Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial

OBJECTIVES: This study compared the efficacy and safety of peginterferon alpha-2a 135 microg/wk, peginterferon alpha-2a 180 microg/wk and interferon alpha-2a in patients with chronic hepatitis C. METHODS: A total of 639 patients received peginterferon alpha-2a 135 microg or 180 microg once weekly, or interferon alpha-2a 3 MIU thrice weekly for 48 wk. RESULTS: Sustained virological responses were significantly higher with peginterferon alpha-2a than with interferon alpha-2a 3 MIU (28% in the 135 microg and 180 microg peginterferon alpha-2a groups vs 11% with interferon alpha-2a, p = 0.001). The proportion of patients with clinically significant histological improvement was lower in the peginterferon alpha-2a 135 microg (48%) than the 180 microg group (58%, p = 0.035 vs peginterferon alpha-2a 135 microg), but similar to that in the interferon alpha-2a group (45%, p = 0.820 vs peginterferon alpha-2a 135 microg and p = 0.017 vs peginterferon alpha-2a 180 microg, respectively). The overall safety profiles were similar for the three treatments. In patients with chronic hepatitis C, peginterferon alpha-2a 135 microg/wk and 180 microg/wk produced similar sustained virological response rates, both of which were significantly higher than that achieved with interferon alpha-2a thrice weekly. A significantly higher proportion of patients treated with the 180 microg dose of peginterferon alpha-2a had clinically significant histological improvement.     

An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.     

Dengue in the deserts: Search and Destroy Operations

Dengue, a viral disease transmitted by the Aedes mosquito has the potential to cause outbreaks in urban settings. Planned and coordinated actions including entomological surveillance need to be undertaken at the community level, through synergized efforts by all partners and stakeholders.The experience of conducting such a Task Force based action plan for prevention and control of dengue, in a desert township is highlighted in this study.     

Mycobacterium avium binds to mouse intestinal mucus aldolase

SETTING: Mycobacterium avium complex (MAC) is known to colonize the gastrointestinal tract of human immunodeficiency virus (HIV) infected patients before causing bacteremia and disseminated disease. However, the mechanism involved in the gastrointestinal colonization is not known. OBJECTIVE: To identify putative intestinal mucus receptors which serve as anchor for MAC colonization. DESIGN: C57BL/6 mouse intestinal mucus was subjected to single and two-dimensional electrophoresis and blotted on nitrocellulose membranes. MAC specific mucus proteins were identified by probing the mucus western blots with biotinylated proteins derived from M.avium strain 101 (MAC101). RESULTS: Biotinylated MAC 101 proteins recognized a 39 kDa intestinal mucus glycoprotein. The protein displaying an isoelectric point (pI) of 9.0, was found to be periodate sensitive but resistant to sialidase, heparinase I and chondroitinase ABC. The internal amino acid sequence of the 39 kDa protein displayed homology with fructose-1-6-bisphosphate aldolase B (aldolase). The proclivity between MAC adhesins and aldolase was confirmed by probing rabbit muscle aldolase with MAC proteins. Furthermore, both 25 and 31 kDa MAC adhesins, superoxide dismutase and heparin binding protein, respectively, were found to bind to aldolase. CONCLUSIONS: MAC binds to intestinal mucus aldolase, conceivably facilitating intestinal colonization of the organism.     

Cost-Effective Isolation of a Process Impurity of Pregabalin

Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin.     

Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer

We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log₂ratio ≥1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.     

Spinal cord pharmacology of adrenergic agonist-mediated antinociception

Intrathecal administration of norepinephrine (NE) and alpha adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (alpha antagonist) but not by propranolol (beta antagonist). Intrathecal administration of isoproterenol (beta agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hindlimbs and tails. The intrathecal NE effect was not antagonized by intrathecal papaverine of bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of either picrotoxin (gamma-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of either naloxone (opiate antagonist) or methysergide (serotinin antagonist). The nociceptive threshold was significantly decreased 1 week after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. Intravenous administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of alpha adrenergic agonists after intrathecal administration were: l-norepinephrine = dl-epinephrine greater than dl-alpha-methyl norepinephrine greater than clonidine greater than or equal to l-phenylephrine greater than or equal to 3,4-dihydroxytolazoline greater than or equal to oxymetazoline. The relative potencies of intrathecally administered alpha antagonists in antagonizing the intrathecal NE effect were: phentolamine greater than phenoxybenzamine greater than tolazoline greater than or equal to yohimbine.     

Knowledge of multidrug-resistant tuberculosis amongst Durban University of Technology students in KwaZulu-Natal,South Africa: the need for integrating public health education

BackgroundKwazulu-Natal is the epicenter of South Africa''s Multidrug-resistant Tuberculosis (MDR-TB) burden which represents a growing threat to public health. Knowledge and awareness of MDR-TB are crucial for effective management and University students are an important vehicle for knowledge transfer of public health education.ObjectiveThis study aimed to evaluate the knowledge of MDR TB and risk factors for transmission, prevention, treatment and control of MDR-TB among Durban University of Technology (DUT) students.MethodsThis quantitative cross-sectional study was conducted among 150 randomly sampled undergraduate students from 3 faculties and data was collected using a validated questionnaire.ResultsWhile a majority of participants (70.67%) had previous knowledge on TB, only 30.67% knew of MDR-TB. Only 23.49% of students reported knowledge of preventative measures associated with MDR TB. Women had a lower probability of having knowledge of MDR-TB compared to men (OR=0.45; CI:0.22,0.95; p<0.05) and students from the Accounting and Informatics faculty were less likely to believe that MDR-TB was a life-threatening illness (OR=0.24; CI:0.05,1.44; p<0.05) and showed limited knowledge of MDR-TB transmission.ConclusionThis study showed that students lacked knowledge of MDR-TB with respect to risk factors, treatment and prevention, which necessitates intervention strategies at a tertiary level to educate and inform students about MDR-TB.