Investigation of TLR2 (-196 to -174del) and TLR9 (T-1486C) Gene Polymorphisms Association with Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) are diseases that result from the combined effects of a predisposing genetic background and several environmental factors, including smoking. Some genes can influence these diseases through genetic inheritance, and their regulation is explained by gene polymorphism. However, Toll-like receptor (TLR) genes have been identified as susceptibility genes for CD and UC. METHODS: A case-control study was performed on a Turkish population composed of 105 healthy controls and  79 CD, 77 UC patients genotyped by Allele-specific PCR and PCR-RFLP for TLR9 (T-1486C) and TLR 2 (-196 to -174del) gene. Genotype and allele frequencies of TLR9 (T-1486C) and TLR 2 (-196 to -174del) gene polymorphisms compared to allele frequencies in CD and UC patients. RESULTS: No statistically significant findings were found between the CD, UC patients, and the control group in terms of both genotype distributions and allele frequencies for TLR 9 (T-1486C; rs187084) and TLR 2 (-196 to -174del; rs111200466) gene polymorphisms in a Turkish population (P > 0.05). CONCLUSION: No association was found between the TLR2 (rs111200466) and TLR 9 (rs187084) gene polymorphisms among IBD patients and the control groups in the Turkish population.

A successful repair of esophageal atresia (EA) with distal tracheoesophageal fistula (TEF) to a 6-day-old child in a low-resource setting. Case report.

INTRODUCTION: Congenital tracheoesophageal fistula (TEF) is a rare and life-threatening anomaly that requires prompt surgical intervention. The case report highlights a successful TEF repair in setting with significant observed cases and low survival rate. CASE PRESENTATION: We present a Type C Tracheoesophageal fistula successfully repaired by a conventional Open Surgical approach. An infant of 3 days born at term with Birth weight of 3 kg, presenting with postprandial regurgitation, choking and abdominal distension followed by early features of pneumonia. Initial chest X-ray with nasogastric (NS) tube catheter revealed features of esophageal atresia (EA) with distal TEF. An echocardiogram (ECHO) was performed, which revealed moderate patent ductus arteriosus (PDA) and small left to right shunt. A successful delayed primary repair was performed on the sixth day of life in the division of pediatric surgery center. CONCLUSION: The successful outcome in this case serves as a testament to the dedication and resourcefulness of the healthcare team. It underscores the importance of high suspicious index, collaboration, adaptability, and skill in providing quality care in low-resource settings, reaffirming the possibility of saving lives even in challenging circumstances.

Varietal susceptibility of certain broad bean seeds to infestation with Callosobruchus maculatus (F.) and Callosobruchus chinensis (L.) (Coleoptera: Bruchidae).

Seeds susceptibility of eight broad bean varieties to Callosobruchus maculatus (F.) and Callosobruchus chinensis (L.) infestation were studied for the first time in free- and no-choice methods in the laboratory of Plant Protection Department, Faculty of Agriculture, Zagazig University. The relation between certain seed physical characteristics and some biological and and infestation parameters of both insects in the two studied methods were evaluated. None of these varieties were resistant to both insects, showing various levels of susceptibility. Biological and infestation parameters were significantly different among varieties except the developmental period. In free- choice method, Giza 3 was the most susceptible variety to both insects, since produced the highest progeny of 246.67 and 75.67 adults and susceptibility index (SI) of 10.25 and 7.42, respectively, while the least susceptible variety was Giza 716. In no- choice method, Nubaria 5 and Sakha 1 were the most susceptible varieties to C. chinensis, while Nubaria 3 and Giza 3 to C. maculatus. Differences between physical characters of varieties were significant. Seed hardness were correlated negatively and seed coat thickness positively with laid eggs, progeny and (SI) of both insects in free-choice method. Also seed coat thickness correlated positively with weight loss and seed damage (%) of C. chinensis and negatively of C. maculatus. To reduce seed losses the cultivation of the least susceptible variety (Giza 716) is encouraged and considered for breeding purposes to avoid insecticide usage.

The Effect of Intraoperative Transesophageal Echocardiography Probe Placement on the Endotracheal Tube Cuff Pressure in Adult Patients Undergoing On-Pump Cardiac Surgery.

OBJECTIVES: The study was directed toward documentation of the effect of transesophageal echocardiography (TEE) probe insertion on the endotracheal tube cuff pressure (CP) in adult patients undergoing on-pump coronary bypass surgery. The primary objective of this study was to assess whether CP reaches supranormal pressures during the different stages of intraoperative TEE examination. The secondary objective was to observe the effect of TEE probe placement on the ventilation parameters. DESIGN: A prospective observational study. SETTING: At a tertiary care cardiac center. PARTICIPANTS: Thirty-four cardiac surgical patients older than 18 years of age who required intraoperative TEE examination. INTERVENTIONS: TEE probe insertion. MEASUREMENTS AND MAIN RESULTS: Following the induction of general anesthesia and tracheal intubation, a TEE probe was introduced. The endotracheal tube CP was recorded at 5 time zones: Before TEE probe insertion, during the insertion of the probe, during probe manipulation, probe in the transgastric position, and during removal of the probe. A nonparametric test was used for comparing intracuff pressure between pairs of time zones. There was a statistically significant difference in CP values between the baseline and those during different time zones (chi-square test = 134.77, degrees of freedom = 4, p = 0.001). There was a statistically significant difference in the peak pressure between different time points compared to baseline (p = 0.0001). CONCLUSIONS: TEE probe placement in patients with tracheal intubation may be associated with a significant increase in CP well above the baseline pressure. With the possibility of the mean arterial pressures during cardiopulmonary bypass being substantially lower than expected, the findings of the current study raised the concern of predisposing the tracheal mucosa to hypoperfusion, with subsequent temporary or permanent tracheal damage. Hence, at least a baseline estimation of the endotracheal tube CP at the time of tracheal intubation, with the help of a pressure gauge in the operating room, may be considered as a safe practice.

Impact of target site mutations and plasmid associated resistance genes acquisition on resistance of Acinetobacter baumannii to fluoroquinolones.

Among bacterial species implicated in hospital-acquired infections are the emerging Pan-Drug Resistant (PDR) and Extensively Drug-Resistant (XDR) Acinetobacter (A.) baumannii strains as they are difficult to eradicate. From 1600 clinical specimens, only 100 A. baumannii isolates could be recovered. A high prevalence of ≥ 78% resistant isolates was recorded for the recovered isolates against a total of 19 tested antimicrobial agents. These isolates could be divided into 12 profiles according to the number of antimicrobial agents to which they were resistant. The isolates were assorted as XDR (68; 68%), Multi-Drug Resistant (MDR: 30; 30%), and PDR (2; 2%). Genotypically, the isolates showed three major clusters with similarities ranging from 10.5 to 97.8% as revealed by ERIC-PCR technique. As a resistance mechanism to fluoroquinolones (FQs), target site mutation analyses in gyrA and parC genes amplified from twelve selected A. baumannii isolates and subjected to sequencing showed 12 profiles. The selected isolates included two CIP-susceptible ones, these showed the wild-type profile of being have no mutations. For the ten selected CIP-resistant isolates, 9 of them (9/10; 90%) had 1 gyrA/1 parC mutations (Ser 81 → Leu mutation for gyrA gene and Ser 84 → Leu mutation for parC gene). The remaining CIP-resistant isolate (1/10; 10%) had 0 gyrA/1 parC mutation (Ser 84 → Leu mutation for parC gene). Detection of plasmid-associated resistance genes revealed that the 86 ciprofloxacin-resistant isolates carry qnrA (66.27%; 57/86), qnrS (70.93%; 61/86), aac (6')-Ib-cr (52.32%; 45/86), oqxA (73.25%; 63/86) and oqxB (39.53%; 34/86), while qepA and qnrB were undetected in these isolates. Different isolates were selected from profiles 1, 2, and 3 and qnrS, acc(6,)-ib-cr, oqxA, and oqxB genes harbored by these isolates were amplified and sequenced. The BLAST results revealed that the oqxA and oqxB sequences were not identified previously in A. baumannii but they were identified in Klebsiella aerogenes strain NCTC9793 and Klebsiella pneumoniae, respectively. On the other hand, the sequence of qnrS, and acc(6,)-ib-cr showed homology to those of A. baumannii. MDR, XDR, and PDR A. baumannii isolates are becoming prevalent in certain hospitals. Chromosomal mutations in the sequences of GyrA and ParC encoding genes and acquisition of PAFQR encoding genes (up to five genes per isolate) are demonstrated to be resistance mechanisms exhibited by fluoroquinolones resistant A. baumannii isolates. It is advisable to monitor the antimicrobial resistance profiles of pathogens causing nosocomial infections and properly apply and update antibiotic stewardship in hospitals and outpatients to control infectious diseases and prevent development of the microbial resistance to antimicrobial agents.

Two new anticancer phenolic derivatives from leaves of Piper betle Linn.

In this study, phytochemical analyses of the chloroform extract of Piper betle L. var. haldia and maghai, Piperaceae, leaves led to the isolation of two new phenolic derivatives: 1-n-decanoyl hydroxy-benzoic acid/1-n-decanoyl phenol (H2) and 3-butylphenol (M1) on the basis of spectroscopic data 1D NMR (1H, 13C) and 2D NMR (1H - 1H COSY, HMBC) as well as ESI-MS, FT-IR and HR-ESI-MS analyses. Compounds H2 and M1 showed excellent antioxidant DPPH free radical scavenging activity with IC50 values of 10.66 µ/mL and 13.65 µg/mL compared to ascorbic acid as a standard antioxidant with an IC50 value of 2.52 µg/mL. Evaluation of cytotoxic activity against two human oral cancer cell lines (SCC-40 and SCC-29B) showed significant effect with GI50 values of 24.08 and 33.08 µg/mL for compound H2 and 35.03 and 47.06 µg/mL for compound M1, compared to Doxorubicin® as a standard cytotoxic drug with GI50 value of < 10 µg/mL.

In Vitro Digestion of Grape Seed Oil Inhibits Phospholipid-Regulating Effects of Oxidized Lipids.

The intake of dietary lipids is known to affect the composition of phospholipids in gastrointestinal cells, thereby influencing passive lipid absorption. However, dietary lipids rich in polyunsaturated fatty acids, such as vegetable oils, are prone to oxidation. Studies investigating the phospholipid-regulating effect of oxidized lipids are lacking. We aimed at identifying the effects of oxidized lipids from moderately (18.8 ± 0.39 meq O2/kg oil) and highly (28.2 ± 0.39 meq O2/kg oil) oxidized and in vitro digested cold-pressed grape seed oils on phospholipids in human gastric tumor cells (HGT-1). The oils were analyzed for their antioxidant constituents as well as their oxidized triacylglycerol profile by LC-MS/MS before and after a simulated digestion. The HGT-1 cells were treated with polar oil fractions containing epoxidized and hydroperoxidized triacylglycerols for up to six hours. Oxidized triacylglycerols from grape seed oil were shown to decrease during the in vitro digestion up to 40% in moderately and highly oxidized oil. The incubation of HGT-1 cells with oxidized lipids from non-digested oils induced the formation of cellular phospholipids consisting of unsaturated fatty acids, such as phosphocholines PC (18:1/22:6), PC (18:2/0:0), phosphoserine PS (42:8) and phosphoinositol PI (20:4/0:0), by about 40%-60%, whereas the incubation with the in vitro digested oils did not affect the phospholipid metabolism. Hence, the gastric conditions inhibited the phospholipid-regulating effect of oxidized triacylglycerols (oxTAGs), with potential implications in lipid absorption.

Treatment outcome of Philadelphia chromosome negative myeloproliferative neoplasms: experience of a single developing country's hematology-oncology centre.

BACKGROUND: Myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are characterized by excessive production of blood cells. Treatment of MPNs patients has an important effect thereby reducing morbidity and mortality. OBJECTIVE: To evaluate the effect of cytoreductive treatment on some hematological and biochemical parameters in MPNs patients treated at a hemato-oncology Centre in Erbil, Iraq. METHODS: A total of 185 patients diagnosed with PV, ET, and PMF (111 males and 74 females with a mean age of 50.8±3.2 years, range: 46-73) were assigned to receive MPNs treatment. Laboratory tests were performed before and after a median period from the initiation of MPNs treatment of 9.3 months (range 5-10 months). RESULTS: Significant differences were noted in Hemoglobin (P<0.003), Hematocrit (P<0.004), Neutrophil (P<0.001) and glutamate pyruvate transferase levels (P<0.01) in PV patients, Platelet count (P<0.002) in ET patients, and both white blood cell count (P<0.004) and Lactate dehydrogenase level (P<0.001) in PMF patients, while no significant differences were found in other parameters at the time of diagnosis and during therapy. CONCLUSION: Clinical and laboratory improvements were presented in MPNs patients. Regular follow up of patients are essential to ensure prescribed treatment in addition to the continual and long-lasting response to therapy and to prevent thrombosis.

GATA 3, an immunohistochemical expression and clinicopathological correlation with breast tumors / 国际药学研究杂志

Background: GTAT 3 is a transcription marker for many tumors including breast tumors. Its play an important role in proliferation and differentiation of cell. Aim: The aim of the present study for assessment GATA 3 expression in Iraqi women with breast tumors and its association with histological grades and pathological stages. Materials and Methods: A retrospective study of 72 FFPET of breast tumors, 57/72 were primary breast malignant tumors (infiltrative ductal carcinoma IDC and infiltrative lobular carcinoma ILC), and 15/72 were benign breast tumors. Results: The nuclear staining of (1% or more) of tumor cells was considered positive expression for GATA 3 (cut off value 1%), 47 of 57 (82.5%) of malignant tumors were positive expression of GATA 3, while 3 of 15 (20.0%) of benign tumors were negative expression, (P 0.05). Conclusion: GATA 3 is a specific markers for breast carcinoma and its can be used for diagnosis of the malignant from benign tumors and it's considered a good prognosis marker for breast cancer.

Chemical composition of essential oil of Thymus vulgaris collected from Saudi Arabian market

Objective: To focus on the analysis of chemical constituents of the Thymus vulgaris L. (locally known as Zaitra or Za'atar; Family: Lamiaceae) which is available in the market of Saudi Arabia. Methods: The Zaitra oil was analyzed by gas chromatography-mass spectrometry. The mass spectra were compared with the standard spectra available in National Institute Standard and Technique library. Results: The results indicated that the Thymus oil is composed of many chemical compounds including a pinene, thymol and caryophyllene which are biologically active and also used in various diseases. Conclusions: It can be concluded that the Thymus vulgaris due to presence of many bioactive compounds can be used as a new potential source of medicine for the treatment of various types of illness.

Synthesis of some benzimidazole derivatives endowed with 1,2,3-triazole as potential inhibitors of hepatitis C virus.

New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent.

The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure-activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement of the amino group. The ligand conformation, binding mode studies and drug like properties were major determinant for selection of molecules for final synthesis. The replacement of amino group with methyl restored the interactions with RNA-template (Tem 799) through bifurcated weak H-bond (C-H...O). This is an interesting finding observed from molecular modeling studies. It was found that 6c-e has anti-HCV activity (EC(50) in 37-46 µM) while 6a, 6b and 6g were inactive. The compound 6f (EC(50) 28 µM) was the most active among the series however it also showed some cytotoxicity (CC(50) 52.8 µM). Except 6f, none of the compounds were found to be cytotoxic (CC(50)>100 µM). The present study discloses structure-based approach for novel anti-HCV lead discovery and opens a future scope of lead optimization.

Potent and selective inhibition of hepatitis C virus replication by novel phenanthridinone derivatives.

A number of novel phenanthridinone derivatives were examined for their inhibitory effect on hepatitis C virus (HCV) replication in Huh-7 cells harboring self-replicating subgenomic viral RNA replicons with a luciferase reporter (LucNeo#2). The activity of compounds was further confirmed by inhibition of viral RNA copy number in different subgenomic and full-genomic replicon cells using real-time reverse transcription polymerase chain reaction. Among the compounds, 4-butyl-11-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-7-methoxy-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-719) was found to be the most active with a 50% effective concentration of 0.063 ± 0.010 µM in LucNeo#2 cells. The compound did not show apparent cytotoxicity to the host cells at concentrations up to 40 µM. Western blot analysis demonstrated that HA-719 reduced the levels of NS3 and NS5A proteins in a dose-dependent fashion in the replicon cells. Interestingly, the phenanthridinone derivatives including HA-719 were less potent inhibitors of JFH1 strain (genobtype 2a HCV) in cell-free virus infection assay. Although biochemical assays revealed that HA-719 proved not to inhibit NS3 protease or NS5B RNA polymerase activity at the concentrations capable of inhibiting viral replication, their molecular target (mechanism of inhibition) remains unknown. Considering the fact that most of the anti-HCV agents currently approved or under clinical trials are protease and polymerase inhibitors, the phenanthridinone derivatives are worth pursuing for their mechanism of action and potential as novel anti-HCV agents.

Fused heterocyclic amido compounds as anti-hepatitis C virus agents.

We identified a fused heteroaromatic amido structure based on the phenanthridine skeleton as a superior scaffold for candidate drugs with potent anti-HCV activity. Among the compounds synthesized, a phenanthridine analogue with a 1,3-dioxolyl group (24) possessed the most potent anti-HCV activity (EC(50) value: 50 nM), with acceptable cytotoxicity. The structural development and structure-activity relationships of these compounds are described.

Evaluation of the power arm in bringing about bodily movement using finite element analysis.

AIM: To evaluate the effectiveness of the power arm in bringing about bodily movement and to determine the ideal length and location of the power arm. METHODS: A geometric model of the maxillary right canine was constructed and subsequently converted to a finite element model. Material property data were represented, boundary conditions were defined, and force was applied. Different situations were simulated in which a power arm of varying vertical lengths were attached at different locations on the tooth--namely, the incisal, middle, and cervical thirds. RESULTS: The amount of bodily movement is maximum when the force is delivered directly at the cervical third. It decreases at the middle third and is least when attached at incisal third. The varying lengths of the power arm for a particular site of attachment does not bring about any change in the movement. CONCLUSION: The attachment of the power arm at the cervical third brought about maximum bodily movement, followed by the middle and incisal thirds. Variations in length of the power arm at different sites of attachment did not bring any change in the outcome. Thus, the point of attachment is critical in bringing about bodily movement.

Highly potent and selective inhibition of bovine viral diarrhea virus replication by γ-carboline derivatives.

Several novel γ-carboline derivatives were identified as selective inhibitors of bovine viral diarrhea virus (BVDV) replication in cell cultures. Among them, 3,4,5-trimethyl-γ-carboline (SK3M4M5M) was the most active against BVDV (Nose strain) in MDBK cells, with a 50% effective concentration of 0.017±0.005µM and a selectivity index of 435. The compound inhibited viral RNA synthesis in a dose-dependent fashion. In a time of drug-addition experiment during a single viral replication cycle, SK3M4M5M lost its antiviral activity when first added at 8h or later after infection, which coincides with the onset of viral RNA synthesis. When selected γ-carboline derivatives, including SK3M4M5M, were examined for their inhibitory effect on the mutant strains resistant to some classes of nonnucleoside BVDV RNA-dependent RNA polymerase inhibitors, all of which target the top of the finger domain of the polymerase, the strains displayed cross-resistance to the γ-carboline derivatives. These results indicate that the γ-carboline derivatives may possibly target a hot spot of the RNA-dependent RNA polymerase. Although SK3M4M5M was highly active against BVDV, the compound proved inactive against hepatitis C virus (HCV) in HCV RNA replicon cells.

Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum malaria: a phase II, multicenter, randomized, dose-finding clinical trial.

BACKGROUND: Drug-resistant Plasmodium falciparum malaria necessitates development of novel drugs for treatment.The present study assessed the efficacy and safety of 3 dose levels of arterolane (RBx 11160), a synthetic trioxolane, for treatment of acute uncomplicated falciparum malaria. METHODS: In this randomized, double-blind, multicenter, parallel-group, dose-finding, phase II trial, 230 patients from 4 centers in Thailand, India, and Tanzania (mainland and Zanzibar) received either 50 mg (n=78), 100mg (n=76), or 200 mg (n=76) of arterolane once daily for 7 days. Patients (aged 13-65 years) with asexual parasite density of 1000-100,000 parasites/microL were included and were followed up for 28 days. The median time to 90% parasite clearance (PC90) was evaluated. RESULTS: The median PC90 was longer in the group receiving the 50-mg dose (19.4 h), compared with the groups receiving the 100-mg dose (12.8 h) and 200-mg dose (12.6 h) (P < .01). The polymerase chain reaction-corrected adequate clinical and parasitological responses on day 28 were 63%, 71%, and 72% for the groups receiving the 50-mg, 100-mg, and 200-mg doses, respectively, by intention-to-treat analysis (odds ratio, 1.55; 95%confidence interval, 0.78-3.06, for comparison of the 200-mg and 50-mg dose groups). Treatment was generally well tolerated. No patient died or experienced any serious adverse event. Mild complaints were reported in <10%of the patients and were similar in the 3 groups. Biochemistry and hematological analyses did not show any signof drug toxicity in any patient. CONCLUSION: Arterolane at daily doses of 100 and 200 mg is a rapidly acting, effective, and safe synthetic antimalarial drug, which may potentially represent an alternative to artemisinin derivatives in antimalarial combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00362050.

Anti-bovine viral diarrhoea virus activity of novel diphenylmethane derivatives.

BACKGROUND: A number of compounds were examined for their inhibitory effects on bovine viral diarrhoea virus (BVDV), a surrogate model of hepatitis C virus, in cell cultures. Among them, some diphenylmethane derivatives were found to be selective inhibitors of BVDV. METHODS: Determination of compounds for their anti-BVDV activity was based on the inhibition of virus-induced cytopathic effect in Madin-Darby bovine kidney cells and reduction of infectious virus particles in culture supernatants. To gain insight into the mechanism of action, the inhibition of viral entry and RNA synthesis in the host cells was also determined by real-time reverse transcription-PCR. RESULTS: Among the test compounds, four diphenylmethane derivatives significantly inhibited BVDV replication with a 50% effective concentration ranging between 6.3 and 10.8 muM. They were not cytotoxic at concentrations up to 100 muM. The representative compound, SH-595A, reduced the virus titre of culture supernatants in a dose-dependent manner. In addition, the compound appeared to somewhat affect viral entry to the host cells. Although SH-595A was inhibitory to viral RNA synthesis, the inhibition was achieved only at high concentrations and was not comparable to its antiviral activity. CONCLUSIONS: The novel diphenylmethane derivatives are effective against BVDV replication and might have a unique mechanism of action.

Structural development studies of anti-hepatitis C virus agents with a phenanthridinone skeleton.

A phenanthridinone skeleton was derived from our previous researches on thalidomide and retinoids as a multi-template for generation of anti-viral lead compounds. Structural development studies focusing on anti-hepatitis C virus activity afforded 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenanthridin-6(5H)-one (10) and 5-butylbenzo[b]phenanthridin-6(5H)-one (39), which showed EC(50) values of approximately 3.7 and 3.2microM, respectively.

Anti-bovine viral diarrhoea virus and hepatitis C virus activity of the cyclooxygenase inhibitor SC-560.

BACKGROUND: A number of compounds were examined for their inhibitory effect on bovine viral diarrhoea virus (BVDV) replication in cell cultures and found that some cyclooxygenase (COX) inhibitors had antiviral activity against the virus. METHODS: Determination of compounds for their anti-BVDV activity was on the basis of the inhibition of virus-induced cytopathogenicity in Mardin-Darby bovine kidney (MDBK) cells. Anti-hepatitis C virus (HCV) activity was assessed by the inhibition of viral RNA synthesis in the subgenomic HCV RNA replicon cells. RESULTS: Among the test compounds, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) was the most active against BVDV, and its 50% effective and cytotoxic concentrations were 10.9 +/-2.8 and 93.9 +/-24.5 microM in virus and mock-infected MDBK cells, respectively. The compound also suppressed BVDV RNA synthesis in a dose-dependent fashion. Studies on the mechanism of action revealed that SC-560 did not interfere with viral entry to the host cells. Furthermore, it was assumed that the antiviral activity of SC-560 was not associated with its inhibitory effect on COX. The combination of SC-560 and interferon-alpha was additive to synergistic in inhibiting BVDV replication. More importantly, the compound proved to be a selective inhibitor of HCV replication. CONCLUSIONS: SC-560 and its derivative might have potential as novel antiviral agents against HCV.