Deflazacort (DFZ, a prodrug) is well absorbed and rapidly metabolized into the active metabolite 21-hydroxydeflazacort (21-OH DFZ) after oral administration. The aim of this study is to evaluate the pharmacokinetic properties of 21-OH DFZ in healthy Chinese volunteers after a single and multiple oral administration of DFZ tablets under fed condition. Twelve volunteers (six males and six females) were administered a single dose of 6 mg or 12 mg or 24 mg of DFZ in three different periods separately, according to the 3 x 3 Latin square design. Between each administration period there was a washout period of one week. The multiple-dose study of 12 mg dose DFZ per day for 7 consecutive days was started after a 1 w washout period when the single-dose study completed. The pharmacokinetic parameters of 21-OH DFZ after the single oral administration of 6 mg, 12 mg and 24 mg DFZ tablets were as follows: (37.7 +/- 11.6), (61.5 +/- 17.7) and (123 +/- 23) ng x mL(-1) for C(max); (1.90 +/- 0.32), (1.96 +/- 0.27) and (2.13 +/- 0.34) h for t1/2; (96.6 +/- 25.9), (190 +/- 44) and (422 +/- 107) ng x h x mL(-1) for AUC(0-14 h), respectively. After the multiple dose administration, the mean plasma concentration at steady-state C(av) was (7.00 +/- 1.66) ng x mL(-1) and the degree of plasma concentration fluctuation DF was 7.7 +/- 1.2. The results showed that the pharmacokinetic characteristics of 21-OH DFZ in healthy Chinese volunteers were linear over the dose range of 6 to 24 mg. No significant gender differences were found in the pharmacokinetics of 21-OH DFZ in healthy Chinese volunteers. After the multiple dose administration of 12 mg DFZ for 7 d, no accumulation of 21-OH DFZ in healthy Chinese volunteers was observed.
Administration, Oral ; Area Under Curve ; Asian Continental Ancestry Group ; Female ; Healthy Volunteers ; Humans ; Male ; Pregnenediones ; pharmacokinetics ; Tablets

Synchronization of estrus and ovulation are of paramount importance in modern livestock improvement programs. These methods are critical for assisted reproduction technologies, including artificial insemination and embryo transfer, that can increase productivity. In the current study, subcutaneous implants containing norgestomet were placed for long (14 days), medium (9 days), and short (5 days) periods of time in 70 crossbred ewes undergoing fixed-time artificial insemination. The resulting effects on estrus synchronization and conception rates were subsequently evaluated. Among the synchronized ewes, 85.7% (60/70) underwent estrus over a period of 72 h after progestagen treatment ceased. The shortest mean interval between withdrawal of the device and onset of estrus (34.2 +/- 8.9 h) was observed in the G14 days of P4 group (p < 0.05). The conception rate of the G14 days of P4 group was statistically higher than that of the other groups (83.3% vs. 60.9% vs. 47.8%; p < 0.05). In conclusion, 14 days of norgestomet treatment produced higher conception rates and a greater number of pregnancies at the beginning of the breeding season.
Animals ; Drug Implants/therapeutic use ; Estrus Synchronization/drug effects/*methods ; Female ; Fertilization/drug effects ; Insemination, Artificial/methods/*veterinary ; Pregnenediones/administration & dosage/*pharmacology ; Sheep

PURPOSE: The DNA methylation mediated by specific DNA methyltransferases (DNMTs), results in the epigenetic silencing of multiple genes which are implicated in human breast cancer. We hypothesized that the natural compounds modulate the expression of DNMTs and their associated proteins in the breast cancer cell lines and affect the methylation mediated gene silencing. METHODS: The DNMTs transcript expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in the tumors and the adjacent normal breast tissues of the patients with invasive ductal breast carcinoma. We tested the hypothesis that the natural compounds, viz., epigallocatechin gallate (EGCG), genistein, withaferin A, curcumin, resveratrol, and guggulsterone, have demethylation potential. To investigate this hypothesis, we analyzed the DNMTs expression at the transcript levels, followed by the analysis of DNMT1 and its associated proteins (HDAC1, MeCP2, and MBD2). RESULTS: The increased DNMTs transcripts expression, viz., DNMT1, DNMT3a, and DNMT3b, in the breast cancer tissues suggest involvement of the DNMTs in the breast carcinogenesis. Quantitative RT-PCR analysis revealed that the treatment with natural compounds, viz., EGCG, genistein, withaferin A, curcumin, resveratrol, and guggulsterone, resulted in a significant decrease in the transcript levels of all the DNMTs investigated. Importantly, these natural compounds decreased the protein levels of DNMT1, HDAC1, and MeCP2. CONCLUSION: Our results demonstrate that the natural compounds, EGCG, genistein, withaferin A, curcumin, resveratrol, and guggulsterone, have the potential to reverse the epigenetic changes. Moreover, their lack of toxicity makes these natural compounds promising candidates for the chemoprevention of the breast cancer. In-depth future mechanistic studies aimed to elucidate how these compounds affect the gene transcription are warranted.
Breast ; Breast Neoplasms ; Catechin ; Cell Line ; Chemoprevention ; Curcumin ; DNA ; DNA Methylation ; Epigenomics ; Genistein ; Humans ; Methylation ; Methyltransferases ; Pregnenediones ; Proteins ; Stilbenes ; Withanolides

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily. It is highly related to the formation of metabolic syndrome and the glucose homeostasis, and therefore represents an important drug target against metabolic diseases and diabetes. In recent years, great progress has been made in the agonists, antagonists, and crystal structures of FXR. The diverse FXR ligands and their structure-activity relationship are reviewed in this article. The advances in the crystal structures of FXR in complex with different ligands are also introduced.
Animals ; Anticholesteremic Agents ; chemical synthesis ; chemistry ; pharmacology ; Azepines ; chemical synthesis ; chemistry ; pharmacology ; Benzene Derivatives ; chemical synthesis ; chemistry ; pharmacology ; Chenodeoxycholic Acid ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Crystallization ; Humans ; Indoles ; chemical synthesis ; chemistry ; pharmacology ; Isoxazoles ; chemical synthesis ; chemistry ; pharmacology ; Ligands ; Molecular Structure ; Multienzyme Complexes ; chemical synthesis ; chemistry ; pharmacology ; Pregnenediones ; chemical synthesis ; chemistry ; pharmacology ; Receptors, Cytoplasmic and Nuclear ; agonists ; antagonists & inhibitors ; metabolism ; Structure-Activity Relationship

Although corticosteroids have immunosuppressive, anti-inflammatory, and anti-allergic effects, allergic reactions are rare. We report a case involving a 52-year-old-female with acute urticaria caused by oral methylprednisolone. The patient had experienced aspirin-exacerbated respiratory disease (AERD) for 13 years with frequent asthma exacerbations. Symptoms of asthma exacerbations improved with short-term treatments of systemic steroids, including methylprednisolone or deflazacort, which had been well tolerated. However, the current admission was prompted by the development of acute generalized urticaria following the oral ingestion of methylprednisolone (8 mg) for relief of symptoms. An oral provocation test with 4 mg oral methylprednisolone led to generalized urticaria 20 minutes later, confirming the causal association. This is the first report of acute urticaria caused by oral methylprednisolone in a patient with AERD.
Adrenal Cortex Hormones ; Asthma ; Drug Hypersensitivity ; Eating ; Humans ; Hypersensitivity ; Methylprednisolone ; Pregnenediones ; Steroids ; Urticaria

OBJECTIVE: To determine the feasibility of using T2 mapping as a quantitative method to longitudinally follow the disease activity in children with Duchenne muscular dystrophy (DMD) who are treated with steroids. MATERIALS AND METHODS: Eleven boys with DMD (age range: 5-14 years) underwent evaluation with the clinical functional score (CFS), and conventional pelvic MRI and T2 mapping before and during steroid therapy. The gluteus muscle inflammation and fatty infiltration were evaluated on conventional MRI. The histograms and mean T2 relaxation times were obtained from the T2 maps. The CFS, the conventional MRI findings and the T2 values were compared before and during steroid therapy. RESULTS: None of the patients showed interval change of their CFSs. On conventional MRI, none of the images showed muscle inflammation. During steroid treatment, two boys showed increased fatty infiltration on conventional MRI, and both had an increase of the mean T2 relaxation time (p < 0.05). The remaining nine boys had no increase in fatty infiltration. Of these, three showed an increased mean T2 relaxation time (p < 0.05), two showed no change and four showed a decreased mean T2 relaxation time (p < 0.05). CONCLUSION: T2 mapping is a feasible technique to evaluate the longitudinal muscle changes in those children who receive steroid therapy for DMD. The differences of the mean T2 relaxation time may reflect alterations in disease activity, and even when the conventional MRI and CFS remain stable.
Adolescent ; Anti-Inflammatory Agents/therapeutic use ; Buttocks ; Child ; Child, Preschool ; Feasibility Studies ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging/*methods ; Male ; Muscle Strength/drug effects ; Muscle, Skeletal/*drug effects/*physiopathology ; Muscular Dystrophy, Duchenne/*drug therapy/*physiopathology ; Observer Variation ; Pregnenediones/therapeutic use ; Prospective Studies

BACKGROUND/AIMS: Steroid therapy is reported to improve the clinical outcome of IgA nephropathy. In addition, recent studies have revealed that deflazacort has fewer side effects than prednisolone. This study examined the effect of steroids and compared the clinical efficacy of deflazacort and prednisolone in patients with IgA nephropathy. METHODS: We retrospectively reviewed 136 patients with biopsy-proven IgA nephropathy who received deflazacort (n=50), prednisolone (n=29), or neither (n=59), and in whom blood pressure was controlled with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. The mean duration of steroid administration was 9.5+/-9.1 months. The initial clinical status and change in the amount of protein in the 24-hour urine were compared among the three groups. RESULTS: The baseline characteristics (age, blood pressure, serum creatinine level, initial protein in the 24-hour urine, and creatinine clearance) did not differ significantly among the groups. The decrement of protein in the 24-hour urine was higher in the deflazacort and prednisolone groups, as compared with the control group (4.4+/-5.4, 4.2+/-1.5, and 2.1+/-3.1 g/day, respectively, p=0.013). The increment in the creatinine clearance was higher in the deflazacort and prednisolone groups, as compared with the control group (11.5+/-16.4, 12.3+/-26.2, and 4.8+/-14.91.3+/-0.9, respectively, p=0.009). There were no significant differences in the above parameters between the deflazacort and prednisolone groups. CONCLUSIONS: Steroid therapy reduces urinary protein excretion in IgA nephropathy, and the clinical efficacy of deflazacort and prednisolone was found to be similar.
Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Blood Pressure ; Creatinine ; Glomerulonephritis ; Glomerulonephritis, IGA ; Humans ; Immunoglobulin A ; Prednisolone ; Pregnenediones ; Proteinuria ; Retrospective Studies ; Steroids

The present study is to investigate the protective actions of guggulsterone against the cytotoxicity produced by exposure to hydrogen peroxide (H2O2) in PC12 cells. It was evaluated by MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] reduction assay, lactate dehydrogenase (LDH) release assay, and the release of nitric oxide (NO). ROS and Ca2+ in cells were evaluated by DCFH and Fura 2-AM, respectively. Mitochondrial membrane potential (MMP) was assessed by the retention of rhodamine 123 (Rh 123). Apoptosis and morphological alteration in PC12 cells were monitored with flow cytometry and electric microscope. Vitamin E, a potent antioxidant, was employed as a comparative agent. The results showed that preincubation of PC12 cells with guggulsterone (0.1 - 10 micromol x L(-1)) prevented cytotoxicity induced by H2O2. Extracellular accumulation of LDH, NO and intracellular accumulation of ROS, Ca2+ resulting from H2O2 were significantly reduced by guggulsterone. Incubation of cells with H2O2 caused a marked decrease in MMP, which was significantly inhibited by guggulsterone. The percentage of H2O2-induced apoptosis in PC12 cells was 24.3%, and decreased in the presence of guggulsterone (0.1 - 10 micromol x L(-1)) by 18.4%, 15.9%, 11.8%, respectively. Guggulsterone exhibited comparable potency against oxidative stress induced by H2O2 in PC12 cells as that of vitamin E. The present findings showed that guggulsterone attenuated H2O2-induced cytotoxicity, extracellular accumulation of LDH and NO, intracellular accumulation of ROS and Ca2+, loss of MMP, and apoptosis, which may represent the cellular mechanisms for its neuroprotective action.
Animals ; Antioxidants ; pharmacology ; Apoptosis ; drug effects ; Calcium ; metabolism ; Commiphora ; chemistry ; Cytoprotection ; drug effects ; Hydrogen Peroxide ; toxicity ; L-Lactate Dehydrogenase ; metabolism ; Membrane Potentials ; drug effects ; Mitochondria ; physiology ; Nitric Oxide ; metabolism ; PC12 Cells ; Plants, Medicinal ; chemistry ; Pregnenediones ; pharmacology ; Rats ; Reactive Oxygen Species ; metabolism

Idiopathic retroperitoneal fibrosis (IRPF) is a rare disease characterized by a retroperitoneal inflammatory proliferative fibrosing process. Hashimoto's thyroiditis is the most common inflammatory condition of the thyroid gland; and is a frequently-occurring autoimmune disorder manifesting predominantly in middle-aged women. We report a rare association of IRPF with Hashimoto's thyroiditis in a 67-year-old man demonstrating good response to steroid therapy.
Aged ; Anti-Inflammatory Agents/therapeutic use ; Hashimoto Disease/*complications/drug therapy ; Humans ; Male ; Pregnenediones/therapeutic use ; Retroperitoneal Fibrosis/*complications/drug therapy/pathology

It has been suspected that various infections, including cytomegalovirus(CMV) infection, are associated with IgA nephropathy. In case of CMV infection, ganciclovir is known to be a treatment of choice for severe CMV infection in general. But ganciclovir has a lot of severe toxicity, so children with normal immunity are seldom treated by ganciclovir when CMV infection is suspected. On the other hand, intravenous immunoglobulin can also be used to treat CMV infection.
Child ; Cytomegalovirus ; Ganciclovir ; Glomerulonephritis, IGA ; Hand ; Humans ; Immunoglobulin A ; Immunoglobulins ; Pregnenediones