共查询到20条相似文献，搜索用时 15 毫秒
1.
| Strategy, Management and Health Policy | | Enabling Technology, Genomics, Proteomics | Preclinical Research | Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics | Clinical Development Phases I‐III Regulatory, Quality, Manufacturing | Postmarketing Phase IV | This study assessed the in vivo antitumor efficacy of a polypeptide‐based poly‐L‐glutamic acid‐gemcitabine conjugate (PG‐G). PG‐G was synthesized by conjugating gemcitabine to poly‐L‐glutamic acid by a carbodiimide reaction. PG‐G was evaluated for its in vivo antitumor efficacy and toxicity using 4T1 murine breast tumor‐bearing mice. The antitumor effects of PG‐G were superior to those of unconjugated gemcitabine in both single and four‐consecutive dosing studies. Tumor regression was observed within 1 day after PG‐G administration and continued for 4–5 days. Thereafter, tumors grew at a slower rate compared with the unconjugated gemcitabine treatment group and other control groups. The main toxicity observed from the Berlin test was an apparent reversible weight loss of 10–12%. The unconjugated gemcitabine treatment group also demonstrated a similar, but reduced, weight loss trend. The present study demonstrates that the PG‐G formulation exhibits a significant antitumor activity in the aspects of tumor growth inhibition and shrinkage that is more robust than the parent drug and other control groups. Thus, the PG‐G dose regimen may be optimized to minimize side effects and render it a potential anticancer therapeutic. 相似文献
2.
The aim of the present study was to evaluate the neuroprotective benefits of rhGLP‐1 in diabetic rats subjected to acute cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Streptozotocin (STZ)‐induced diabetic rats were pretreated with rhGLP‐1 (10, 20, or 40 μg/kg ip, tid) for 14 days. During this time, body weight and fasting blood glucose levels were assessed. Rats were then subjected to MCAO 90 min/R 24 h. At 2 and 24 h of reperfusion, rats were evaluated for neurological deficits and blood samples were collected to analyze markers of brain injury. Rats were then sacrificed to assess the infarction volume. rhGLP‐1 pretreatment lowered blood glucose levels, improved neurological scores, attenuated infarct volumes, and reduced the blood levels of S100 calcium‐binding protein B (S100B), neuron‐specific enolase (NSE), and myelin basic protein (MBP). rhGLP‐1 has neuroprotective benefits in diabetic rats with cerebral ischemia/reperfusion injury and could potentially be used as a prophylatic neuroprotectant in diabetic patients at high risk of ischemic stroke. Drug Dev Res 77 : 124–133, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
3.
Human adrenomedullin (hAM), a hypotensive peptide, also has anti‐inflammatory effects. hAM can reduce the severity of the dextran sulphate sodium (DSS)‐ and 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in animal models. Furthermore, in a clinical study, hAM treatment reduced the Disease Activity Index in ulcerative colitis. However, these therapeutic effects required continuous administration of hAM as the half‐life of native hAM is quite short in blood. To resolve this problem, hAM N‐terminal was conjugated with two kinds of polyethylene glycol (PEG); 5 kDa PEG or 60 kDa PEG (5 kDa PEG‐hAM and 60 kDa PEG‐hAM respectively). In a previous study, 5 kDa PEG‐hAM stimulated cAMP production and prolonged the plasma half‐life compared with native hAM. Herein we examine the effect of PEG‐hAM in the DSS colitis model. Treatment with both PEG‐hAM preparations reduced the total inflammation score. In addition, the plasma half‐life of 60 kDa PEG‐hAM was much longer than 5 kDa PEG‐hAM. In summary, a single subcutaneous administration of 60 kDa PEG‐hAM reduced the total inflammation score in mice with DSS‐induced colitis. Therefore, these results suggest that 60 kDa PEG‐hAM is a possible therapeutic agent for the treatment of inflammatory bowel disease. Drug Dev Res 78 : 129‐134, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
4.
The objective of this study was to formulate a self‐nanoemulsifying oral drug delivery system (SNEDDS) for the poorly water‐soluble trans‐Cinnamic acid ( t‐CA SNEDDS) that could be evaluated for its antihyperglycemic efficacy in comparison to the parent t‐CA in an alloxan‐induced diabetic rat model. A SNEDDS formulation consisting of 60% surfactant (Kolliphor EL), 10% co‐surfactant (PEG 400) and 30% oil (isopropyl myristate) proved to be optimal. t‐CA SNEDDS (80 mg/kg, p.o.), t‐CA suspension (80 mg/kg, p.o.), and Metformin Hydrochloride Tablets (230 mg/kg, p.o.) were administer qdfor 30 days to diabetic rats. After treatment the body weight of diabetic rats was increased, blood glucose levels, total cholesterol, and triglyceride in the serum tended to be normalized, while the levels of alanine aminotransferase and aspartate aminotransferase were markedly decreased. The effects of t‐CA SNEDDS were superior to that of the t‐CA suspension. The present study demonstrated that t‐CA was effective in attenuating the effects of alloxan treatment and that t‐CA SNEDDS with a more favorable absorption and enhanced bioavailability is more effective than t‐CA. Drug Dev Res 76 : 8282–93, 2015. © 2015 Wiley Periodicals, Inc. 相似文献
5.
A novel series of ten 5‐hydroxy, 5‐substituted benzene sulfonamide pyrimidine‐2,4,6‐triones were synthesized and their structures ascertained using 1H‐NMR, 13C‐NMR, mass and elemental analysis. These compounds were subsequently tested for inhibition of MMP‐2 and MMP‐9 where most exhibited activity with compound 5i being the most potent against MMP‐2 and MMP‐9 with IC 50 values of 2.35 nM and 8.24 nM, respectively. Compound 5i was further analyzed in a mouse LPS‐induced acute lung injury model where it had protective activity. Histochemical studies indicated that 5i improved the vascular integrity of the lung. Drug Dev Res 77 : 251–257, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
6.
| Strategy, Management and Health Policy | | Enabling Technology, Genomics, Proteomics | Preclinical Research | Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics | Clinical Development Phases I‐III Regulatory, Quality, Manufacturing | Postmarketing Phase IV | 3,5‐Di‐ t‐butylcatechol (DTCAT) stimulates the rat skeletal muscle sarcoplasmic reticulum ryanodine receptor (RyR). In the present study, its effects on the contractile response of diaphragm preparation were characterized using electrically stimulated phrenic nerve–diaphragm preparations and diaphragm strips. DTCAT reduced, concentration‐dependently, twitch contraction of the phrenic nerve–diaphragm preparation evoked by both direct and indirect stimulation and increased spontaneous tone. Twitch amplitude reduction was irreversible, while the increase of spontaneous tone was only partially reversible upon DTCAT washout. In diaphragm strips, caffeine > 4‐chloro‐ m‐cresol >> 3,5‐diisopropylcatechol ? ryanodine > DTCAT enhanced spontaneous tone, whereas quercetin reduced it with all the compounds reducing twitch amplitude. DTCAT‐induced contracture was partly dependent on extracellular Ca 2+ influx and antagonized by a Cd 2+/La 3+ mixture. In intact skeletal muscle preparations, DTCAT behaved as a RyR agonist. 相似文献
7.
A new series of 5‐aryl and 5‐arylethenylisoxazole carboxylate derivatives was synthesized and evaluated for in vitro activity against Mycobacterium tuberculosis H 37R v. Several compounds exhibited minimum inhibitory concentrations in the low micromolar range (2.3–11.4 μM). A variety of substituents introduced around the isoxazole ring allowed the delineation of preliminary SARs for this new series of compounds. 相似文献
8.
| Strategy, Management and Health Policy | | Enabling Technology, Genomics, Proteomics | Preclinical Research | Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics | Clinical Development Phases I‐III Regulatory, Quality, Manufacturing | Postmarketing Phase IV | Nebulized corticosteroid drugs have several shortcomings due to their poor water solubility and nonoptimal deposition pattern. The aims of this study were to investigate the in vitro and in vivo characteristics of beclomethasone dipropionate (BDP)‐loaded sterically stabilized phospholipid nanomicelles (SSMs) of a polyethylene glycol–phosphatidylethanolamine conjugate as a pulmonary delivery system. The particle size distribution and zeta potential measurements were 14.60 ± 1.11 nm and ?46.94 ± 3.27 mV, respectively. The solubility of BDP was highly improved by at least 1,300 times its actual solubility. No chemical interaction was found between the PEGylated polymer and BDP as demonstrated by the Fourier transform infrared results. The in vitro aerodynamic of the aerosolized BDP‐SSMs using an Omron nebulizer showed an improvement in the aerodynamic values, with a significant deposition in the seven‐stage Next Generation Impactor. The BDP‐SSMs showed a prolonged dissolution profile of about 3 days. Intratracheal administration of the BDP‐SSMs (1 mg/kg) 12 or 23 h before a challenge in the asthmatic rat model led to a significant reduction in the inflammatory cell counts in bronchoalveolar lavage fluid samples compared with the administration of solubilized BDP. The SSM system appears to be an effective way of improving the therapeutic index of nebulized, poorly soluble corticosteroids. 相似文献
9.
| Strategy, Management and Health Policy | | Preclinical Research | A series of caffeic acid amides with extended P1′ groups were synthesized and tested for their inhibitory activities on matrix metalloproteinase (MMP)‐1, MMP‐2, and MMP‐9. Compound 3f showed considerable inhibitory activities against MMP‐2, MMP‐9, and best selectivity over MMP‐1. Preliminary structure–activity relationship analysis and docking studies indicated that caffeic acid amides with electron‐donating groups at p‐position of amino phenyl group showed better inhibitory activities and selectivity than those with electron‐withdrawing groups. The findings of this study would provide information for the exploitation and utilization of caffeic acid as MMP inhibitor for metastatic tumor treatment. 相似文献
10.
Isorhanmetin (ISH) exhibits a wide range of biological properties including anticancer, anti‐oxidant and anti‐inflammatory activities. However, the pharmacological properties of isorhamnetin ‐3 ‐O‐glucuronide (IG), a glycoside derivative of ISH, have not been extensively examined. The objective of this study was to examine the anti‐inflammatory properties of IG and its underlying mechanism in lipopolysaccharide (LPS)‐challenged RAW264.7 macrophage cells in comparison with its aglycone, ISH. IG suppressed LPS‐induced extracellular secretion of the proinflammatory mediators, nitric oxide (NO) and PGE 2, and proinflammatory protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2. IG also increased expression of heme oxygenase‐1 (HO‐1). IG attenuated LPS‐induced activation of c‐Jun N‐terminal kinase (JNK) and p38 in a concentration‐dependent manner with negligible suppression of extracellular signal‐regulated kinases (ERK) phosphorylation. In conclusion, this study demonstrates that IG exerts anti‐inflammatory activity by increasing HO‐1 expression and by suppressing JNK and p38 signaling pathways in LPS‐challenged RAW264.7 macrophage cells. Drug Dev Res 77 : 143–151, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
11.
A new series of pyridazinone‐based thioderivatives and pyridazine analogs was synthesized and tested for their ability to bind to the three human formyl peptide receptor (FPR) isoforms (FPR1, FPR2, and FPR3) and to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Among the pyridazin‐3(2 H)‐one derivatives tested, analogs 8b and 8c were mixed FPR1/FPR2 agonists, with median effective concentration values in the micromolar range, and were able to activate chemotaxis and Ca 2+ flux in human neutrophils in the low micromolar range. Molecular docking studies showed that interaction of a ligand with Arg205 of FPR1 is important for FPR1 agonist activity. For FPR2, differences in activity between oxygen‐containing compounds and their thio‐analogs were due to steric bulkiness of sulfur‐containing groups. 相似文献
12.
A series of novel symmetric and asymmetric 4‐(carbonyloxyphenyl)‐1,4‐dihydropyridines (DHPs) was synthesized and evaluated for calcium channel blocking, vasodilatory and antihypertensive properties. Some of these new DHPs displayed potent calcium channel blocking and good vasodilatory activities. Heart rate remained relatively constant in comparison with blood pressure changes in the case of these newly synthesized compounds, thereby decreasing the probability of reflex tachycardia, a major side effect of nifedipine. The most potent compound, ethyl methyl 4‐(3‐isopropylcarbonyloxyphenyl)‐2,6‐dimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate (14c) exhibited antihypertensive activity comparable with the standard drug—nifedipine. 相似文献
13.
Hepatocellular carcinoma (HCC) is one of the most malignant and frequent cancers with a high metastatic potential. The prevention of HCC metastasis is a critical target for effective therapies in HCC. Gambogic acid (GA), a natural compound obtained from Garcinia hanburyi has reported anticancer activity in cell lines. However, the antimetastatic mechanisms of GA are unclear, particularly with respect to HCC. In this study, the influence of GA on migration and invasion of SK‐HEP1 cells was evaluated. At concentrations above 0.6 μM, GA reduced cell proliferation in SK‐HEP1 cells without affecting proliferation of noncancerous HEK‐293 cells. GA also suppressed migration and invasion of SK‐HEP1 cells. GA downregulated the expression of the integrin β1/rho family GTPase signaling pathway, suppressed the actin rearrangement related to cell cytoskeleton and migration and decreased matrix metalloproteinases MMP‐2, MMP‐9, and NF‐κB expression involved in cancer invasion. These results suggest that GA may be a potential lead in developing an antimetastatic therapeutic for the treatment of HCC. © 2015 Wiley Periodicals, Inc. Drug Dev Res 73 : 132–142, 2015. © 2015 Wiley Periodicals, Inc. 相似文献
14.
Given nuclear‐power‐plant incidents such as the 2011 Japanese Fukushima‐Daiichi disaster, an urgent need for effective medicines to protect against and treat the harmful biological effects of radiation is evident. To address such a challenge, we describe potential strategies herein including mitochondrial and epigenetic‐driven methods using lipoic and butyric acid ester conjugates of carnitine. The antioxidant and other therapeutically beneficial properties of this class of agents may protect against ionizing radiation and resultant mitochondrial dysfunction. Recent studies of the compounds described herein reveal the potential—although further research and development is required to prove the effectiveness of this approach—to provide field‐ready radiation‐protective drugs. Drug Dev Res 76 : 167–175, 2015. © 2015 Wiley Periodicals, Inc. 相似文献
15.
The efficacy of anti‐TNF agents in the treatment of multiple immune‐mediated inflammatory diseases (IMIDs) has increased their daily use. However, concerns remain regarding their long‐term safety profile. Using a literature‐based review of the infectious and malignant complications of anti‐TNF biologics in IMIDs including psoriasis, Rheumatoid Arthritis, and inflammatory bowel disease, this review presents current evidence relative to the safety of anti‐TNF agents in the context infections and malignancy in adults with IMIDs. Treatment with anti‐TNF biologics is an effective treatment option with known risks that can be mitigated by appreciating the safety aspects and via a thorough screening and continuous monitoring of the patient. Drug Dev Res 76 : 419–427, 2015. © 2015 Wiley Periodicals, Inc. 相似文献
16.
Formyl peptide receptors (FPRs) are G‐protein‐coupled receptors that play an important role in the regulation of inflammatory process and cellular dysfunction. In humans, three different isoforms are expressed (FPR1, FPR2, and FPR3). FPR2 appears to be directly involved in the resolution of inflammation, an active process carried out by specific pro‐resolving mediators that modulate specific receptors. Previously, we identified 2‐arylacetamido pyridazin‐3(2 H )‐ones as FPR1‐ or FPR2‐selective agonists, as well as a large number of mixed‐agonists for the three isoforms. Here, we report a new series of 2‐arylacetamido pyridazinones substituted at position 5 and their development as FPR agonists. We also synthesized a new series of 2‐oxothiazolones bearing a 4‐bromophenylacetamido fragment, which was fundamental for activity in the pyridazinone series. The compounds of most interest were 4a , a potent, mixed FPR agonist recognized by all three isotypes (FPR1 EC 50 = 19 nM, FPR2 EC 50 = 43 nM, FPR3 EC 50 = 40 nM), and 4b , which had potent activity and a preference for FPR2 (EC 50 = 13 nM). These novel compounds may represent valuable tools for studying FPR activation and signaling. Drug Dev Res 78 : 49–62, 2017. © 2016 Wiley Periodicals, Inc. 相似文献
17.
A series of mono‐carbonyl curcumin analogs with different substituents at the 4/4’‐position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines using a methyl thiazolyl tetrazolium assay. Several of the curcumin analogs, especially B114, exhibited a wide‐spectrum of anti‐tumor properties in all tested cell lines, indicating their potential in as anti‐cancer lead compounds. Further toxicity testing in the NRK‐52E kidney cell line revealed that the analogs A111, A113, and B114 had comparable or higher safety than curcumin. These data suggested that the introduction of appropriate substituents in the 4/4’‐positions could be a promising approach for curcumin‐based drug design. Drug Dev Res 77 : 43–49, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
18.
Rhizoma Coptidis (RC), the root of Coptis chinensis Franch, a species in the genus Coptis (family Ranunculaceae), has been commonly prescribed for the treatment of diabetes in Chinese traditional herbal medicine applications. The present study is focused on the assessment of the antihyperglycemia and antidiabetic hyperlipidemia effect of five protoberberine alkaloids, berberine (BBR), coptisine (COP), palmatine (PAL), epiberberine (EPI), and jatrorrhizine (JAT), separated from R. Coptidis in hepatocellular carcinoma HepG2 cells and diabetic KK‐Ay mice. Protoberberine alkaloids are effective in modulating hyperglycemia and hyperlipidemia. After adding BBR and COP to culture medium, glucose consumption of HepG2 cells was increased. In KK‐Ay mice assays, suppressed fasting blood glucose level and ameliorated glucose tolerance were observed after BBR/COP administration. After treated with berberine and coptisine, in the same dose of 5 µg/mL, the glucose consumption of HepG2 cells were promoted and, respectively, reached 96.1% and 17.6%. Body weight, food consumption, water intake, and urinary output of KK‐Ay mice were reduced after treated with EPI. Serum total cholesterol and triglyceride of mice were decreased after treated with palmatine and jatrorrhizine. Serum high‐density lipoprotein cholesterol of mice was increased after palmatine, jatrorrhizine, and berberine administrated. Moreover, hepatomegaly was attenuated in JTR‐treated mice. Suggested that these protoberberine alkaloids from R. Coptidis have potential curative effect for diabetes. Drug Dev Res 77 : 163–170, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
19.
Osteoarthritis (OA) is a widely prevalent degenerative joint disease that severely impairs the health of the elderly population resulting in a heavy economic burden worldwide. Coenzyme Q10 (CoQ10) has shown anti‐inflammatory effects in some diseases. The present study aimed to investigate if CoQ10 would suppress catabolic responses of interleukin (IL)‐1β‐induced chondrocytes. Rat chondrocytes were cultured and pretreated with CoQ10, and then stimulated with or without IL‐1β (10 ng/ml). The expression and production of matrix metalloproteinase (MMP)‐3, MMP‐9, and MMP13 were determined using real‐time PCR and Western blotting. CoQ10 suppressed MMP‐3, MMP‐9, and MMP13 production induced by IL‐1β, and markedly inhibited IL‐1β‐induced MAPK pathways in rat chondrocytes. The present study provides insight into potential mechanisms by which CoQ10 protects against degeneration of cartilage in patients with OA, which may lead to new approaches for the treatment of OA.Drug Dev Res 78 : 403‐410, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
20.
| Preclinical Research & Development | Angelicin is a furocoumarin derived from Psoralea corylifolia L. fruit that has anti‐inflammatory and anti‐tumor activity. In the present study, the effect of angelicin in enhancing tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptotic cell death was studied in Caki (renal carcinoma) cells. Angelicin alone and TRAIL alone had no effect on apoptosis, but in combination these compounds markedly induced apoptosis in the cancer cell lines while not inducing apoptosis in normal cells. The combination treatment induced accumulation of the sub‐G1 population, DNA fragmentation, and activated caspase 3 activity in Caki cells, induced down‐regulation of c‐FLIP expression post‐translationally, and over‐expression of c‐FLIP markedly blocked apoptosis induced by combined treatment with angelicin plus TRAIL. This study provides evidence that angelicin might be a TRAIL sensitizer. 相似文献
|
下载免费PDF全文