoked stimulatory effect on GABA outflow declined to values found after veratridine (1microM) without HFS. After co-incubation of sulpiride and the competitive D1-like receptor antagonist R-(+)-SCH-23390, the effect of sulpiride on HFS plus veratridine-evoked GABA outflow was completely reversed. Neither sulpiride nor SCH-23390 had any influence on the effect of HFS on veratridine-induced DA outflow. No effect of HFS on glutamate outflow was observed in all experiments. These results led us to suggest that in our model HFS primarily affects GABAergic neurons. These neurons are embedded in a neuronal network with a GABA-dopamine circuit, and thus, HFS interacts with a neuronal network, not only with one neurotransmitter system or one neuron population.

Neuronal electrical high frequency stimulation modulates presynaptic GABAergic physiology.

Electrical high frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) has dramatic beneficial motor effects in advanced Parkinson's disease (PD). However, the mechanisms underlying these clinical results remain unclear. It is proposed that the gamma-aminobutyric acid (GABA) system is involved in the effectiveness of DBS. To prove this hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro; GABA and glutamate (GLU) outflow from striatal slices of normal or kainic acid-lesioned rats were measured after o-phthaldialdehyde sulphite derivatization using HPLC with electrochemical detection. Our results could demonstrate that high frequency stimulation (HFS) did not modulate basal GABA outflow in the perfusate. In the presence of submaximal concentrations of the voltage-gated sodium channel opener veratridine, HFS significantly enhanced GABA outflow. When the GABA transporter inhibitor, nipecotic acid, was added to the incubation medium, the HFS effects decreased to nearly control values. Destruction of striatal GABAergic neurons by kainic acid completely reversed the effects of HFS on GABA outflow. In the present study no effect of HFS on glutamate outflow was observed under any condition. These results suggest that HFS has a specific effect on GABAergic neuronal terminals resulting in an enhancement of extracellular GABA in the caudate nucleus. This effect is probably due to an inhibitory effect of HFS on the GABA uptake system rather than to stimulation of vesicular GABA release from GABAergic neurons, which are both associated with the presynaptic GABAergic physiology.