Objective To study the bioequivalence and safety of two olmesartan medoxomil and hydrochlorothiazide tablets in Chinese healthy subjects.Methods A total of 24 healthy subjects underwent fasting and postprandial tests in a single-center,randomized,open-label,single-dose,two-formulation,two-sequence,two-period,self-cross-over controlled design.The subjects were administered a single oral dose of the test formulation and reference formulation(each containingolmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg)in a random cross-over fashion.The plasma concentrations of olmesartan and hydrochlorothiazide were determined by LC-MS/MS.The non-compartmental model analysis of olmesartan and hydrochlorothiazide was conducted using WinNonlin 7.0 software to calculate pharmacokinetic parameters and assess bioequivalence.Results In the fasting test,the pharmacokinetic parameters of olmesartan of test and reference were as follows:Cmax were(798.35±206.78)and(664.52±168.25)ng·mL-1,AUC0-t were(4 430.71±1 294.87)and(3 976.67±1 083.54)h·ng·mL-1,AUC0-∞ were(4 551.67±1 303.06)and(4 090.37±1 103.97)h·ng·mL-1.The pharmacokinetic parameters of hydrochlorothiazide of test and reference were as follows:Cmax were(92.39±35.96)and(96.15±38.76)ng·mL-1,AUC0_t were(548.69±217.11)and(564.41±208.68)h·ng·mL-1,AUC0-∞ were(603.04±228.59)and(619.26±223.27)h·ng·mL-1.In the fed test,the pharmacokinetic parameters of olmesartan of T and R were as follows:Cmax were(583.15±149.48)and(550.57±104.76)ng·mL-1,AUC0-t were(3 585.18±952.72)and(3 292.19±904.58)h·ng·mL-1,AUC0-∞ were(3 696.05±996.55)and(3 396.30±923.41)h·ng·mL-1.The pharmacokinetic parameters of hydrochlorothiazide of test and reference were as follows:Cmax were(70.30±17.88)and(74.70±21.65)ng·mL-1,AUC0-t were(476.60±119.39)and(492.91±144.81)h·ng·mL-1,AUC0-∞ were(523.37±132.67)and(535.81±151.92)h·ng·mL-1.In fasting and fed condition,the 90％confidence interval(90％CI)of Cmax,AUC0-t and AUC0-∞ of olmesartan and hydrochlorothiazide were in 80.00％-125.00％.Conclusion The two olmesartan medoxomil and hydrochlorothiazide tablets were bioequivalent under fasting and fed conditions,and good security.

BACKGROUNDMutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome (MFS). This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneurysms/dissection.

METHODSTwo patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed.

RESULTSWe found a novel mutation (c.8547T > G, p.Tyr2849X) in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3' end of fibrillin-1 gene (exons 64 and 65), we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death.

CONCLUSIONSThese results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3' end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.

Adult ; Female ; Fibrillin-1 ; Fibrillins ; Genotype ; Humans ; Male ; Marfan Syndrome ; etiology ; genetics ; Microfilament Proteins ; genetics ; Middle Aged ; Mutation ; Phenotype

Adult ; Aged ; Aged, 80 and over ; Carcinoma ; metabolism ; pathology ; Female ; Gallbladder Neoplasms ; metabolism ; pathology ; Humans ; Immunohistochemistry ; Kangai-1 Protein ; metabolism ; Male ; Middle Aged ; NM23 Nucleoside Diphosphate Kinases ; metabolism ; Tomography, Spiral Computed

OBJECTIVETo observe the expressions of the substance P (SP) mRNA and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5 - S2 spinal cord in the rat model of chronic prostatitis pain, and to investigate the changes in the activation of astrocytes and influence of SP on this activation in rat spinal cord astrocytes cultured in vitro.

METHODSThe rat model of chronic prostatitis pain was established by injection of complete Freund's adjuvant (CFA) and assessed by the tail flick threshold test, the control rats injected with sodium chloride and all observed at 0, 14 and 28 days. Changes in the expressions of SP mRNA, NK-1R, glial fibrillary acidic protein (GFAP), tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) in the posterior horn of the L5 - S2 spinal cord were detected by RT-PCR and Western blot. Rat spinal cord astrocytes were cultured in vitro and divided into a control group, cultured with ITS cell culture fluid, and two experiment groups, with Group 1 stimulated with SP at the concentration of 10(-9) - 10(-6) mol/L for 12 hours followed by determination of the expressions of TNF-alpha, IL-1beta, NO and NOS by ELISA and nitrate reductase and colorimetric methods, and Group 2 at 10(-7) mol/L for 0, 24, 48 and 72 hours followed by detection of the GFAP expression by Western blot.

RESULTSThe expressions of SP mRNA, NK-1 R, GFAP, TNF-alpha and iNOS in the posterior horn of the L5 - S2 spinal cord were obviously higher in the rat prostatitis pain models than in the controls, successively higher at 28 than at 14 and 0 d (P < 0.01), and so was the expression of GFAP at 28 than at 14 d in the experiment groups (P < 0.05). SP induced a gradual increase at 10(-7) mol/L in the expression of GFAP in the spinal cord astrocytes at 0 -72 h, significantly different from that of the control group (P < 0.01), and it promoted the excretion of TNF-alpha and IL-1beta and the activity of NO and NOS at 10(-9) - 10(-6) mol/L at 12 h in a concentration-dependent manner, with marked differences between the experiment and control groups (P < 0.01, P < 0.05). But a decreased excretion of IL-1 beta was observed in the 10(-6) mol/L group, though with no significant difference from the control (P > 0.05).

CONCLUSIONChronic prostatitis pain could upregulate the expressions of the excitatory transmitter SP and receptor in the L5 - S2 spinal cord, and result in the activation of astrocytes and increased excretion of proinflammatory cytokines, which may be associated with the persistence and generalization of prostatitis pain.

Animals ; Astrocytes ; metabolism ; Chronic Disease ; Male ; Nitric Oxide Synthase Type II ; metabolism ; Pain ; metabolism ; Prostatitis ; metabolism ; Rats ; Receptors, Neurokinin-1 ; metabolism ; Spinal Cord ; cytology ; metabolism ; pathology ; Substance P ; metabolism

OBJECTIVETo investigate the expression of two tumor metastasis suppressor genes nm23 and KAI1 in gallbladder adenocarcinoma, and their clinicopathological significance.

METHODSSpecimens and clinical data from 31 gallbladder adenocarcinoma patients were collected. Histopathological grading and the expression of nm23 and KAI1 were detected by HE and immunohistochemical staining, respectively. All cases were followed up for at least three years.

RESULTSImmunohistochemical staining showed that the positive rate of nm23 and KAI1 proteins was 71.0% (22/31) and 61.3% (19/31), respectively. The positive expression rates of nm23 and KAI1 proteins in the early stage carcinomas were significantly higher than those in the moderate and advanced stage ones (P exact = 0.0051 and P exact = 0.0084), and both had an negative correlation with clinicopathologic stage (P trend = 0.0047 and P trend = 0.0058). There was a significant difference in the expression of nm23 and KAI1 proteins among well, moderately and poorly differentiated carcinomas (P exact = 0.0328 and P exact = 0.0020). The expression of nm23 and KAI1 was positively correlated with histopathological grade (P trend = 0.0086 and P trend = 0.0006). There was also a significant difference in the expression of nm23 and KAI1 proteins between 17 survival and 14 dead patients (P exact = 0.0038 and P exact = 0.0001 ). A synergistic effect of nm23 and KAI1 protein on the survival was observed , and seemed to be more important than any individual gene alone (P exact = 0.0005).

CONCLUSIONThe expressions of nm23 and KAI1 proteins are negatively correlated with clinical stage, but positively with histopathological grade in gallbladder adenocarcinoma. These two tumor metastasis suppressor genes may act synergistically to inhibit the tumor metastasis.

Adenocarcinoma ; metabolism ; pathology ; surgery ; Adult ; Aged ; Aged, 80 and over ; Cell Membrane ; metabolism ; Cholecystectomy ; Cytoplasm ; metabolism ; Female ; Follow-Up Studies ; Gallbladder Neoplasms ; metabolism ; pathology ; surgery ; Gene Expression Regulation, Neoplastic ; Humans ; Kangai-1 Protein ; metabolism ; Male ; Middle Aged ; NM23 Nucleoside Diphosphate Kinases ; metabolism ; Neoplasm Metastasis ; Neoplasm Staging ; Survival Rate

Carcinoma ; metabolism ; Cell Differentiation ; genetics ; Gallbladder Neoplasms ; genetics ; metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Kangai-1 Protein ; genetics ; metabolism ; NM23 Nucleoside Diphosphate Kinases ; genetics ; metabolism

BACKGROUNDProstatodynia remains a difficult clinical problem. Resiniferatoxin (RTX), an ultrapotent vanilloid, can produce a selective and long-lasting desensitization of nociception via C-fiber sensory neurons. Substance P (SP) and calcitonin gene-related peptide (CGRP) released from C-fibers are key neurotransmitters in visceral pain. In this study, we evaluated the analgesic effect of intrathecal RTX on rat prostatodynia.

METHODSMale Sprague-Dawley rats were divided into 3 groups for different treatment. In group A, sham operation was preformed. In group B, 100 microl complete Freund's adjuvant (CFA) was injected into the rat's bilateral ventral prostate to induce chronic inflammation. In group C, after prostatitis formed, 50 microl 10 nmol/L RTX was injected into the rat's lumbosacral (L5-S2) vertebral canal. SP and CGRP contents in the spinal cord were investigated by immunohistochemistry and radioimmunoassay (RIA). Their transcriptional levels in dorsal root ganglion (DRG) were determined by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, pelvic nerve afferent discharge was recorded to explore the neuro-electrophysiological mechanisms underlying RTX-induced effect.

RESULTSSP and CGRP released in the spinal cord and their synthesis in DRG were increased significantly in response to CFA-induced chronic prostatitis, whereas this increase was effectively inhibited by intrathecal RTX. Meanwhile, pelvic nerve afferent electrical activity was enhanced significantly in rats with chronic prostatitis, but it was attenuated markedly in RTX-treated rats paralleled by the change of neuropeptides.

CONCLUSIONSIntrathecal RTX administration could produce an analgesic effect on rat prostatodynia. Suppression of pelvic nerve afferent electrical activity may be a crucial mechanism underlying RTX-induced analgesia. RTX intrathecal application may present a novel analgesic strategy of prostatodynia.

Analgesics ; administration & dosage ; Animals ; Calcitonin Gene-Related Peptide ; analysis ; genetics ; Diterpenes ; administration & dosage ; Injections, Spinal ; Male ; Prostatitis ; drug therapy ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Substance P ; analysis ; genetics

OBJECTIVETo evaluate the effects of arginine modified chitosan or hexadecylated modified chitosan as gene carriers on the cellular uptake by vascular smooth muscle cells and its in vitro cytotoxicity. METHODS Plasmid DNA was labeled with alpha-32P-dATP and complexed with the modified chitosans or unmodified chitosan to form nanoparticle complexes by complex coacervation method. Uptake of all kinds of chitosan/ DNA nanoparticle complexes (CNC) by A10 cells was measured by beta-liquid scintillation counting. The in vitro cytotoxicity of the CNC was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay.

RESULTSThe diameters of the CNC ranged from 55.9-174.9 nm and the zeta potentials were from 10. 8 mV for the arginine modified chitosan/DNA nanoparticle complexes (ACNC) to 1.8 mV for the hexadecylated chitosan/DNA nanoparticle complexes (HCNC). The cellular uptake of the modified chitosan/ DNA nanoparticle complexes (MCNC) by A10 cells increased significantly when compared with the unmodified chitosan/DNA nanoparticle complexes (UCNC) (P < 0.05), with the HCNC at N/P ratio of 1:1 and the ACNC at ratio of 8:1 showing the highest cellular uptake (1.3 fold higher than UCNC, P < 0.05). MCNC were much less cytotoxic when compared with Lipofectamine 2000-DNA nanoparticles.

CONCLUSIONDNA nanoparticle complexes prepared with either arginine or hexadecylated modified chitosan can improve the cellular uptake of the DNA, while the in vitro cytotoxicity of both of the modified chitosan is much less than that of Lipofectamine 2000.

Animals ; Antigen-Antibody Complex ; Arginine ; pharmacology ; Chitosan ; chemistry ; pharmacology ; Citric Acid ; analogs & derivatives ; pharmacology ; Cytotoxicity, Immunologic ; DNA ; pharmacology ; Genetic Vectors ; Nanoparticles ; Rats

OBJECTIVETo evaluate the effect of sexual-nerve-sparing radical cystectomy.

METHODSThirty-two male patients were treated with sexual-nerve-sparing radical cystectomy in our hospital in the past 5 years. The age of the patients ranged from 38 to 72 years, with the course of the disease ranging from 2 days to 20 years. All of them were potent preoperatively. Radical cystectomy was performed antegradely and retrogradely with the neurovascular bundle spared.

RESULTSThe patients were followed up for 6 to 54 months, 3 achieved sexual activity of Grade I, 6 Grade II and 23 Grade III after the operation. The recovery time of erectile function ranged from 2 to 14 months, averaging at 4. 5 months.

CONCLUSIONWhenever condition suits, sexual-nerve-sparing radical cystectomy is to be strongly recommended.

Adult ; Aged ; Coitus ; Cystectomy ; methods ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Penile Erection ; Penis ; innervation

OBJECTIVETo investigate the clinical features, pathology, diagnosis and treatment of inverted urothelial papilloma.

METHODSA total of 151 cases of urothelial inverted papilloma were analysed retrospectively. Of the cases, 134 were male and 17 were female, with a mean age of 54 years old. Most patients complained of painless gross hematuria. The diagnosis could be established mainly by ultrasonic, intravenous urography, retrograde pyelography, cystoscope and pathology. Among them, 7 cases who had the papilloma at upper urinary tract underwent nephroureterectomy except one. One hundred and forty-four cases had the papilloma at low urinary tract, with 124 treated by transurethral bladder tumor resection (TURBT), among which 11 cases accompanying benign prostatic hyperplasia were treated by transurethral prostatic resection, 3 by transurethral resection of prostatic urethral tumor, 15 by partial cystectomy, 2 by total cystectomy.

RESULTSOne hundred and eighteen cases were followed up 1 year to 12.5 years (mean 6.3 years). Intravesical recurrence was found in 5 cases. Of them 2 cases developed malignance in 8 and 30 months postoperatively, and 1 case underwent total cystectomy.

CONCLUSIONSInverted urothelial papilloma is a benign tumor, which appears male predominant. Most of the lesions are found in the bladder. TURBT is the preferred treatment choice for inverted papilloma of the bladder. Although this disease has a good prognosis, regular follow-up observations are necessary.

Adult ; Aged ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Papilloma, Inverted ; diagnosis ; pathology ; surgery ; Retrospective Studies ; Urologic Neoplasms ; diagnosis ; pathology ; surgery