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1.
Metabolism ; 155: 155912, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38609038

ABSTRACT

Saroglitazar (SARO), a dual peroxisome proliferator activated receptor (PPAR)-α/γ agonist, has been used to treat metabolic diseases such as insulin resistance and diabetic dyslipidemia in patients with non-alcoholic fatty liver disease (NAFLD). SARO, administered at a dose of 4 mg/day, has been consistently studied in clinical trials with different time points ranging from 4 to 24 weeks with NAFLD patients. Due to its PPAR-γ agonistic action, SARO prevents adipose tissue-mediated fatty acid delivery to the liver by increasing insulin sensitivity and regulating adiponectin and leptin levels in adipose tissue. In hepatocytes, SARO induces fatty acid ß-oxidation in mitochondria and transcriptionally activates lipid metabolizing genes in peroxisomes. SARO inhibits insulin resistance, thereby preventing the activation of sterol regulatory element-binding proteins -1c and carbohydrate response element binding protein in hepatocytes through its PPAR-α agonistic action. SARO treatment reduces lipotoxicity-mediated oxidative stress by activating the nuclear factor erythroid 2-related factor 2 and transcriptionally expressing the antioxidants from the antioxidant response element in the nucleus through its PPAR-γ agonistic action. SARO provides a PPAR-α/γ-mediated anti-inflammatory effect by preventing the phosphorylation of mitogen-activated protein kinases (JNK and ERK) and nuclear factor kappa B in hepatocytes. Additionally, SARO interferes with transforming growth factor-ß/Smad downstream signaling, thereby reducing liver fibrosis progression through its PPAR-α/γ agonistic actions. Thus, SARO improves insulin resistance and dyslipidemia in NAFLD, reduces lipid accumulation in the liver, and thereby prevents mitochondrial toxicity, oxidative stress, inflammation, and fibrosis progression. This review summarizes the possible molecular mechanism of SARO in the NAFLD.


Subject(s)
Non-alcoholic Fatty Liver Disease , PPAR alpha , PPAR gamma , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Animals , Phenylpropionates/therapeutic use , Phenylpropionates/pharmacology , Insulin Resistance , Pyrroles
2.
Eur J Pediatr ; 183(5): 2141-2153, 2024 May.
Article in English | MEDLINE | ID: mdl-38366267

ABSTRACT

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8- < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors (n = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE (n = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (n = 3/38, 8%), acute cardiac failure, pneumonia, or anemia (n = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (n = 2), PAH (n = 2), COVID-19 (n = 1), acute right ventricular failure (n = 1), and failure to thrive (n = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC.    Conclusion: Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8- < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results.    Trial registration: NCT01342952, April 27, 2011. What is Known: • The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults. What is New: • This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8-<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. • Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results.


Subject(s)
Phenylpropionates , Pulmonary Arterial Hypertension , Pyridazines , Humans , Pyridazines/adverse effects , Pyridazines/therapeutic use , Pyridazines/administration & dosage , Phenylpropionates/administration & dosage , Phenylpropionates/adverse effects , Phenylpropionates/therapeutic use , Male , Child , Female , Adolescent , Treatment Outcome , Pulmonary Arterial Hypertension/drug therapy , Antihypertensive Agents/adverse effects , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Dose-Response Relationship, Drug , Walk Test , Hypertension, Pulmonary/drug therapy
3.
Int Immunopharmacol ; 128: 111469, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38211480

ABSTRACT

Osteoarthritis (OA) is a prevalent joint disorder pathologically correlated to chondrocyte ferroptosis. Gamma-oryzanol (γ-Ory), as a first-line drug for autonomic disorders, aroused our interest because of its antioxidant, lipid-lowering, and hypoglycemic potential. The purpose of this study was to investigate the potential impact and mechanism of γ-Ory in treating OA. And the inhibition of γ-Ory in extracellular matrix molecule (ECM) degradation, ferroptosis, and Keap1-Nrf2 binding in IL-1ß-exposed chondrocytes was detected via immunoblotting, immunofluorescence, and co-immunoprecipitation. Micro-CT, SO staining, and immunofluorescence have been conducted to assess the impact of γ-Ory treatment on ACLT-mediated OA in rats at both imaging and histological stages. We found that γ-Ory dose-dependently suppressed IL-1ß-induced ECM deterioration and chondrocyte ferroptosis. Our animal experiments revealed that γ-Ory delayed ACLT-mediated OA development. Mechanistically, γ-Ory interfered with the binding of Keap1 to Nrf2 to promote the latter's nuclear import, thereby increasing the expression of detoxification enzymes. Summarily, our works support γ-Ory's potential as a candidate drug for the treatment of OA.


Subject(s)
Ferroptosis , Osteoarthritis , Phenylpropionates , Animals , Rats , Chondrocytes/metabolism , Interleukin-1beta/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Osteoarthritis/drug therapy , Phenylpropionates/therapeutic use
4.
Biol Pharm Bull ; 46(10): 1403-1411, 2023.
Article in English | MEDLINE | ID: mdl-37779041

ABSTRACT

Antioxidants are promising therapeutics for treating oxidative stress-mediated liver diseases. Previously, we studied a potent natural antioxidant, ferulic acid, and developed a liposomal formulation of ferulic acid (ferulic-lipo) to improve its solubility. Ferulic-lipo significantly attenuated oxidative damage in the liver by inhibiting reactive oxygenase species (ROS). However, antioxidative liposomes must be less reactive with ROS prior to reaching the target sites to effectively neutralize existing ROS. But ferulic-lipo tends to be oxidized before reaching the liver. Besides, γ-oryzanol has been reported to decompose into ferulic acid in vivo; accordingly, we hypothesized that γ-oryzanol could be employed as a natural prodrug of ferulic acid to improve stability and antioxidative effectiveness. Therefore, in this study, we prepared a liposomal formulation of γ-oryzanol (γ-ory-lipo) and investigated its therapeutic effects in a CCl4-induced rat model of liver injury. We found that γ-ory-lipo has a higher chemical stability than does free γ-oryzanol. Although the antioxidative effect of γ-ory-lipo was lower than that of ferulic-lipo, pretreatment of the HepG2 cells with γ-ory-lipo improved the viability of CCl4-treated cells to a similar level as treatment with ferulic-lipo. γ-Oryzanol was shown to be converted into ferulic acid in vitro and in vivo. Furthermore, intravenous administration of γ-ory-lipo exhibited a similar effectiveness as ferulic-lipo against CCl4-induced hepatotoxicity, which should be the due to the conversion of γ-oryzanol into ferulic acid. These findings demonstrated that γ-ory-lipo could be a good natural prodrug of ferulic acid for eradicating its stability problem.


Subject(s)
Liver Diseases , Nanoparticles , Phenylpropionates , Prodrugs , Rats , Animals , Prodrugs/pharmacology , Prodrugs/therapeutic use , Reactive Oxygen Species , Oxidative Stress , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antioxidants/metabolism , Phenylpropionates/pharmacology , Phenylpropionates/therapeutic use
5.
Clin Res Hepatol Gastroenterol ; 47(7): 102174, 2023 08.
Article in English | MEDLINE | ID: mdl-37380128

ABSTRACT

AIM: This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of 4 mg saroglitazar treatment in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). METHODS: PubMed, Embase, Scopus, Cochrane CENTRAL, medRxiv (pre-print), bioRxiv (pre-print), and ClinicalTrials.gov databases were searched for relevant studies. The primary outcome was the change in the serum alanine transaminase (ALT) level. The secondary outcomes were changes in liver stiffness, liver function test parameters, and metabolic parameters. Pooled mean differences were calculated using random-effects models. RESULTS: Of 331 studies that were screened, ten were included. Treatment with adjunct saroglitazar showed a reduction in ALT [mean difference: 26.01 U/L (95% CI: 10.67 to 41.35); p = 0.009; i2: 98%; moderate GRADE evidence] and aspartate transaminase [mean difference: 19.68 U/L (95% CI: 8.93 to 30.43); p<0.001; i2: 97%; moderate GRADE evidence] levels. There was a significant improvement in liver stiffness [mean difference: 2.22 kPa (95% CI: 0.80 to 3.63); p = 0.002; i2: 99%; moderate GRADE evidence]. There were significant improvements in glycated hemoglobin [mean difference: 0.59% (95% CI: 0.32 to 0.86); p<0.001; i2: 78%; moderate GRADE evidence], total cholesterol [mean difference: 19.20 (95% CI: 1.54 to 36.87); p = 0.03; i2: 95%; moderate GRADE evidence], and triglyceride [mean difference: 105.49 mg/dL (95% CI: 11.18 to 199.80); p = 0.03; i2: 100%; moderate GRADE evidence] levels. Saroglitazar treatment was safe. CONCLUSION: Treatment with adjunct 4 mg saroglitazar could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters (serum glucose and lipid profile) in patients with NAFLD or NASH.


Subject(s)
Non-alcoholic Fatty Liver Disease , Phenylpropionates , Humans , Pyrroles/therapeutic use , Pyrroles/metabolism , Pyrroles/pharmacology , Phenylpropionates/therapeutic use , Phenylpropionates/metabolism , Phenylpropionates/pharmacology , Liver Function Tests , Alanine Transaminase , Liver/metabolism
6.
Liver Transpl ; 29(9): 979-986, 2023 09 01.
Article in English | MEDLINE | ID: mdl-36847136

ABSTRACT

NAFLD is common after liver transplantation (LT) and is associated with an increased metabolic burden. Currently, there is a paucity of investigations into the treatment of post-LT NAFLD. In the present study, we evaluated the safety and efficacy of saroglitazar, a novel dual peroxisome proliferator-associated receptor α/γ agonist, on the treatment of post-LT NAFLD and metabolic burden. This is a phase 2A, single-center, open-label, single-arm study in which patients with post-LT NAFLD received saroglitazar magnesium 4 mg daily for 24 weeks. NAFLD was defined by a controlled attenuation parameter ≥264 dB/m. The primary endpoint was the reduction in liver fat as measured by MRI proton density fat fraction (MRI-PDFF). Secondary MRI-based metabolic endpoints included visceral adipose tissue, abdominal subcutaneous adipose tissue volumes, muscle fat infiltration, and fat-free muscle volume. Saroglitazar treatment led to a reduction in MRI-PDFF from 10.3±10.5% at baseline to 8.1±7.6%. A relative 30% reduction from baseline MRI-PDFF value was noted in 47% of all patients and 63% of patients with baseline MRI-PDFF >5%. Reduction in serum alkaline phosphatase was an independent predictor of MRI-PDFF response. Saroglitazar did not decrease fat-free muscle volume nor increase muscle fat infiltration, but did lead to a mild increase in visceral adipose tissue and abdominal subcutaneous adipose tissue. The study drug was well tolerated and a mild nonsignificant increase in serum creatinine was noted. Saroglitazar did not affect the weight. The study provides preliminary data demonstrating the safety and metabolic benefits of saroglitazar in LT recipients and underscores the importance of future studies to establish its efficacy after LT.


Subject(s)
Liver Transplantation , Non-alcoholic Fatty Liver Disease , Phenylpropionates , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Liver Transplantation/adverse effects , Liver/diagnostic imaging , Phenylpropionates/therapeutic use , Magnetic Resonance Imaging
7.
Turk J Med Sci ; 53(5): 1312-1320, 2023.
Article in English | MEDLINE | ID: mdl-38813032

ABSTRACT

Background/aim: A significant cause of mortality and morbidity in the neonatal era is hypoxic-ischemic encephalopathy (HIE). This study examined the histopathological analysis and neuroprotective impact of syringin (SYR) in an experimental HIE rat model. Material and methods: On the 7th postnatal day, 24 Wistar albino rats were evaluated in 3 groups using the HIE model under gas anesthesia. In the experiment, Group A received 10 mg/kg SYR plus dimethyl sulfoxide (DMSO), Group B received DMSO only, and Group C served as a sham group. Immunohistochemical techniques were used to assess apoptotic cell measurement and proinflammatory cytokines (TNF-α and IL-1ß primary antibodies). Results: Rats suffering from hypoxic-ischemic brain damage had their apoptosis assessed. The SYR and sham groups had statistically fewer cells undergoing apoptosis (p < 0.001). There was no difference between the groups in terms of IL-1ß and TNF-α during immunohistochemical staining. Neuronal degeneration was significantly lower in the histological evaluation of the hippocampus in the SYR group (p = 0.01). A statistically significant difference (p = 0.01) was observed between the SYR and the control groups regarding pericellular and perivascular edema. Conclusion: SYR reduced apoptosis, perivascular and pericellular edema, and neuronal degeneration in rat cerebral tissue. These results raise the possibility that SYR may have a neuroprotective effect on the harm brought on by HIE. This is the first investigation of SYR's function within the HIE paradigm.


Subject(s)
Animals, Newborn , Disease Models, Animal , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Rats, Wistar , Animals , Neuroprotective Agents/pharmacology , Hypoxia-Ischemia, Brain/pathology , Hypoxia-Ischemia, Brain/drug therapy , Rats , Phenylpropionates/pharmacology , Phenylpropionates/therapeutic use , Glucosides/pharmacology , Glucosides/therapeutic use , Apoptosis/drug effects , Interleukin-1beta/metabolism
9.
Can Vet J ; 63(5): 497-503, 2022 05.
Article in English | MEDLINE | ID: mdl-35502246

ABSTRACT

Although sildenafil is used in dogs with severe pulmonary hypertension, they sometimes become resistant and clinical signs deteriorate over time. The objective of this study was to determine the benefits of adjunct ambrisentan therapy in dogs with sildenafil-refractory pulmonary hypertension. In 5 dogs with severe pulmonary hypertension with deteriorating clinical signs despite ongoing sildenafil treatment, adding ambrisentan improved appetite, activity, and respiratory functions. Although peak tricuspid valve regurgitation velocity, as measured by Doppler echocardiography, did not necessarily decrease after ambrisentan administration, there was improved partial pressure of arterial oxygen and the alveolar-arterial oxygen gradient, with no apparent side effects. We concluded that ambrisentan has potential as an adjunct treatment in dogs with pulmonary hypertension that are refractory to sildenafil therapy. Key clinical message: Ambrisentan improved clinical signs in dogs with sildenafil-refractory pulmonary hypertension.


Le traitement d'appoint à l'ambrisentan a eu des avantages cliniques chez cinq chiens atteints d'hypertension pulmonaire réfractaire au sildénafil. Bien que le sildénafil soit utilisé chez les chiens souffrant d'hypertension pulmonaire sévère, ils deviennent parfois résistants et les signes cliniques s'aggravent avec le temps. L'objectif de cette étude était de déterminer les avantages d'un traitement d'appoint à l'ambrisentan chez les chiens souffrant d'hypertension pulmonaire réfractaire au sildénafil. Chez cinq chiens souffrant d'hypertension pulmonaire sévère avec détérioration des signes cliniques malgré un traitement continu au sildénafil, l'ajout d'ambrisentan a amélioré l'appétit, l'activité et les fonctions respiratoires. Bien que la vitesse maximale de régurgitation de la valve tricuspide, mesurée par échocardiographie Doppler, n'ait pas nécessairement diminué après l'administration d'ambrisentan, la pression partielle d'oxygène artériel et le gradient alvéolo-artériel d'oxygène ont été améliorés, sans effets secondaires apparents. Nous avons conclu que l'ambrisentan a un potentiel en tant que traitement d'appoint chez les chiens souffrant d'hypertension pulmonaire qui sont réfractaires au traitement par le sildénafil.Message clinique clé:L'ambrisentan a amélioré les signes cliniques chez les chiens souffrant d'hypertension pulmonaire réfractaire au sildénafil.(Traduit par Dr Serge Messier).


Subject(s)
Dog Diseases , Hypertension, Pulmonary , Phenylpropionates , Animals , Dog Diseases/drug therapy , Dogs , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/veterinary , Oxygen , Phenylpropionates/therapeutic use , Pyridazines , Sildenafil Citrate/therapeutic use
10.
Sci Rep ; 12(1): 2631, 2022 02 16.
Article in English | MEDLINE | ID: mdl-35173236

ABSTRACT

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for their antipyretic, analgesic, and anti-inflammatory properties. However, various aspects of NSAID-induced lower gastrointestinal tract injury remain unclear, and effective prophylaxis has not been established. Based on its pharmacological effect and clinical trials, rebamipide may prevent lower gastrointestinal tract injury, although this evidence is limited by the small scale of trials. The present study used the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Event Reporting Database (JADER) to assess the efficacy of rebamipide in combination with loxoprofen and diclofenac in preventing NSAID-induced lower gastrointestinal tract injury. The calculated reporting odds ratio and 95% confidence interval (CI) for rebamipide in combination with loxoprofen and diclofenac were 1.15 (95% CI 0.88-1.51) and 1.28 (95% CI 0.82-2.01) for FAERS, and 0.50 (95% CI 0.35-0.71) and 0.43 (95% CI 0.27-0.67) for JADER, respectively. No signal was detected when combining drugs. These results suggest a prophylactic effect of rebamipide on NSAID-induced lower gastrointestinal tract injury.


Subject(s)
Adverse Drug Reaction Reporting Systems , Alanine/analogs & derivatives , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/prevention & control , Gastrointestinal Tract , Quinolones/therapeutic use , Alanine/administration & dosage , Alanine/therapeutic use , Databases, Factual , Diclofenac/administration & dosage , Diclofenac/therapeutic use , Drug Therapy, Combination , Humans , Japan , Phenylpropionates/administration & dosage , Phenylpropionates/therapeutic use , Quinolones/administration & dosage , United States , United States Food and Drug Administration
11.
J Clin Pharm Ther ; 47(2): 146-156, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34319626

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH. METHODS: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index. RESULTS: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02). WHAT IS NEW AND CONCLUSION: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.


Subject(s)
Antihypertensive Agents/therapeutic use , Bosentan/therapeutic use , Endothelin Receptor Antagonists/therapeutic use , Phenylpropionates/therapeutic use , Pulmonary Arterial Hypertension/drug therapy , Pyridazines/therapeutic use , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Bosentan/administration & dosage , Bosentan/adverse effects , Endothelin Receptor Antagonists/administration & dosage , Endothelin Receptor Antagonists/adverse effects , Humans , Liver Function Tests , Network Meta-Analysis , Phenylpropionates/administration & dosage , Phenylpropionates/adverse effects , Pyridazines/administration & dosage , Pyridazines/adverse effects , Randomized Controlled Trials as Topic , Walk Test
12.
J Hepatol ; 76(1): 75-85, 2022 01.
Article in English | MEDLINE | ID: mdl-34487750

ABSTRACT

BACKGROUND & AIM: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. METHODS: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. RESULTS: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. CONCLUSIONS: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS. GOV IDENTIFIER: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.


Subject(s)
Liver Cirrhosis, Biliary/drug therapy , Phenylpropionates/pharmacology , Pyrroles/pharmacology , Double-Blind Method , Female , Humans , Liver Cirrhosis, Biliary/physiopathology , Male , Middle Aged , Phenylpropionates/therapeutic use , Placebos , Pyrroles/therapeutic use , Treatment Outcome
13.
Sci Rep ; 11(1): 24445, 2021 12 27.
Article in English | MEDLINE | ID: mdl-34961782

ABSTRACT

The aim of this study is to evaluate the preemptive analgesic effects of dexamethasone (DEX) alone or combined with non-steroidal anti-inflammatory drugs (NSAIDs) in third molar surgeries. The subjects were divided into five groups (n = 20 teeth/group); subjects received only 8 mg of dexamethasone 1 h before the surgical procedure (DEX group), or in combination with etodolac (DEX + ETO), ketorolac (DEX + KET), ibuprofen (DEX + IBU), loxoprofen (DEX + LOX). Paracetamol 750 mg was provided as the number of rescue analgesics (NRA). Salivary PGE2 expression was measured preoperatively and at 48 h. Edema and Maximum mouth opening (MMO) were measured postoperatively at 48 h and 7 days. A visual analog scale (VAS) was performed postoperatively at 6, 12, 24, 48, 72 h, and 7 days. Salivary expression of PGE2 showed a decrease only for the DEX group. Edema and MMO and NRA consumption showed no significant differences among the groups (P > 0.05). The VAS showed a significantly lower pain perception at 6 h after the surgery for the DEX + ETO and DEX + KET groups (P < 0.05). The combination of DEX and NSAIDS should be considered for preemptive acute postsurgical pain management in third molar surgery. In some drug associations such as dexamethasone 8 mg + NSAIDS (ETO and KET) in the pre-operative time, only a few rescue analgesics are necessary.


Subject(s)
Analgesics/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Dexamethasone/therapeutic use , Molar, Third/surgery , Tooth Extraction , Adolescent , Adult , Drug Therapy, Combination , Etodolac/therapeutic use , Female , Glucocorticoids/therapeutic use , Humans , Ibuprofen/therapeutic use , Ketorolac/therapeutic use , Male , Phenylpropionates/therapeutic use , Prospective Studies , Tooth Extraction/methods , Young Adult
14.
Medicine (Baltimore) ; 100(41): e27334, 2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34731104

ABSTRACT

RATIONALE: Pulmonary veno-occlusive disease (PVOD) is a kind of rare and fatal pulmonary arterial hypertension (PAH). Different from other subtypes of PAH, PVOD patients have a very poor prognosis because of the progressive nature of pulmonary vascular involvement and fatal pulmonary edema induced by PAH-targeted drugs. Lung transplantation is the only choice for these patients. PATIENT CONCERNS: We reported 2 cases of PVOD which was misdiagnosed as idiopathic pulmonary arterial hypertension initially due to the lack of typical findings of PVOD. Right heart catheterization was done. The results showed severe PAH with mean pulmonary artery pressure at 76 mmHg and 68 mmHg. DIAGNOSIS: The diagnosis of idiopathic pulmonary arterial hypertension was corrected by eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) mutation screening. Biallelic mutations (c.1387delT (p. Arg463fs); c.989-990 delAA (p. Lys330fs)) were detected by next-generation sequencing for whole exome from blood sample. The presence of biallelic EIF2AK4 mutation was sufficient to confirm the diagnosis of PVOD. INTERVENTIONS: The 2 patients had good response to PAH-targeted therapy (Ambrisentan 10 mg once a day and tadalafil 20 mg once a day) in the following 1 year. OUTCOMES: Because the patients had a good response to targeted drugs, the treatment of the 2 cases was unchanged. Over 1-year period, they still have a good response to PAH-targeted drugs. There was no sign of pulmonary edema. LESSONS: All these results may indicate that PVOD is not so rare and typical findings of PVOD are lacking in some patients. EIF2AK4 mutation screening by next-generation sequencing maybe useful to differentiate PVOD from other PAH subtypes. PVOD is a heterogeneity population and different patients have different characteristics including response to PAH-targeted therapy. How to pick off this portion of patients timely is the core issue. Further study is necessary to answer this question.


Subject(s)
Antihypertensive Agents/therapeutic use , Phenylpropionates/therapeutic use , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/drug therapy , Pyridazines/therapeutic use , Tadalafil/therapeutic use , Vasodilator Agents/therapeutic use , Adult , Diagnostic Errors , Drug Therapy, Combination , High-Throughput Nucleotide Sequencing , Humans , Male , Protein Serine-Threonine Kinases , Pulmonary Arterial Hypertension/diagnosis , Pulmonary Veno-Occlusive Disease/genetics
15.
Biomed Pharmacother ; 144: 112357, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34794234

ABSTRACT

Higher global prevalence of non-alcoholic fatty liver disease (NAFLD) is associated with obesity, steatosis, and insulin resistance (IR), and often progresses to steatohepatitis (NASH). Even after more than twenty years of research, there is still no FDA approved therapy for the treatment of fatty liver disease/NASH though, Saroglitazar - a dual PPAR α/γ agonist has been recently approved as a therapeutic option for the fatty liver disease in India. Hepatoprotective Ayurvedic formulations are widely used and are considered safe. In the present study, C57BL/6 male mice on HFHF diet for four weeks were treated with vehicle, Saroglitazar (3 mg/kg/po), and Hepano - a formulation of five herbs (200 mg/kg/po), at the human equivalent therapeutic doses for additional eight weeks. These animals were evaluated after 12 weeks for obesity, body mass index (BMI), systemic insulin resistance, hyperglycaemia, dyslipidaemia, and hepatic lipid accumulation. Differential liquid chromatography-mass spectrometry (LC-MS/MS) based lipidomics analysis demonstrated significant changes in the different class of lipids [phospholipids, sphingolipids, diglycerides and triglycerides (TG)] in HFHF fed group. The protective effects of both Saroglitazar and Hepano were evident against IR, obesity and in the modulation of different class of lipids in the circulation and hepatic tissue. Saroglitazar reduced TG as well as modulated phospholipids levels, while Hepano modulated only phospholipids, ceramides, oxidised lipids, and had no effect on hepatic or circulating TG levels in HFHF fed mice. In addition, in vitro studies using HepG2, THP1 and LX2 cells demonstrated safety of both the test substances where Hepano possess better anti-inflammatory as well as anti-fibrotic potential. Overall, Saroglitazar seems to be more efficacious than Hepano in the regimen used against HFHF induced IR, obesity, and dyslipidaemia.


Subject(s)
Diet, High-Fat , Fatty Liver/prevention & control , Fructose/adverse effects , Hypolipidemic Agents/therapeutic use , Insulin Resistance , Lipid Metabolism/drug effects , Liver/metabolism , Obesity/prevention & control , Phenylpropionates/therapeutic use , Pyrroles/therapeutic use , Animals , Cell Line , Diet , Fatty Liver/etiology , Humans , Lipidomics , Lipids/blood , Liver/drug effects , Male , Mice , Mice, Inbred C57BL , Obesity/etiology
16.
BMC Pharmacol Toxicol ; 22(1): 53, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34593018

ABSTRACT

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have become significant global health concerns. In the present study, we aimed to investigate the effects of saroglitazar, a dual PPARα/γ agonist, fenofibrate, a PPAR-α agonist, and pioglitazone, a PPAR-γ agonist on an animal model of NASH. METHODS: Male Wistar rats were fed a high-fat (HF) emulsion via gavage for 7 weeks to induce NASH. The HF-treated rats were grouped into four groups to receive saroglitazar, pioglitazone, fenofibrate, or vehicle. We measured body and liver weight, liver enzymes, serum levels of adiponectin and leptin. We also performed histopathological examinations and gene expression analysis of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF- α), transforming growth factor-beta (TGF-ß), and monocyte chemoattractant protein 1 (MCP-1). RESULTS: Body weight was markedly normalized by both saroglitazar and fenofibrate, while the liver index only decreased significantly with saroglitazar. Saroglitazar corrected ALT, AST, leptin, and adiponectin levels better than pioglitazone and fenofibrate. All PPAR agonists significantly attenuated the upregulation of the proinflammatory and TGF-ß genes, which correlated with the improved steatosis, inflammation of liver tissue, and fibrotic lesions. CONCLUSIONS: As documented by our results, the dual activation of PPARα/γ by saroglitazar could effectively improve steatosis, fibrosis, and aspects of necro-inflammation in the HF-induced NASH model more than fenofibrate and pioglitazone, and it can be more beneficial in the management of NASH.


Subject(s)
Liver Cirrhosis/drug therapy , Non-alcoholic Fatty Liver Disease/drug therapy , PPAR alpha/agonists , PPAR gamma/agonists , Phenylpropionates/therapeutic use , Pyrroles/therapeutic use , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Cytokines/genetics , Disease Models, Animal , Gene Expression Regulation/drug effects , Liver/drug effects , Liver/pathology , Liver Cirrhosis/blood , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Male , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Phenylpropionates/pharmacology , Pyrroles/pharmacology , Rats, Wistar
17.
Drug Discov Ther ; 15(5): 278-280, 2021 Nov 21.
Article in English | MEDLINE | ID: mdl-34707073

ABSTRACT

To help stop the coronavirus disease 2019 (COVID-19) pandemic, vaccines are currently the most critical tool. However, the COVID-19 mRNA vaccines frequently cause systemic side effects shortly after the injection, such as fever, headache and generalized fatigue. In our survey, after receiving the second dose of the COVID-19 vaccine, 80% developed fever, 62% headache and 69% generalized fatigue. Among people who required antipyretics, the average durations of fever and headache were significantly shorter in those who took non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, loxoprofen and ibuprofen, than those who took acetaminophen. In our patch-clamp studies, NSAIDs effectively suppressed the delayed rectifier K+-channel (Kv1.3) currents in T-lymphocytes and thus exerted immunosuppressive effects. Because of this pharmacological property, the use of NSAIDs should be more effective in reducing the vaccine-induced systemic side effects that are caused primarily by the enhanced cellular immunity.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19 Vaccines/adverse effects , Immunosuppressive Agents/therapeutic use , Acetaminophen/therapeutic use , Adolescent , Aspirin/therapeutic use , Fatigue/drug therapy , Fatigue/etiology , Fever/drug therapy , Fever/etiology , Headache/drug therapy , Headache/etiology , Humans , Ibuprofen/therapeutic use , Patch-Clamp Techniques , Phenylpropionates/therapeutic use , Young Adult
18.
Biol Pharm Bull ; 44(9): 1210-1219, 2021.
Article in English | MEDLINE | ID: mdl-34471049

ABSTRACT

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (α, γ, and ß/δ) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPARα/γ dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPARα/γ remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPARα-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPARγ-LBD. Saroglitazar was located at the center of "Y"-shaped PPARγ-ligand-binding pocket (LBP), just as it was in the respective region of PPARα-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPARγ-LBD from that in PPARα-LBD to interact with Phe264. PPARδ-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPARδ-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPARα-LBD and PPARγ-LBD but not PPARδ-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARδ-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPARα/γ dual or PPARα/γ/δ pan agonists.


Subject(s)
Hypolipidemic Agents/pharmacology , PPAR alpha/ultrastructure , PPAR gamma/ultrastructure , Phenylpropionates/pharmacology , Pyrroles/pharmacology , Binding Sites , Crystallography, X-Ray , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dyslipidemias/drug therapy , Dyslipidemias/etiology , Humans , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/therapeutic use , Lipid Metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , PPAR alpha/agonists , PPAR alpha/isolation & purification , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/isolation & purification , PPAR gamma/metabolism , Phenylpropionates/chemistry , Phenylpropionates/therapeutic use , Protein Domains , Pyrroles/chemistry , Pyrroles/therapeutic use , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Recombinant Proteins/ultrastructure
19.
Toxins (Basel) ; 13(7)2021 06 23.
Article in English | MEDLINE | ID: mdl-34201686

ABSTRACT

This study aimed to investigate the feasibility of a combined treatment of bee venom acupuncture (BVA) and non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of non-specific chronic neck pain (NCNP). Patients with NCNP for ≥3 months were randomly allocated to a BVA, NSAIDs, or combined group (1:1:1), receiving 6 sessions of BVA, loxoprofen (180 mg daily), or a combination, respectively, for 3 weeks. Recruitment, adherence, and completion rates were calculated to assess feasibility. Bothersomeness, pain, disability, quality of life, depressive status, treatment credibility, and adverse events were assessed. In total, 60 participants were enrolled, and 54 completed the trial. Recruitment, adherence, and completion rates were 100%, 95%, and 90%, respectively. Bothersomeness, pain, disability, and depressive symptoms significantly improved in all groups after treatment (p < 0.05). The combined group showed continuous improvement during the follow-up period (p < 0.05). Quality of life was significantly improved (p < 0.05), and treatment credibility was maintained in the BVA and combined groups. No serious adverse events were reported. Combined treatment of BVA and NSAIDs are feasible for the treatment of NCNP, showing high persistence of the effect, credibility, and safety. Additional trials with longer follow-up are needed to confirm this effect.


Subject(s)
Acupuncture Therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Bee Venoms/therapeutic use , Chronic Pain/therapy , Neck Pain/therapy , Phenylpropionates/therapeutic use , Adult , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Quality of Life , Single-Blind Method , Treatment Outcome
20.
Biomed Pharmacother ; 140: 111796, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34098194

ABSTRACT

Normal brain functioning involves the interaction of interconnected molecular and cellular activities, which appear to alter normal to abnormal brain functioning when worsened, contributing to the emergence of neurological disorders. There are currently millions of people who are living with brain disorders globally and this will rise if suitable prevention strategies are not explored. Nutraceutical intended to treat numerous health goals with little adverse effect possible together can be more beneficial than pharmaceutical monotherapy for fostering balanced brain functioning. Nutraceutical provides a specific composition of effective macronutrients and micronutrients that are difficult to synthesize in the laboratory. Numerous elements of rice fibers in rice bran are characterized as natural anti-oxidant and having potential anti-inflammatory activity. The rice bran captures interest among the researchers as it is widespread, affordable, and rich in nutrients including protein, fat, carbohydrates, bioactive components, and dietary fiber. This review covers the neuroprotective multiplicity of rice bran and its constituents to deter pathological conditions of the brain and to facilitate balanced brain functioning at the same time.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Nervous System Diseases/diet therapy , Neuroprotective Agents/therapeutic use , Oryza , Phenylpropionates/therapeutic use , Plant Extracts/therapeutic use , Rice Bran Oil/therapeutic use , Tocotrienols/therapeutic use , Animals , Dietary Supplements , Humans , Serotonin/metabolism
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