BACKGROUNDNifekalant may prevent atrial fibrillation (AF) and possibly be useful in treatment of atrial tachyarrhythmia in patients with severe heart failure. This study investigated the electophysiologic effect of nifekalant on the acute atrial remodeling in rapid atrial pacing (RAP) model of canine.

METHODSTwelve mongrel dogs subjected to rapid stimulation (400 beats/min) at left atrial appendage (LAA) for 24 hours, were randomized into the control group (rapid pacing only, n = 6) and the nifekalant group (intravenous nifekalant therapy immediately after RAP, n = 6). Atrial electrophysiological parameters were measured in right atrium, coronary sinus, LAA, posterior wall of left atrium (PWLA) and left superior pulmonary vein (LSPV), before and after the RAP.

RESULTSIn the control group, the effective refractory periods (ERP) were shortened greatly at all sites, paced dogs had substantially shorter ERPs in the high right atrium, LAA, and LSPV, but fewer changes in the PWLA, the coefficient variation of ERP (COV ERP) was increased significantly. After rapid atrial stimulation, the inducibility of AF increased significantly [induction number: pre-RAP vs post-RAP, 1.00 +/- 0.89 vs 8.17 +/- 2.79, P < 0.01; duration of AF: pre-RAP vs post-RAP, (450.34 +/- 362.59) ms vs (9975.77 +/- 4376.99) ms, P < 0.01]. In the nifekalant group, although the ERPs were prolonged at all sites compared with those in pre-RAP state, only the value at LSPV differed significantly from that in pre-RAP state [pre-RAP vs post-RAP, (102.50 +/- 5.24) ms vs (132.51 +/- 5.20) ms, P < 0.01]; the COV ERP did not change statistically in this group. The inducibility of AF slightly increased but insignificantly after pacing [induction number: pre-RAP vs post-RAP, 0.83 +/- 0.75 vs 1.67 +/- 0.82, P = 0.19; duration of AF: pre-RAP vs post-RAP, (378.67 +/- 317.88) ms vs (1124.08 +/- 1109.77) ms, P = 0.06]. Conduction time values did not alter significantly in either of the two groups after RAP.

CONCLUSIONSIn canine RAP model, nifekalant inhibited ERP shortening and ERP heterogeneity increasing, decreased AF induction. Nifekalant can reverse acute electrical remodeling effect in this model.

Animals ; Anti-Arrhythmia Agents ; pharmacology ; Cardiac Pacing, Artificial ; Dogs ; Female ; Male ; Pyrimidinones ; pharmacology ; Refractory Period, Electrophysiological ; drug effects

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) act by irreversibly binding to the H+-K+-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H+-ATPase in osteoclasts. METHODS: We investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H+-K+-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period. RESULTS: Twenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age > or =60 years was an independent predictor for the changes in serum calcium and urine DPD. CONCLUSIONS: In elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H+-ATPase in osteoclasts.
Aged ; Amino Acids/drug effects/urine ; Bone Remodeling/*drug effects ; Bone and Bones/*metabolism ; Calcium/blood ; Female ; Humans ; Intention to Treat Analysis ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Osteoclasts/*metabolism ; Prospective Studies ; Proton Pump Inhibitors/*pharmacology ; Pyrimidinones/*pharmacology ; Tetrahydroisoquinolines/*pharmacology

OBJECTIVEKawasaki disease (KD) is an acute febrile, multi-system endangeitis, which is mainly found in early childhood. Its etiology is still unknown. A great deal of clinical evidence and epidemiologic data suggest that KD is correlated with an acute immune dysfunction caused by infection. Many evidences in the past suggested that over-expression of proinflammatory cytokines, co-stimulatory molecules and chemokines, which were observed in KD, may contribute to the pathologic lesion of vascular endothelial cells. But the causative factors are still unknown. Toll-like receptor is a type I trans-membrane protein which could recognize ligands of pathogenic microbes, induce interferon beta (IFN-beta) and promote gene transcription of proinflammatory cytokines, co-stimulatory molecules and chemokines. This study was designed to investigate the role of MyD88-independent signal transduction of Toll-like receptor 4 in immunological pathogenesis of KD.

METHODSThirty-two children with KD and 16 age-matched healthy children were studied. Reverse-transcription PCR (RT-PCR) and real-time PCR were used to evaluate the mRNA levels of Toll-like receptor 4 and the molecules such as Toll-IL-1-receptor domain containing adaptor inducing IFN-beta (TRIF), TRIF-related adaptor molecule (TRAM), TANK-binding kinase 1 (TBK-1), IFN-beta, interferon-gamma-inducible protein 10 (IP-10), regulated on activation normal T cells expressed and secreted (RANTES), inducible nitric oxide synthase (iNOS) and suppressor of cytokine signaling 1 (SOCS-1) in monocytes/macrophages (MC), which participate in MyD88-independent signal transduction of toll-like receptors. Expression of costimulatory molecules such as CD40 in MC was analyzed by flow cytometry. Methylation-specific PCR was performed to analyze the methylation status of cytosine-phosphate-guanine (CpG) motif in SOCS-1 gene.

RESULTS(1) Compared with healthy controls, transcription levels of the molecules such as TLR4, TRIF, TRAM, TBK-1 and IFN-beta, were significantly up-regulated during acute phase of KD (P < 0.05), and down-regulated after treatment with intravenous immunoglobulin therapy. (2) Expression of iNOS and chemokines such as IP10 and RANTES in MC during acute phase of KD was remarkably elevated (P < 0.05), and down-regulated to some extents after treatment with intravenous immunoglobulin therapy. (3) Expression of costimulatory molecule CD40 in MC increased significantly during acute phase of KD [(6.19 +/- 2.25)% vs. (2.00 +/- 1.37)%, P < 0.05], while the protein levels of CD40 in KD-coronary artery lesion (CAL)(+) group was found to be significantly higher than that of KD-CAL-group [KD-CAL, (9.63 +/- 2.96)% vs. (4.12 +/- 1.91)%, P < 0.05]. (4) Expression levels of SOCS-1 mRNA were significantly up-regulated during acute phase of KD [(4.31 +/- 0.83) x 10(-3) vs. (1.09 +/- 0.23) x 10(-3), P < 0.05], and the levels of SOCS-1 gene in KD-CAL(+) group was found to be significantly lower than that of KD-CAL(-) group [(5.73 +/- 1.04) x 10(-3) vs (1.94 +/- 0.46) x 10(-3), P < 0.05]. (5) The CpG island of SOCS-1 DNA in KD patients was remarkably demethylated [(26.9 +/- 8.6)% vs (5.9 +/- 1.4)%, P < 0.05], and demethylation levels of SOCS-1 in KD-CAL(-) group were higher than that in KD-CAL+ group [(35.1 +/- 10.3)% vs. (13.2 +/- 3.7)%, P < 0.05].

CONCLUSIONAberrant activation of MyD88-independent pathways of Toll-like receptor 4 may be one of the factors causing disturbed immunological function in KD.

Child ; Humans ; Interleukin-1 ; metabolism ; Macrophages ; drug effects ; pathology ; Nitric Oxide Synthase Type II ; metabolism ; Pyrimidinones ; pharmacology ; Signal Transduction ; drug effects ; physiology ; Thiazoles ; pharmacology ; Toll-Like Receptor 4 ; metabolism ; Toll-Like Receptors ; deficiency ; drug effects ; metabolism

The severe acute respiratory syndrome (SARS) pandemic caught the world by surprise in 2003 and spread rapidly within a relatively short period of time. Hence, randomised placebo-controlled clinical trials on the treatment of SARS were not possible. Our understanding was obtained from observational, cohort studies, case series and reports. Nevertheless, such information is useful in providing clinical management guidelines and directing future research in case SARS recurs. Early in the pandemic, a combination of ribavirin and corticosteroids was adopted as the standard treatment in Hong Kong, Canada and elsewhere because of the apparent good results of the first few patients. Subsequent reports showed that ribavirin was associated with a high rate of toxicity and lacked in vitro antiviral effect on SARS-coronavirus (SAR-CoV). The timing and dosage regimens of steroid in the treatment of SARS are controversial. Pulse methylprednisolone 250 to 500 mg/day for 3 to 6 days has been reported to have some efficacy in a subset of patients with "critical SARS", i.e., critically ill SARS patients with deteriorating radiographic consolidation, increasing oxygen requirement with PaO2 <10 kPa or SpO2 <90% on air, and respiratory distress (rate of 30/min). Prolonged therapy with high-dose steroids, in the absence of an effective antimicrobial agent, could predispose patients to complications such as disseminated fungal infection, and avascular necrosis. Kaletra (400 mg ritonavir and 100 mg lopinavir), a protease inhibitor used in the treatment of human immunodeficiency virus infection, may be considered for early treatment of SARS patients, preferably in a randomised double-blind placebo-controlled clinical trial setting. Interferon (IFN) is not recommended as standard therapy in SARS. However, there are enough data on in vitro activity of IFN preparations and a few clinical studies for these products to support a controlled trial if SARS recurs. Many other experimental treatments have been tried in an uncontrolled manner, and they should not be recommended as standard therapy.
Adrenal Cortex Hormones ; pharmacology ; therapeutic use ; Antiviral Agents ; pharmacology ; therapeutic use ; Clinical Competence ; Disease Outbreaks ; prevention & control ; Global Health ; Humans ; Immunoglobulins ; pharmacology ; therapeutic use ; Immunologic Factors ; pharmacology ; therapeutic use ; Interferons ; pharmacology ; therapeutic use ; Lopinavir ; Practice Guidelines as Topic ; Protease Inhibitors ; pharmacology ; therapeutic use ; Pyrimidinones ; pharmacology ; therapeutic use ; Ribavirin ; pharmacology ; therapeutic use ; SARS Virus ; drug effects ; Severe Acute Respiratory Syndrome ; drug therapy ; epidemiology

OBJECTIVETo study the therapeutic efficacy of 48-week telbivudine treatment on cirrhosis resulting from chronic hepatitis B.

METHODS80 patients were equally divided into two groups, and treated with telbivudine 600 mg or lamivudine 100mg once daily for 48 weeks, respectively. The changes of virological and biochemical markers, PTA, Child-Pugh score, and viral resistance were observed at the different time points after antiviral treatment.

RESULTSThe mean of serum HBV DNA level in telbivudine group before treatment was (6.52+/-1.33) log10 copies/ml, and the mean reduction of serum HBV DNA was (2.09+/-1.30), (2.83+/-1.22), (3.23+/-1.27), (3.42+/-1.32), (3.65+/-1.30), (3.67+/-1.43) log10 copies/ml at 2, 4, 8, 12, 24, 48 weeks, respectively. The proportion of patients with serum HBV DNA undetectable was 92.5% (37/40) at 24, 48 weeks. At week 24 and 48, the rates of HBeAg/anti-HBe seroconversion were 30.0% (6/20), 35.0% (7/20), respectively. ALT, AST, albumin, total bilirubin, PTA, and Child-Pugh score were improved (P less than 0.05). Mutation of YMDD observed in telbivudine group was 5.0%. The mean reduction of serum HBV-DNA and the proportion of patients with undetectable serum HBV-DNA were greater in telbivudine group than in lamivudine group (P less than 0.05).

CONCLUSIONSTelbivudine can rapidly and effectively inhibit the replication of HBV in patients with cirrhosis resulting from chronic hepatitis B, and the resistance mutation rate was low. In addition, telbivudine treatment can improve the liver function.

Adult ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Drug Resistance, Viral ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; drug effects ; immunology ; Hepatitis B, Chronic ; complications ; drug therapy ; Humans ; Lamivudine ; pharmacology ; therapeutic use ; Liver Cirrhosis ; drug therapy ; etiology ; Male ; Middle Aged ; Nucleosides ; pharmacology ; therapeutic use ; Pyrimidinones ; pharmacology ; therapeutic use ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Virus Replication ; drug effects

It was recently shown that several new synthetic 2-alkylsulfanyl-6-benzyl-3, 4-dihydropyrimidin-4(3H)-one (S-DABO) derivatives demonstrated anti-HIV-1 activity. Three of the derivatives namely RZK-4, RZK-5 and RZK-6 were used in this study to explore their inhibitory effects on a variety of HIV strains. These compounds at a concentration of 200 microg mL(-1) almost completely inhibited the activity of recombinant HIV-1 reverse transcriptase. All of the three compounds reduced replication of HIV-1 laboratory-derived strains, low-passage clinical isolated strain, and the drug resistant strain. In particular RZK-6 showed potent activity against the HIV-1 drug resistant strain. In general, the antiviral activities are similar in magnitude to nevirapine (NVP), which is a non-nucleoside reverse transcriptase inhibitor approved by FDA. The therapeutic indexes of these compounds were remarkable, ranging from 3704 to 38462 indicating extremely low cytotoxicity. These results suggest that the three S-DABO derivatives in this study have good potential for further development in anti-HIV-1 therapy. It may be particularly useful to target at the non-nucleoside reverse transcriptase inhibitors resistant HIV-1 strain.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; Benzyl Compounds ; chemical synthesis ; chemistry ; pharmacology ; Cell Line ; Drug Resistance, Viral ; HIV Reverse Transcriptase ; antagonists & inhibitors ; metabolism ; HIV-1 ; drug effects ; Humans ; Pyrimidinones ; chemical synthesis ; chemistry ; pharmacology ; Reverse Transcriptase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Virus Replication ; drug effects

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Drug Resistance, Viral ; Guanine ; analogs & derivatives ; pharmacology ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; drug effects ; Hepatitis B, Chronic ; blood ; drug therapy ; virology ; Humans ; Lamivudine ; pharmacology ; therapeutic use ; Nucleosides ; pharmacology ; therapeutic use ; Organophosphonates ; pharmacology ; therapeutic use ; Pyrimidinones ; pharmacology ; therapeutic use ; Reverse Transcriptase Inhibitors ; pharmacology ; therapeutic use ; Tenofovir ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Virus Replication

OBJECTIVETo investigate the efficacy of telbivudine on intrauterine hepatitis B virus (HBV) infection during the last stage of pregnancy.

METHODS61 pregnant chronic hepatitis B (CHB) patients were enrolled and 31 patients were treated by telbivudine 600 mg once daily, 30 patients in the control group were not received antiviral treatment. Maternal HBV DNA level and the HBsAg positive rate in newborns were investigated.

RESULTSThe levels of serum HBV DNA in patients treated with Telbivudine were significantly reduced (t = 19.09, P less than 0.01). Compared with the control group, serum HBV DNA levels were significantly lower in telbivudine treated patients than those in the control group before parturition (t = 23.64, P less than 0.01). The infection rate of 7-month newborns were 0 and 13.33% (4/30), in telbivudine group and control group, respectively (x2 = 4.29, probability value less than 0.05).

CONCLUSIONSTelbivudine treatment can block intrauterine infection in pregnant chronic hepatitis B patients.

Administration, Oral ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Female ; Hepatitis B Surface Antigens ; blood ; Hepatitis B virus ; drug effects ; Hepatitis B, Chronic ; drug therapy ; transmission ; virology ; Humans ; Infant ; Infant, Newborn ; Infectious Disease Transmission, Vertical ; prevention & control ; Nucleosides ; pharmacology ; therapeutic use ; Pregnancy ; Pregnancy Complications, Infectious ; drug therapy ; virology ; Pyrimidinones ; pharmacology ; therapeutic use ; Thymidine ; analogs & derivatives ; Treatment Outcome

OBJECTIVETo investigate the expression of serine protease Omi/HtrA2 in kidneys of postasphyxial neonatal rats, and to study the effects of Ucf-101 on apoptosis and the expression of Omi/HtrA2 in these rats.

METHODSSeventy-two neonatal Wistar rats of 7-10 days old were randomly divided into 3 groups: control, postasphyxial model, Ucf-101-treated postasphyxialThe postasphyxial model was established by normobaric asphyxiaExpression of Omi/HtrA2 was determined with streptavidin-peroxidase immunohistochemistry 2, 24 and 48 hrs after asphyxia. Terminal deoxynuleotidyl-mediated nick end labeling (TUNEL) was used to ascertain the apoptosis of renal cells.

RESULTSCompared with the control group, OmiHtrA2 expression in renal cells began to increase 2 hrs after asphyxia and peaked at 24 hrs. The expression of Omi/HtrA2 in the Ucf-101-treated postasphyxial group was significantly lower than that in the postasphyxial model group (P<0.01). TUNEL-positive cells began to increase 2 hrs after asphyxia and peaked at 24 hrs in the postasphyxial model group when compared with the control group. The number of TUNEL-positive cells in the Ucf-101-treated postasphyxial group was significantly lower than that in the postasphyxial model group at all time points (P<0.01).

CONCLUSIONSThe expression of Omi/HtrA2 in kidneys is increased in postasphyxial neonatal rats. The increased Omi/HtrA2 expression may play an important role in the development of postasphyxial renal injury. Treatment with Ucf-101 can reduce the expression of Omi/HtrA2 in kidneys of postasphyxial neonatal rats and thus reduce renal tububar epithelial cell apoptosis.

Animals ; Animals, Newborn ; Apoptosis ; drug effects ; Asphyxia Neonatorum ; drug therapy ; metabolism ; pathology ; Female ; High-Temperature Requirement A Serine Peptidase 2 ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Infant, Newborn ; Kidney ; chemistry ; Male ; Mitochondrial Proteins ; analysis ; antagonists & inhibitors ; Pyrimidinones ; pharmacology ; therapeutic use ; Rats ; Rats, Wistar ; Serine Endopeptidases ; analysis ; Thiones ; pharmacology ; therapeutic use