Effects of chewing tobacco on corneal endothelium in patients with diabetes mellitus.

OBJECTIVE: To determine the impact of tobacco chewing on corneal endothelial structure in patients with diabetes mellitus (DM). METHODS: Corneal endothelial parameters (endothelial cell count, ECD; coefficient of variation, CV; hexagonality, Hex, and central corneal thickness, CCT) were analysed in 1234 eyes of 1234 patients using non-contact specular microscopy (EM 4000 Tomey Nishi-Ku, Nagoya, Aichi, Japan). The study group (with a present history of tobacco chewing) comprising of 948 subjects, with 473 having DM was compared with age and gender-matched control group comprising of 286 subjects (139 having DM) with no history of tobacco use in any form. RESULTS: Tobacco chewers had a significantly reduced ECD (P = 0.024) and Hex (P = 0.009) as compared with non-chewers. Similar results were noted in ECD (P = 0.004) and Hex (P = 0.005) in patients with DM. Tobacco chewers had a significantly decreased ECD values among males, HbA1C ≤ 7.5% and duration of DM ≤ 20 years, and significantly decreased Hex among those with >50 years of age, females, and duration of DM > 20 years. The CV and CCT values were comparable between the study and the control groups. Tobacco chewers showed a significant association of ECD with age, HbA1C, and duration of DM; CV with HbA1C; Hex with age and duration of DM; and CCT with gender, age, HbA1C and duration of DM. CONCLUSIONS: Tobacco chewing may negatively impact corneal health, especially confounded by additional factors like age and DM. These factors must be accounted for in the pre-operative evaluation of such patients prior to any intra-ocular surgery.

Association of anthropometric parameters as a risk factor for development of diabetic retinopathy in patients with diabetes mellitus.

OBJECTIVE: To study the relationship of body fat distribution in patients with diabetes mellitus (DM), and its long-term complications like diabetic retinopathy (DR), in Indian population. METHODS: This was a prospective, cross-sectional observational study involving 1773 subjects diagnosed with DM and 1778 age and gender-matched individuals. The patients with DM were assessed for the presence and severity of DR. Severe non-proliferative DR and proliferative DR were categorised as sight threatening DR (STDR). Anthropometric parameters, i.e., neck circumference (NC); mid-upper arm circumference (MAC); waist circumference (WC); hip circumference (HC); mid-thigh circumference (MTC) and body mass index (BMI) were measured using standardised technique. RESULTS: The mean age was 59.33 ± 9.32 for DM group, and 66.03 ± 11.04 for non-DM group. DM group showed significantly greater NC, WC, and MTC and significantly reduced MAC and weight. HC and BMI were comparable between the groups. There was a significant positive correlation of MAC and WC (with any level of DR) and MAC, WC, and weight (for STDR); and a significant negative correlation of HC and MTC (with any level of DR) and NC, HC, MTC, and BMI (for STDR). Multiple logistic regression analysis confirmed that WC was the single most important predictor for any level of DR and STDR. CONCLUSIONS: Association of body fat distribution with DM and DR appears multifactorial. However, central obesity signified by waist circumference appears to be the significant risk related to the development of DR and STDR in Indian population.

Conjunctival Autograft versus Combined Amniotic Membrane and Mini-Simple Limbal Epithelial Transplant for Primary Pterygium Excision.

PURPOSE: To compare outcomes of conjunctival autograft (CAG) and combined amniotic membrane with mini-simple limbal epithelial transplant (mini-SLET) after primary pterygium excision. METHODS: All consenting adults with primary pterygium were included in this study. After pterygium excision, patients were randomized to receive either CAG or mini-SLET and both grafts were held in place with fibrin glue. The patients were followed-up at days 1, 3, 7, 14, and 30 and subsequently at the third, sixth, and ninth months. The recurrence rate was considered as the primary outcome measure whereas the operating time, postoperative symptoms, and surgical complications were considered the secondary outcome measures. RESULTS: The study comprised of 264 eyes of 264 patients, of which 233 (88%) completed the nine months of follow-up. Of these, 118 (51%) received CAG and 115 (49%) received mini-SLET. The groups were comparable at baseline. Recurrence of pterygium was seen in two (1.6%) eyes in the CAG group and three (2.6%) eyes in the mini-SLET group (P = 0.68). Operative time for mini-SLET (20.33 ± 1.28 min) was significantly higher than that for CAG (12.01 ± 1.26 min) (P < 0.001). Graft displacement was observed in one case in group II (P = 0.999). The Lim Bon Siong (foreign body sensation, lacrimation, pain, and irritation) score in the CAG group was statistically significant for all four symptoms at days 1 and 3; however, at day 7, foreign body sensation, pain, and irritation scores were significantly higher for the CAG group. CONCLUSION: In this study, the overall recurrence rate was very low and comparable between mini-SLET and the established technique of CAG after performing the primary pterygium excision. Despite a longer surgical time, mini-SLET appears to be a viable option for the management of primary pterygium.

Association of severity of diabetic retinopathy with corneal endothelial and thickness changes in patients with diabetes mellitus.

OBJECTIVE: To analyse the central corneal thickness, endothelial cell density and morphology in patients with diabetes mellitus (DM). METHODS: We analysed corneal endothelium, i.e. central corneal thickness (CCT), endothelial cell density (ECD), coefficient of variation in cell size (CV), and hexagonality (Hex) with specular microscopy in patients with type 2 DM and compared with age-matched controls. The influence of diabetic retinopathy (DR) severity, duration of DM, and level of glycosylated haemoglobin (HbA1c) was also analysed. RESULTS: The study cohort included 592 eyes of 592 diabetic patients and 596 eyes of 596 control subjects. A significant difference was found in CCT (522.1 ± 36.6 µm in DM, 514.9 ± 37.1 µm in controls; P = 0.001), ECD (2484.5 ± 299.5 cells/mm2 in DM, 2555.9 ± 258.2 cells/mm2 in controls; P = 0.017), CV (40.3 ± 6.1 in DM, 37.2 ± 6.1 in controls; P < 0.001) and Hex (39.9 ± 5.2 in DM, 44.6 ± 6.0 in controls; P < 0.001). The longer duration of DM ( > 10 years) and poor glycaemic control (HbA1c > 7.5%) were associated with similar results. A significantly reduced ECD (P < 0.001) and Hex (P = 0.001) and higher CV (P = 0.007) and CCT (P = 0.01) was noted when assessed against various stages of DR. Multivariate analysis showed that increasing age was significantly associated with lower ECD (P < 0.001), Hex (P < 0.001), and CCT (P = 0.004); and a higher CV (P < 0.001). CONCLUSIONS: DM has deleterious effects on corneal endothelium and thickness. The presence of DR may further warrant a thorough corneal evaluation, especially when planning intraocular surgery.

Health economic burden of patients with phenylketonuria (PKU) - A retrospective study of German health insurance claims data.

This retrospective matched-cohort analysis compared health-economic burdens of adults (≥18 years; n = 377) with phenylketonuria (PKU) and age/gender-matched non-PKU controls (n = 3770) in Germany. Healthcare costs and resource-utilization were analyzed for the year 2015. Differences between groups were tested using 95% CI of mean differences (MD). PKU patients had significantly higher mean costs in total (MD €3307, 95% CI €1736-€4879), for pharmaceuticals (MD €1912, 95% CI €1195-€2629) [including dietary amino-acid supplements (MD €1268, 95% CI €864-€1672)], and outpatient costs (MD €395, 95% CI €115-€675). Inpatient costs (MD €904, 95% CI -€293 to €2100) and costs for aids and remedies (MD €97, 95% CI -€10 to €203) were also higher in PKU patients. PKU patients had more outpatient visits and stayed longer in hospital. Adult PKU patients incur higher total healthcare costs than non-PKU controls, especially regarding pharmaceuticals and outpatient costs, and more frequent resource-utilization, resulting in higher health-economic burden for the statutory healthcare system.

Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin.

Modified carbocyclic nucleosides (4a-g) constituting 7-deazapurine, 4'-methyl, exocyclic double bond and 2',3'-hydroxy were synthesized. NOE and X-ray studies of 4c confirmed the α-configuration of 4'-methyl. The anti-HBV assay demonstrated 4e (IC50 = 3.4 µM) without notable cytotoxicity (CC50 = 87.5 µM) as a promising lead for future exploration.

Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria.

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 µmol/L in the US. Recently, the European Commission also approved pegvaliase for treatment of PKU patients aged 16 years or older with blood Phe >600 µmol/L. The analyses presented below were conducted to provide comparative evidence on long-term treatment effectiveness of pegvaliase versus standard of care in adults with PKU. Adult patients (≥18 years) with baseline blood Phe >600 µmol/L who had enrolled in the pegvaliase phase 2 and phase 3 clinical trials were propensity score-matched to historical cohorts of patients treated with "sapropterin + diet" or with "diet alone". These cohorts were derived from the PKU Demographics, Outcome and Safety (PKUDOS) registry and compared for clinical outcomes including blood Phe concentration and natural intact protein intake after 1 and 2 years. Propensity scores were estimated using logistic regression with probability of treatment as outcome (i.e. pegvaliase, "sapropterin + diet", or "diet alone") and patient demographic and disease severity covariates as predictors. An additional analysis in adult PKU patients with baseline blood Phe ≤600 µmol/L comparing non-matched patient groups "sapropterin + diet" to "diet alone" using PKUDOS registry data only was also conducted. The analyses in patients with baseline blood Phe >600 µmol comparing pegvaliase with "sapropterin + diet" (N = 64 matched pairs) showed lower mean blood Phe concentrations after 1 and 2 years with pegvaliase (505 and 427 µmol/L) versus "sapropterin + diet" (807 and 891 µmol/L); mean natural intact protein intake after 1 and 2 years was 49 and 57 g/day respectively with pegvaliase versus 23 and 28 g/day with "sapropterin + diet". The analysis comparing pegvaliase with "diet alone" (N = 120 matched pairs) showed lower mean blood Phe at 1 and 2 years with pegvaliase (473 and 302 µmol/L) versus "diet alone" (1022 and 965 µmol/L); mean natural intact protein intake after 1 and 2 years was 47 and 57 g/day with pegvaliase and 27 and 22 g/day with "diet alone". Considerably more patients achieved blood Phe ≤600, ≤360, and ≤120 µmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe after 1 and 2 years of pegvaliase versus standard treatments. The analysis in patients with baseline blood Phe ≤600 µmol/L showed lower blood Phe after 1 and 2 years with "sapropterin + diet" (240 and 324 µmol/L) versus "diet alone" (580 and 549 µmol/L) and greater percentages of patients achieving blood Phe targets ≤600, ≤360, and ≤120 µmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe. These results support pegvaliase as the more effective treatment option to lower Phe levels in adults with PKU who have difficulty keeping blood Phe ≤600 µmol/L with "diet alone". For patients with blood Phe ≤600 µmol/L, adding sapropterin to dietary management is an appropriate treatment option, for those responsive to the treatment.

Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of 4'-methyl-6'-substituted aristeromycins.

The need of long-term treatment for chronic HBV, emergence of drug-resistant viruses and inefficiency of currently approved therapies to eliminate covalently closed circular DNA (cccDNA), mandates identification of potent and selective inhibitors of HBV replication with novel mechanisms of action. Entecavir, a carbocyclic guanosine nucleoside analog, is the most potent inhibitor of HBV replication on the market. Moreover, the naturally occurring carbocyclic nucleosides aristeromycin are known for their wide range of antiviral activities. In this research, we have utilized BINAP directed rhodium catalyzed reductive carbocyclization of 1,6-enynes (8a-b) through asymmetric hydrogenation which is an approach, not yet explored in carbocyclic sugar synthesis. Interestingly, we obtained exclusive anti-(9a) and Z-anti (9b) carbocyclic sugars. The new aristeromycin analogs (10a-b) with scaffold combination of entecavir and aristeromycin were then synthesized using the Mitsunobu reaction followed by deprotection.

Corneal Endothelial Alterations in Chronic Renal Failure.

PURPOSE: To evaluate the corneal endothelial changes in patients with chronic renal failure. METHODS: A total of 128 corneas of 128 subjects were studied, and 3 groups were formed. The first, the dialyzed group, composed of 32 corneas of 32 patients; the second, the nondialyzed group, composed of 34 corneas of 34 patients; and the third, the age-matched control group, composed of 64 corneas of 64 healthy subjects were examined by a specular microscope and the endothelial parameters were compared. The dialyzed group (enhanced level of toxins in the blood) was further analyzed to assess the influence of blood urea, serum creatinine, serum calcium, and serum phosphorus including the duration of dialysis on corneal endothelium. RESULTS: On comparing the 3 groups using analysis of variance and posthoc tests, a significant difference was found in the central corneal thickness (CCT) and endothelial cell density (CD) between the control (CCT: 506 ± 29 µm, CD: 2760 ± 304 cells/mm) and dialyzed groups (CCT: 549 ± 30 µm, CD: 2337 ± 324 cells/mm) [P < 0.001 (CCT); P < 0.001 (CD)]; control and nondialyzed groups (CCT: 524 ± 27 µm, CD: 2574 ± 260 cells/mm) [P = 0.023 (CCT); P = 0.016 (CD)]; and dialyzed and nondialyzed groups [P = 0.002 (CCT); P = 0.007 (CD)]. Using the linear generalized model, a significant correlation was found between the endothelial parameters and blood urea only [P = 0.006 (CCT), 0.002 (coefficient of variation), 0.022 (CD), and 0.026 (percentage of hexagonality)], although the correlation was poorly positive for CCT but poorly negative for the remaining endothelial parameters. CONCLUSIONS: Corneal endothelial alteration is present in patients with chronic renal failure, more marked in patients undergoing hemodialysis and with raised blood urea level.

Synthesis and anti-HBV activity of α-stereoisomer of aristeromycin based analogs.

The potential antiviral activity of aristeromycin type of derivatives (I) is limited by associated toxicity due to its possible 5'-O-phosphorylation and S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitory activity. Aristeromycin structure has major pharmacophoric motif as 5'-OH and adenosine base, which may have significant role in enzyme binding followed by activity and or toxicity. Thus, the structural optimization to alter this major motif by replacing with its bioisostere and changing the 5'-O conformation through stereochemistry reversal was of interest. Thus, the inverted stereochemistry at 4'-position coupled with bioisostere of adenosine base in the target compounds (6-7) to access antiviral potential. The stereoselective formation of a key stereoisomer (2a) was achieved exclusively from neplanocin sugar (1a) by reduction in a single step. The novel target molecules (6-7) were synthesized in 4 steps with 55-62% yield. Compound 6 was analyzed by single crystal X-ray diffraction, which confirms the stereoselective formation of α-analogs with highly puckered cyclopentane ring and 2'-endo conformation. The compound 6 shown significant anti-hepatitis B virus activity of 6.5µM with CC50>100µM and yielded a promising lead with novel structural feature.

Regioselective Synthesis of Pyrazolo[3,4-D]Pyrimidine Based Carbocyclic Nucleosides as Possible Antiviral Agent.

Carbocyclic nucleosides are considered as nucleoside mimetic having high therapeutic potentials, however diverse exploration is still limited due to their synthetic difficulties. The major challenges are associated with the preparation of new base and carbocyclic sugar key intermediates. The modified base may provide conformational advantage to achieve better nucleoside mimetics and may also help in increasing the drug-like properties. In this manuscript, we report the use of acetamidine hydrochloride to synthesize 6-methyl-4-amino-pyrazolo[3,4-d]pyrimidine base and regioselective synthesis of six new carbocyclic nucleosides (6a-f) for antiviral evaluation. Theoretical investigations were carried out on the basis of thermodynamic and kinetic stability using MM based energy optimizations and QM based transition state search for the significant regioselectivity, which was further experimentally analyzed by NOE and UV spectroscopy.

The Budget Impact of Biosimilar Infliximab (Remsima®) for the Treatment of Autoimmune Diseases in Five European Countries.

INTRODUCTION: Inflammatory autoimmune diseases (rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, and psoriatic arthritis) have a considerable impact on patients' quality of life and healthcare budgets. Biosimilar infliximab (Remsima(®)) has been authorized by the European Medicines Agency for the management of inflammatory autoimmune diseases based on a data package demonstrating efficacy, safety, and quality comparable to the reference infliximab product (Remicade(®)). This analysis aims to estimate the 1-year budget impact of the introduction of Remsima in five European countries. METHODS: A budget impact model for the introduction of Remsima in Germany, the UK, Italy, the Netherlands, and Belgium was developed over a 1-year time horizon. Infliximab-naïve and switch patient groups were considered. Only direct drug costs were included. The model used the drug-acquisition cost of Remicade. The list price of Remsima was not known at the time of the analysis, and was assumed to be 10-30% less than that of Remicade. Key variables were tested in the sensitivity analysis. RESULTS: The annual cost savings resulting from the introduction of Remsima were projected to range from €2.89 million (Belgium, 10% discount) to €33.80 million (Germany, 30% discount). If any such savings made were used to treat additional patients with Remsima, 250 (Belgium, 10% discount) to 2602 (Germany, 30% discount) additional patients could be treated. The cumulative cost savings across the five included countries and the six licensed disease areas were projected to range from €25.79 million (10% discount) to €77.37 million (30% discount). Sensitivity analyses showed the number of patients treated with infliximab to be directly correlated with projected cost savings, with disease prevalence and patient weight having a smaller impact, and incidence the least impact. CONCLUSION: The introduction of Remsima could lead to considerable drug cost-related savings across the six licensed disease areas in the five European countries. FUNDING: Mundipharma International Ltd.

Corneal infection by Pseudomonas stutzeri following excision of trigeminal nerve schwannoma.

A 25-year-old woman underwent intracranial surgery for trigeminal nerve schwannoma (TGNS) with persistent left-sided facial hypoaesthesia. Two months later, she developed a central corneal ulceration. Scraping of the corneal lesion revealed Gram-negative bacilli. Genus level identification was achieved using standard techniques and species level identification, revealing Pseudomonas stutzeri, was aided by a VITEK 2 compact system. Broad-spectrum fortified antibiotics were initially started followed by species-sensitive fortified antibiotics. Ocular surface toxicity developed a week later; this was managed with a non-fortified antibiotic. The epithelial defect healed in 3 weeks with subsequent corneal scar formation. Visual rehabilitation was achieved with deep anterior lamellar keratoplasty. Six months following surgery, the patient had a visual acuity of 20/40 with -1.25 170° -0.5 refractive correction and a clear graft. This case report, for the first time, highlights P. stutzeri, an aetiological agent of corneal ulcer following excision of TGNS and its successful management.

Patient reported burden of asthma on resource use and productivity across 11 countries in Europe.

INTRODUCTION: Asthma affects 30 million people in Western Europe, leading to substantial burden on healthcare systems and economies. REcognise Asthma and LInk to Symptoms and Experience (REALISE™) was a large European survey across 11 countries assessing patient attitudes and behaviors towards their asthma. The present study utilizes REALISE™ data to understand resource use and absenteeism in asthma. METHODS: Data were collected on absenteeism and healthcare resource use from 8000 asthma patients (aged 18-50 years) across the 11 countries. All data were patient reported. Odds ratios (ORs) were calculated against the country with the lowest proportion of respondents for hospitalization (as a proxy for lowest resource use). RESULTS: Patient characteristics were broadly similar across countries. However, self-reported asthma control status varied. More than 50% of respondents in most countries considered primary healthcare professionals (HCPs), i.e., general practitioners and nurses, the main HCP they see about their asthma. However, in some countries, specialists or nurses were considered the main HCP. Hospitalization was lowest amongst patients in the Netherlands. Resource use and productivity loss varied widely across the countries; ORs for hospitalization ranged from 1 in Sweden to 4 in Norway and for productivity loss from 0.6 in Sweden to 2.6 in Italy, compared with the Netherlands. CONCLUSION: This study quantified utilization of healthcare resources in asthma (number of visits of HCPs, hospitalization, and accident and emergency visits) as well as absenteeism and showed that differences exist across countries. The differences in primary care and specialist use suggest a possible difference in healthcare delivery across countries. FUNDING: Mundipharma International Limited, Cambridge, UK.

Comparison of efficacy of three surgical methods of conjunctival autograft fixation in the treatment of pterygium.

Our aim primarily was to compare the recurrence rate with three techniques of conjunctival fixation (suture versus fibrin glue versus autologous in situ blood coagulum) over bare sclera following pterygium excision. Ninety eyes of 90 patients with primary pterygium were randomly divided into three groups: group I (30 eyes) underwent autografting and fixation with 8-0 vicryl sutures, group II (30 eyes) with fibrin glue and group III (30 eyes) with autologous in situ blood coagulum. The patients were reviewed on 2nd day, weeks 1 and 4, and at every 3 months till 12 months after surgery. Rate of recurrence was similar (p = 0.585) across the three groups. Time taken for surgery for Group 1 was more as compared to group 2 (p < 0.001) and group 3 (p < 0.001). Also, group 2 cases took significantly more time as compared to group 3 (p < 0.001). Postoperative patient discomfort (foreign body sensation, epiphora, pain and irritation) was more in suture-assisted autografting as compared to the other two groups. However, at some points along the time line, patient discomfort was significantly more in group III as compared to group II. Complications like graft retraction, graft displacement and cyst formation were seen in a few patients but were not statistically significant across the three groups. All three techniques were found to be useful methods and were associated with similar rate of recurrence.

Customised component corneal transplantation: a blessing for three patients.

The existing acute shortage of good quality donor corneas in a developing country like India, prompted us to attempt customised component corneal transplantation. Using this surgical strategy, one corneoscleral button was used for three recipients. Anterior and posterior lamellar discs were used for anterior lamellar keratoplasty and Descemet's stripping endothelial keratoplasty in patients with superficial corneal scar and pseudophakic bullous keratopathy, respectively. From the remnant peripheral corneoscleral rim, a patch graft was taken and used for a case of perforated corneal ulcer. Postoperatively, the two earlier mentioned cases achieved visual acuities of 20/30 and 20/60, respectively, whereas the latter mentioned patient with the patch graft achieved good tectonic stability. This case report highlights the optimal utilisation of a corneoscleral button by customising it for three recipients. Moreover, a patch graft has been introduced in the armamentarium of customised component corneal transplantation for the first time.

Antiviral activity of novel 2'-fluoro-6'-methylene-carbocyclic adenosine against wild-type and drug-resistant hepatitis B virus mutants.

Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (9) was synthesized and evaluated its anti-HBV activity. The titled compound demonstrated significant antiviral activity against wild-type as well as lamivudine, adefovir and double lamivudine/entecavir resistant mutants. Molecular modeling study indicate that the 2'-fluoro moiety by a hydrogen bond, as well as the van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug resistant mutants.

Structure-activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase.

Carbocyclic 6-benzylthioinosine analogues were synthesized and evaluated for their binding affinity against Toxoplasma gondii adenosine kinase [EC.2.7.1.20]. Various substituents on the aromatic ring of the 6-benzylthio group resulted in increased binding affinity to the enzyme as compared to the unsubstituted compound. Carbocyclic 6-(p-methylbenzylthio)inosine 9n exhibited the most potent binding affinity. Docking simulations were performed to position compound 9n into the T. gondii adenosine kinase active site to determine the probable binding mode. Experimental investigations and theoretical calculations further support that an oxygen atom of the sugar is not critical for the ligand-binding. In agreement with its binding affinity, carbocyclic 6-(p-methylbenzylthio)inosine 9n demonstrated significant anti-toxoplasma activity (IC(50)=11.9microM) in cell culture without any apparent host-toxicity.

Efficacy of 2'-C-methylcytidine against yellow fever virus in cell culture and in a hamster model.

Yellow fever virus (YFV) continues to cause outbreaks of disease in endemic areas where vaccine is underutilized. Due to the effectiveness of the vaccine, antiviral development solely for the treatment of YFV is not feasible, but antivirals that are effective in the treatment of related viral diseases may be characterized for potential use against YFV as a secondary indication disease. 2'-C-methylcytidine (2'-C-MeC), a compound active against hepatitis C virus, was found to have activity against the 17D vaccine strain of YFV in cell culture (EC(90)=0.32 microg/ml, SI=141). This compound was effective when added as late as 16 h after virus challenge of Vero cells. When administered to YFV-infected hamsters 4 h prior to virus challenge at a dose as low as 80 mg/kg/d, 2'-C-MeC was effective in significantly improving survival and other disease parameters (weight change, serum ALT, and liver virus titers). Disease was improved when compound was administered beginning as late as 3 d post-virus infection. Broadly active antiviral compounds, such as 2'-C-MeC, represent potential for the development of compounds active against related viruses for the treatment of YFV.

(-)-Carbodine: enantiomeric synthesis and in vitro antiviral activity against various strains of influenza virus including H5N1 (avian influenza) and novel 2009 H1N1 (swine flu).

Enantiomerically pure cyclopentyl cytosine [(-)-carbodine 1] was synthesized from d-ribose and evaluated for its anti-influenza activity in vitro in comparison to the (+)-carbodine, (+/-)-carbodine and ribavirin. (-)-Carbodine 1 exhibited potent antiviral activity against various strains of influenza A and B viruses.