scholarly journals Enhanced Efficacy and Reduced Hepatotoxicity by Combination of Gnaphalium affine Extract and Benzbromarone in the Treatment of Rats with Hyperuricemic Nephropathy

2021 ◽  
Author(s):  
Fei Liu ◽  
Xi-Zi Liu ◽  
Qian Yang ◽  
Shi-Yi Han ◽  
Si-Yang Fan
Keyword(s):  
Synergistic Effects ◽  
Oral Intake ◽  
Q Value ◽  
First Line ◽  
Dosing Interval ◽  
Serum Alanine Aminotransferase ◽  
Beneficial Effects ◽  
Lowering Therapy ◽  
Half Dose ◽  
Reduced Toxicity

Simultaneous oral intake of herbal medicine with chemical drugs may result in beneficial pharmacodynamic efficacy, including additive and synergistic effects with reduced toxicity. Gnaphalium affine D. Don (GAD) is a traditional Chinese Medicine that has been used for the management of hyperuricemia and gout. Benzbromarone (BBR) is one of the first-line drugs used for urate-lowering therapy in China but is toxic to the liver. The present study aimed to determine the effects of GAD and BBR, both alone and in co-treatment (with dosing interval of 1 hour), on chronic hyperuricemic nephropathy (HN) and hepatotoxicity in rats. Our data indicated that GAD significantly inhibited the elevation of serum uric acid, blood urea nitrogen, and creatinine levels in chronic HN rats at doses of 450 and 900 mg/kg/day. The rise in serum alanine aminotransferase and aspartate aminotransferase in BBR (or vehicle)-treated HN rats was significantly reduced by pre- (or post)-administration of GAD (450 mg/kg/day). The q-value >1.15 (by Jin method) indicated synergistic effects of co-treatments of BBR (50 mg/kg) with GAD (450 mg/kg). The synergistic beneficial effects were validated by comparison of BBR alone at a dose of clinical usage (4.5 mg/kg/day, in two divided doses) and BBR + GAD at half dose plus half dose (2.25 + 225 mg/kg/day) or half dose plus full dose (2.25 + 450 mg/kg/day). In conclusion, co-treatment with GAD and BBR holds promise for the management of hyperuricemia and gout.

scholarly journals Beneficial Pharmacokinetic Drug Interactions: A Tool to Improve the Bioavailability of Poorly Permeable Drugs

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 106 ◽  
Author(s):  
Werner Gerber ◽  
Johan Steyn ◽  
Awie Kotzé ◽  
Josias Hamman
Keyword(s):  
Structural Changes ◽  
Synergistic Effects ◽  
Oral Intake ◽  
Therapeutic Window ◽  
Routes Of Administration ◽  
Beneficial Effects ◽  
Pharmacodynamic Interactions ◽  
Pharmacokinetic Interactions ◽  
Alternative Routes ◽  
Uptake Transporters

Simultaneous oral intake of herbs, supplements, foods and drugs with other drug(s) may result in pharmacokinetic or pharmacodynamic interactions with the latter. Although these interactions are often associated with unwanted effects such as adverse events or inefficacy, they can also produce effects that are potentially beneficial to the patient. Beneficial pharmacokinetic interactions include the improvement of the bioavailability of a drug (i.e., by enhancing absorption and/or inhibiting metabolism) or prolongation of a drug’s plasma level within its therapeutic window (i.e., by decreasing excretion), whereas beneficial pharmacodynamic interactions include additive or synergistic effects. Mechanisms by which pharmacokinetic interactions can cause beneficial effects include enhancement of membrane permeation (e.g., structural changes in the epithelial cell membranes or opening of tight junctions), modulation of carrier proteins (e.g., inhibition of efflux transporters and stimulation of uptake transporters) and inhibition of metabolic enzymes. In the current review, selected pharmacokinetic interactions between drugs and various compounds from different sources including food, herb, dietary supplements and selected drugs are discussed. These interactions may be exploited in the future to the benefit of the patient, for example, by delivering drugs that are poorly bioavailable in therapeutic levels via alternative routes of administration than parenteral injection.

Oral Intake of Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 Prevents Collagen-Induced Arthritis in Mice

2002 ◽  
Vol 65 (1) ◽  
pp. 153-160 ◽  
Author(s):  
HIROSHI KANO ◽  
TSUTOMU KANEKO ◽  
SHUICHI KAMINOGAWA
Keyword(s):  
Oral Intake ◽  
Type Ii Collagen ◽  
Inhibitory Effect ◽  
Lactobacillus Delbrueckii ◽  
Broth Culture ◽  
Control Group ◽  
Collagen Induced Arthritis ◽  
Beneficial Effects ◽  
Ifn Γ ◽  
Lactobacillus Delbrueckii Subsp

Oral intake of some lactic acid bacteria can have beneficial effects on the host by activating immune responses and enhancing resistance to infection by pathogens. In this study, effects of Lactobacillus sp. on the development of autoimmune disease were examined in mice with collagen-induced arthritis (CIA). CIA, a model of some types of rheumatoid arthritis (RA), can be induced in DBA/1J mice by immunizing them with bovine type II collagen (bCII). Oral intake of skimmed milk (SM) fermented with Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (SM/OLL1073R-1) was found to markedly inhibit the development of CIA in these mice, compared with a control group fed the control foodstuff. The inhibitory effect of SM fermented with L. delbrueckii subsp. bulgaricus OLL1102 (SM/OLL1102) or fresh SM was weaker than that of SM/OLL1073R-1. A deMan Rogosa Sharpe (MRS) broth culture of OLL1073R-1 without any major components of SM had the same inhibitory effect as SM/OLL1073R-1, suggesting that the inhibitory effect of SM/OLL1073R-1 is attributable not only to SM components but also to OLL1073R-1 cells, their metabolites, or both. We found that SM/OLL1073R-1 and SM caused reduced secretion of the cytokine IFN-γ by lymph node cells (LNCs) in response to bCII. However, SM/OLL1102 did not affect the secretion of IFN-γ. A polysaccharide fraction secreted by OLL1073R-1 also exhibited the inhibitory effects on both development of CIA and secretion of IFN-γ.

scholarly journals Modified FOLFOX6 as a first-line treatment for patients with advanced gastric cancer with massive ascites or inadequate oral intake

2018 ◽  
Vol Volume 11 ◽  
pp. 8301-8307 ◽  
Author(s):  
Hiroki Osumi ◽  
Daisuke Takahari ◽  
Keisho Chin ◽  
Mariko Ogura ◽  
Takashi Ichimura ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Oral Intake ◽  
Line Treatment ◽  
First Line ◽  
Massive Ascites ◽  
Modified Folfox6 ◽  
Inadequate Oral Intake ◽  
First Line Treatment

Shock Etiologies and Fluid Management in Liver Failure

2018 ◽  
Vol 39 (05) ◽  
pp. 538-545 ◽  
Author(s):  
Emmanuel Weiss ◽  
Catherine Paugam-Burtz ◽  
Samir Jaber
Keyword(s):  
Liver Failure ◽  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Fluid Management ◽  
Hypovolemic Shock ◽  
Oral Intake ◽  
Chronic Liver ◽  
Volume Responsiveness ◽  
Beneficial Effects ◽  
Poor Oral Intake

AbstractLiver failure can occur in patients with or without underlying chronic liver disease (mainly cirrhosis) and is, respectively, termed acute on chronic liver failure or acute liver failure (ALF). In both cases, it is associated with marked systemic inflammation and profound hemodynamic disturbances, that is, increased cardiac output, peripheral vasodilation, and decreased systemic vascular resistance, on top of several superimposed etiologies of shock. In patients with cirrhosis, sepsis is the main cause of intensive care unit admission but portal hypertension-related gastrointestinal hemorrhage is also common. Septic shock is also particularly frequent in patients with ALF and can complicate the initial hypovolemic shock related to poor oral intake, vomiting, and encephalopathy prior to admission. Given the susceptibility of the liver to hypoxia and also the potential deleterious effects of fluid on liver function, the assessment of hemodynamic status and volume responsiveness is especially important in these patients. However, one should keep in mind that the hyperdynamic state and low systemic vascular resistance in liver failure may bias the accuracy of some hemodynamic monitoring devices. Fluid therapy should use crystalloids, and balanced salt solutions may limit the risk of hyperchloremic acidosis and subsequent adverse kidney events. Nevertheless, the beneficial effects of albumin resuscitation have been demonstrated in patients with cirrhosis and may reflect more than mere volume expansion.

scholarly journals First‐line mFOLFOX6 for peritoneally disseminated gastric cancer with massive ascites or inadequate oral intake

2018 ◽  
Vol 29 ◽  
pp. v23
Author(s):  
H. Osumi ◽  
D. Takahari ◽  
K. Chin ◽  
M. Ogura ◽  
T. Ichimura ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Oral Intake ◽  
First Line ◽  
Massive Ascites ◽  
Inadequate Oral Intake

scholarly journals Metformin discontinuation in patients beginning second-line glucose-lowering therapy: results from the global observational DISCOVER study programme

BMJ Open ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. e034613
Author(s):  
Kamlesh Khunti ◽  
Marilia B Gomes ◽  
Mikhail Kosiborod ◽  
Antonio Nicolucci ◽  
Stuart Pocock ◽  
...  
Keyword(s):  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Glucose Lowering ◽  
Factors Associated ◽  
Lowering Therapy ◽  
Metformin Monotherapy ◽  
Study Programme ◽  
Glucose Lowering Therapy

ObjectivesTo evaluate the extent to which patients with type 2 diabetes discontinue metformin therapy when initiating second-line treatment and factors associated with metformin discontinuation, using baseline data from the DISCOVER study programme.DesignDISCOVER is a 3-year, prospective, observational study programme including data from 38 countries across 6 continents from 2014 to 2019.SettingPrimary and secondary healthcare centres, hospitals and specialist diabetes centres in both urban and rural locations.ParticipantsA total of 15 992 patients with type 2 diabetes initiating second-line glucose-lowering therapy.Primary and secondary outcome measuresThe proportion of patients who discontinued metformin as a second-line therapy and the factors associated with this treatment change.ResultsOf the 14 668 patients (from 37 countries) with valid treatment data, 11 837 (80.7%) received metformin as first-line glucose-lowering therapy; 8488 (71.7%) received metformin monotherapy and 3349 (28.3%) received metformin as part of a combination therapy. Overall, treatment with metformin was discontinued in 15.1% (1782) of patients who received first-line metformin (14.1% (1194) and 17.6% (588) in those who received metformin as monotherapy and as part of a combination, respectively); this proportion varied across regions from 6.9% (54) in Africa to 20.6% (628) in South-East Asia. On metformin discontinuation, 73.6% (1311) of patients received a non-insulin monotherapy at second line. Factors associated with an increased odds of metformin discontinuation were older age (≥75 years) and having a history of chronic kidney disease. The probability of metformin monotherapy discontinuation was lower in patients from Africa than in those from Europe.ConclusionsA substantial number of patients discontinued taking metformin when beginning second-line therapy. Most of these patients subsequently received a non-insulin monotherapy at second line, in contradiction to international guidelines and potentially leaving them at an increased risk of hyperglycaemia and associated adverse outcomes.Trial registration numbersNCT02322762 and NCT02226822.

scholarly journals L-Carnosine Stimulation of Coenzyme Q10 Biosynthesis Promotes Improved Mitochondrial Function and Decreases Hepatic Steatosis in Diabetic Conditions

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 793
Author(s):  
Cheng Schwank-Xu ◽  
Elisabete Forsberg ◽  
Magnus Bentinger ◽  
Allan Zhao ◽  
Ishrath Ansurudeen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Mitochondrial Function ◽  
Diabetes Complications ◽  
Synergistic Effects ◽  
Coenzyme Q ◽  
Protective Effects ◽  
Beneficial Effects

Mitochondrial dysfunction in type 2 diabetes leads to oxidative stress, which drives disease progression and diabetes complications. L-carnosine, an endogenous dipeptide, improves metabolic control, wound healing and kidney function in animal models of type 2 diabetes. Coenzyme Q (CoQ), a component of the mitochondrial electron transport chain, possesses similar protective effects on diabetes complications. We aimed to study the effect of carnosine on CoQ, and assess any synergistic effects of carnosine and CoQ on improved mitochondrial function in a mouse model of type 2 diabetes. Carnosine enhanced CoQ gene expression and increased hepatic CoQ biosynthesis in db/db mice, a type 2 diabetes model. Co-administration of Carnosine and CoQ improved mitochondrial function, lowered ROS formation and reduced signs of oxidative stress. Our work suggests that carnosine exerts beneficial effects on hepatic CoQ synthesis and when combined with CoQ, improves mitochondrial function and cellular redox balance in the liver of diabetic mice. (4) Conclusions: L-carnosine has beneficial effects on oxidative stress both alone and in combination with CoQ on hepatic mitochondrial function in an obese type 2 diabetes mouse model.

Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 564-564 ◽  
Author(s):  
Anthony B. El-Khoueiry ◽  
Richard D. Kim ◽  
William P. Harris ◽  
Max W. Sung ◽  
Dirk Waldschmidt ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Synergistic Effects ◽  
Immunomodulatory Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
First Line ◽  
Open Label ◽  
Dose Escalation Study ◽  
Advanced Hcc ◽  
First Line Treatment

564 Background: REG is a multikinase inhibitor with immunomodulatory activity and PEMBRO is an anti-PD-1 monoclonal antibody. Both are approved as monotherapy for patients (pts) with HCC previously treated with sorafenib. Based on their potential synergistic effects, we conducted a phase 1b study of REG plus PEMBRO for first-line treatment of advanced HCC. Methods: This is an ongoing, open-label, dose-escalation study in pts with advanced HCC who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day PO for 3 weeks on/1 week off plus PEMBRO 200 mg IV q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg) or reduced (80 mg) based on the modified toxicity probability interval design; the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the maximum tolerated dose (MTD) and recommended phase 2 dose, and to assess antitumor activity. Results: As of August 23, 2019, 29 pts have been treated at the REG 120 mg level. Median age is 65 years (range 32–81); 41%/55% of pts are BCLC stage B/C; 100% are Child–Pugh A; ECOG status 0/1 is 72%/28%. Dose-limiting toxicities occurred in 4/18 evaluable pts: grade (Gr) 3 increased ALT/AST with Gr 2 increased bilirubin (n = 2); Gr 3 rash (n = 2). The MTD of REG in the combination was 120 mg. Most common Gr 3 or 4 treatment-emergent adverse events (TEAEs) are shown (n = 29). There were no Gr 5 TEAEs. 59%/31% of pts had REG/PEMRO-related Gr 3 or 4 TEAEs. Dose modifications (reductions or interruptions) of REG/PEMBRO for drug-related TEAEs occurred in 59%/31% of pts. Of 23 evaluable pts, 7 (30%) had a partial response (PR) and 14 (61%) had stable disease (RECIST v1.1); 1 additional pt had PR by mRECIST. Conclusions: The combination of REG plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging antitumor activity. Accrual is continuing at REG 120 mg dose and an expansion cohort evaluating REG 80 mg plus PEMBRO is planned. Clinical trial information: NCT03347292. [Table: see text]

scholarly journals Eugenol and Isoeugenol In Association with Antifungal Against Cryptococcus neoformans

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Pinheiro L. S. ◽  
Sousa J. P. ◽  
Sousa J. P. ◽  
Barreto N. A. ◽  
Dantas T B ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Synergistic Effects ◽  
Antagonistic Effect ◽  
Antifungal Drugs ◽  
Antifungal Effect ◽  
Beneficial Effects ◽  
Combined Use ◽  
Antifungal Effects

The antifungal therapy combined is used in clinical practice of several mycoses as it may increase the efficacy of the treatment. The use of natural products (phytochemicals) in combination with conventional antifungal drugs has been related to beneficial effects, mainly synergistic effects. The aim of this study was to evaluate the effect of the combined use of eugenol / isoeugenol, compounds with recognized antimicrobial activity, in association with antifungal amphotericin B against strains of Cryptococcus neoformans. The combined antifungal effect were be determined from the Fraction Inhibitory Concentration index - checkerboard technique. The results obtained in this study showed that eugenol in combination with amphotericin B had antagonistic effect against the strains of C. neoformans, LM 615 and INCQS 40221 (FIC index 6.0 and 4.0), respectively. The combination of the isoeugenol and amphotericin B also showed antagonistic effects for both the LM 615 strain and INCQS 40221 (FIC index 6.0 and 5.0), respectively. This study contributed to the understanding of the antifungal effects of the association of phenylpropanoids (eugenol / isoeugenol) with amphotericin B. Further studies are needed to evaluate and compare the effects of the association of these phytochemicals with other conventional antifungal drugs used against C. neoformans.

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