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Biomedical subjects

J F Barrett

Publications and source records attributed to J F Barrett.

At least 37 records · Page 2Linked to original sources
PubMed2001

Quinolone, everninomycin, glycylcycline, carbapenem, lipopeptide and cephem antibacterials in clinical development.

The development of antibacterials was a very successful endeavor in the pharmaceutical company repertoire through the late 1970s, when interest in investing in antibiotic research and development temporarily waned. More recently, there have been a number of failures in late stage development or post-launch of human antibiotics. The answer to the dilemma of less-than-desired success may be the introduction of novel classes of agents, as well as development of new agents in traditional classes. This review provides an overview of the various "miscellaneous" antibacterials in development, excluding glycopeptides, macrolides, ketolides, and oxazolidinones. Among the agents highlighted in this review are the clinical candidates of quinolones, everninomycins, carbapenems, lipopeptides, glycylcyclines, and cephems. In several cases, certain quinolone agents described in this review will have been approved for marketing before press time.

4-Quinolones↗
PubMed2001

MC-207110 Daiichi Seiyaku/Microcide Pharmaceuticals.

Microcide and Daiichi are collaborating on the discovery of new bacterial efflux pump inhibitorsfor the treatment of drug-resistant Pseudomonas aeruginosa and other bacterial infections. The bacterial efflux pump technology program focuses on Gram-negative bacteria that have developed antibiotic resistance by means of the efflux pump [192681], [341408]. MC-207110 was the initial screening hitfrom Microcide's library and is a low molecular weight dipeptide amide, which shows minimal antibacterial activity but potentiated the activity of levofloxacin by 8-fold at 10 microg/ml. This lead is being optimized to improve on its biological and pharmacological profile [341183]. Optimization studies have been conducted on MC-207110, yielding a class of broad-spectrum efflux pump inhibitors for P aeruginosa. A member of this class has demonstrated in vivo activity against P aeruginosa in a murine neutropenic thigh model [351686].

Animals↗
PubMed2001

Oritavancin. Eli Lilly & Co.

Oritavancin (LY-333328), a lead glycopeptide from a series targeted at vancomycin-resistant bacteria, especially enterococci, is under development by Eli Lilly for the potential treatment of bacterial infections. It entered phase III trials in the US in January 2001 [396223] and the company expects to submit an NDA by 2003 [396478]. Oritavancin has been reported to have activity comparable to that of vancomycin and teicoplanin (Aventis Pharma AG), but retains activity against glycopeptide-resistant bacterial strains [407519]. The bactericidal activity of oritavancin suggests that it may prove useful as a single agent therapy in the treatment of antibiotic-resistant enterococci. Although its mechanism of action is unclear, dimerization of the glycosyl portion stabilizing D-Ala-D-Ala binding has been suggested [337644].

Anti-Bacterial Agents↗
PubMed2001

American Society of Microbiology - 101st General Meeting. 20-24 May 2001, Orlando, FL, USA.

Sessions on prokaryotic genomics, bioinformatics, antibiotic resistance, intrinsic antibacterial resistance, and the identification of novel targets were the main highlights of this year's American Society Microbiology (ASM) meeting. In addition, updates on the status of antimicrobial developmental candidates and recently approved agents, were also discussed.

Journal Article↗
PubMed2000

Identification of CDK4 as a target of c-MYC.

The prototypic oncogene c-MYC encodes a transcription factor that can drive proliferation by promoting cell-cycle reentry. However, the mechanisms through which c-MYC achieves these effects have been unclear. Using serial analysis of gene expression, we have identified the cyclin-dependent kinase 4 (CDK4) gene as a transcriptional target of c-MYC. c-MYC induced a rapid increase in CDK4 mRNA levels through four highly conserved c-MYC binding sites within the CDK4 promoter. Cell-cycle progression is delayed in c-MYC-deficient RAT1 cells, and this delay was associated with a defect in CDK4 induction. Ectopic expression of CDK4 in these cells partially alleviated the growth defect. Thus, CDK4 provides a direct link between the oncogenic effects of c-MYC and cell-cycle regulation.

Animals↗
PubMed2000

Fetal response to maternally administered morphine.

OBJECTIVE: We sought to determine the effects of maternally administered morphine on fetal response. STUDY DESIGN: Singleton pregnancies requiring fetal blood sampling were enrolled. Only study patients were given morphine intramuscularly. Maternal vital signs, fetal heart rate, biophysical profile score, and umbilical artery Doppler indices (systolic/diastolic ratio, resistance index, and pulsatility index) were completed before and after fetal blood sampling. Maternal and cord blood morphine concentrations were measured. RESULTS: Ten study and 6 control patients were enrolled. A significantly lower biophysical profile score was observed in study patients (P =.001) as a result of absent fetal breathing movements and nonreactive nonstress tests. Gross and fine fetal movements were unaffected. A significant correlation was measured between the biophase morphine concentration and each of the Doppler indices. CONCLUSION: Morphine administered to the mother causes a significant decrease in the biophysical profile score. Correlation between the biophase morphine concentration and the Doppler indices was calculated. These results suggest that morphine acts as a vasoconstrictor of the placental vasculature but do not support the use of intramuscular morphine to suppress fetal movement.

Analgesics, Opioid↗
PubMed2000

Cervical length as a predictor of pre-term birth in twin gestations.

The aim of this study was to determine the predictive value of cervical length as a risk factor for spontaneous pre-term birth in twin gestations. A retrospective chart review was carried out on patients with twin pregnancies referred to our multiples' clinic. Cervical length was measured by transvaginal ultrasonography. Patients with an indicated pre-term delivery or intervention were excluded from the analysis. Outcomes included preterm delivery < 28 and < 35 weeks gestation. After extracting the data, 2 x 4 tables were constructed. Likelihood ratios were then generated for cervical lengths < or = 2.0 cm, < or = 2.5 cm, < or = 3.0 cm, and > 3.0 cm. Because of the limited number of measurements taken < 25 weeks gestation, we elected to collapse the tables, thereby achieving more meaningful results. For measurements taken before 30 weeks gestation, a shorter cervix did predict delivery < 28 weeks gestation (likelihood ratios for cervical lengths < or = 2.0 cm, < or = 2.5 cm, < or = 3.0 cm, and > 3.0 cm were 4.43, 1.94, 0.97, and 1.02, respectively). The probability of preterm delivery < 35 weeks gestation increased with decreasing cervical length (likelihood ratios for cervical length < or = 2.0 cm, < or = 2.5 cm, < or = 3.0 cm, and > 3.0 cm were 2.58, 1.66, 1.38, and 0.81, respectively). A shorter cervix measured before 30 weeks gestation was a stronger predictor of preterm delivery < 28 weeks compared to < 35 weeks gestation. Cervical length was not predictive of preterm delivery if measured after 30 weeks. Cervical length is predictive of preterm delivery < 28 weeks and < 35 weeks gestation when measured before 30 weeks gestation. No trend was seen when measured after 30 weeks gestation. A prospective study is currently underway to confirm these results.

Anthropometry↗
PubMed2000

SMI's 2nd Annual Superbugs and Superdrugs Conference: innovations in anti-infectives.

The emergence of the 'Superbugs', resistant bacterial pathogens, is being aggressively met by the anti-infective community, both academia and industry, with an assortment of classical and novel approaches to control these resistant pathogens. The launch of improved quinolones (gatifloxacin and moxifloxacin), the launch of a new class of protein synthesis inhibitors (oxazolidinones; linezolid) and the ushering-in of the applied genomics age, all offer hope for the future control of resistant bacteria. The seemingly imminent development and completion of the first lipopeptide, daptomycin, offers great hope for the control of Gram-positive resistant pathogens. The first cationic peptide, IB-367, designed to combat the niche medical need of mucositis and the development of a specific antistaphylococcal glycopeptide. BI-397, all will precede the first wave of genomic-targets-based drug candidates, as the antimicrobial genomics effort remains in the target identification and validation stages of early discovery.

Anti-Bacterial Agents↗
PubMed2000

100th American society for microbiology annual meeting.

The 100th ASM Annual Meeting, attended by approximately 10,000 delegates, continued the trend of concentrating on bacteria and antibacterial therapy, mixed with genomics and a diverse number of additional topics. Of the various marketable drug classes, the quinolones received attention with respect to susceptibility studies and several drug comparison studies. New marketable drugs were also of interest, especially given the reservoirs of resistance presented by several speakers. Drugs in development include the antibacterial daptomycin and protegrins and the antifungal lipodepsinonapeptides and echinocandins, to name a few. It is still unclear whether or not antibiotic treatment regimens for Chlamydia pneumonia will he necessary, as association of this bacteria with several chronic diseases, such as atherosclerosis and asthma, was discussed. The development of novel antibiotics was highlighted and the potential role that microbial genomics technology could play was a recurring theme. In fact, a number of symposia treated the increasingly popular topic of genomics in a variety of themes, including phenotyping arrays, transcriptional profiling, proteomics, expression profiling, genome sequencing, target areas or essentiality of genes via gene knockout systems, the role of genomics in pharmaceutical development and fungal genomics. Similarly, genomics plays a role in developing a deeper appreciation for classical areas of interest in microbial physiology, such as gene regulation, cell division, fatty acid biosynthesis, DNA replication and cell signalling. Even in the bio-inorganic field of study in microbial metabolite activation, genomics plays a role. The sequencing of the large gene clusters of the auxiliary proteins necessary to synthesise or activate the metallo-proteins provided insights into the mechanisms of activation of these microbial enzymes, including the genes for the nif gene cluster in Azotobacter vinelandii, the urease from Kiebsiella aerogenes and the three hydrogenases in Ralstonia eutropha.

Anti-Bacterial Agents↗
PubMed2000

Linezolid Pharmacia Corp.

Linezolid is an oxazolidinone developed by Pharmacia (formerly Pharmacia & Upjohn) for the treatment of multi-resistant Gram-positive infections [187765,317456]. It binds to ribosomal 50S subunits, most likely within domain V within the 23S rRNA peptidyl transferase and a secondary interaction with the 30S subunit. This results in inhibition of the initiation of protein translation at an early point, which is probably N-formylmethionyl-tRNA [335843]. No direct action on DNA or RNA synthesis has been observed [220169]. Linezolid resistance due to a 23S rRNA mutation may emerge in Enterococci during therapy with this antimicrobial, and may be associated with clinical failure [368652]. Following FDA approval, linezolid was launched in May 2000 [368526,368652]. In April 2000, the FDA approved linezolid injection, tablets and oral suspension for the treatment of patients with infections caused by Gram-positive bacteria. It is indicated for adults in the treatment of nosocomial pneumonia, community-acquired pneumonia (CAP), complicated and uncomplicated skin and skin structure infections and vancomycin-resistant enterococcus (VRE) infections caused by methicillin-resistant Staphylococcus aureus (MRSA), VRE faecium and penicillin-susceptible Streptococcus pneumoniae [363503]. The FDA, however, did not grant Pharmacia indications for linezolid in the treatment of CAP due to either penicillin-resistant S aureus (PRSA) or MRSA. In May 2000, Merrill Lynch predicted sales for 2000 to be US $50 million, rising to US $760 million in 2004 [366910]. In February 2000, P&U predicted that peak sales of the drug had the potential to reach in excess of US $750 million [358429]. In February 1999, Morgan Stanley Dean Witter predicted sales of US $40 million in 2000 rising to US $275 million in 2005 [319855]. In December 1998, Deutsche Bank predicted sales of US $100 million in 2000 rising to US $300 million in 2002 [316769].

Acetamides↗
PubMed2000

Moxifloxacin Bayer.

Bayer has launched the fluorinated oxoquinolone, moxifloxacin, as a treatment for bacterial infection. It was launched in Germany for the treatment of respiratory tract infections in September 1999, and regulatory approval in the other EU member states was expected to be completed early in 2000, with marketing throughout the EU by the end of 2000 [336340,340358]. Moxifloxacin received FDA approval in December 1999 and it was launched in the same month [350407,350415,365913]. By July 2000, the drug had been launched in Japan [375976]. In February 1999, Lehman Brothers predicted 95% probabilities that moxifloxacin would reach the US and ex-US markets, and launch onto these market in 1999. Peak annual sales of US $500 million in 2005 (US) and US $800 million in 2007 (ex-US) are predicted [319225].

Animals↗
PubMed2000

American Society of Microbiology - 100th General Meeting.

Symposium sessions on genomics, surveillance, and pharmaceutical intervention opportunities were highlights of this annual ASM meeting. Two-component signal transduction was highlighted by both academic and industrial representatives, as was prokaryotic genomics. Recurring themes throughout the meeting were the contribution of efflux mechanisms to worldwide resistance, target modifications responsible for fluoroquinolone resistance, and the role of structural biology in the discovery and exploitation of bacterial targets.

Journal Article↗
PubMed1999

6-oxa isosteres of anacardic acids as potent inhibitors of bacterial histidine protein kinase (HPK)-mediated two-component regulatory systems.

A series of 6-oxa isosteres of anacardic acids (6-higher alkyl/alkenyl-2-hydroxybenzoic acids) was synthesised and several members were discovered to be among the most potent inhibitors (IC50 values < or = 5 microM) of the bacterial two-component regulatory systems, KinA/SpoOF and NRII/NRI, reported to date. The Gram-positive antibacterial activity in selected strains is also presented.

Anacardic Acids↗