Articles including New Antibiotic

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ANTIBIOTIC TESTING: Pharmaceutical company begins phase I clinical trial

of inhaled doripenem

Peninsula Pharmaceuticals, Inc., announced that patient enrollment has

begun in a phase I trial of an inhaled formulation of its lead product

candidate, doripenem, a broad-spectrum carbapenem antibiotic.

The double-blind, placebo-controlled, sequential dose escalation phase I

trial will evaluate the safety and tolerability of inhaled doripenem in

healthy volunteers. Last year, the company announced positive results

from a pre-clinical in vitro study of doripenem in isolates of

Pseudomonas aeruginosa and Burkholderia cepacia from patients with

cystic fibrosis (CF).

In that study, doripenem demonstrated between a two-fold and 64-fold

increase in activity relative to the other antibiotics tested against P.

aeruginosa isolates. P. aeruginosa is a Gram-negative bacterium that is

the most common cause of deadly pulmonary infections in people with CF.

Doripenem also demonstrated better in vitro activity against B. cepacia,

a less common pathogen that is associated with high mortality in CF

patients, than the other tested antibiotics.

" We are excited to expand our clinical program to include an inhaled

formulation of doripenem, " said Redman, MD, senior director of

clinical development at Peninsula.

" We are encouraged by the positive results of our CF in vitro and in

vivo studies conducted this past year and hope this first study in

humans will continue to demonstrate the value of this compound. "

" CF is a progressive disease. The frequency and severity of lung

infections in a person with CF have a direct correlation to the

inflammation and subsequent deterioration of lung tissue which, in most

cases, leads to death, " said J. Beall, PhD, president and chief

executive officer of the Cystic Fibrosis Foundation.

" To address this, we need new treatment options that will help curb

these infections and reduce the resulting inflammation. We are hopeful

that doripenem will become a new option for people with CF infected with

P. aeruginosa and/or

B. cepacia. "

Doripenem is a new member of the carbapenem class of antibacterials.

Doripenem has demonstrated in vitro activity against many Gram-positive

bacteria. This includes penicillin-resistant Streptococcus pneumoniae

and methicillin-sensitive Staphylococcus aureus, and resistant

Gram-negative bacteria, including extended spectrum

beta-lactamase-producing strains (bacteria that produce enzymes which

reduce the activity of beta-lactam antibiotics), Pseudomonas aeruginosa

and Klebsiella pneumoniae.

Peninsula believes that current in vitro and in vivo data support its

clinical development as a therapeutic agent for a number of serious

bacterial infections.

Peninsula is developing both

intravenous and inhaled formulations of doripenem for commercialization

in North America, South America, and Europe. Shionogi &   Co., Ltd.,

the inventor of doripenem, has filed a New Drug Application for

doripenem in Japan with the Japanese Ministry of Health, Labor, and

Welfare.

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Gene conjugates can be delivered to the airway of fetal sheep in utero

" Cystic fibrosis is a common lethal genetic disease caused by functional

absence of the cystic fibrosis transmembrane conductance regulator

(CFTR). Although a candidate disease for in utero gene therapy,

demonstration of potentially therapeutic levels of transgene expression

in the fetal airways after minimally invasive gene delivery is a

mandatory prerequisite before application of this approach in humans can

be considered. We report here on the delivery of a beta-galactosidase

expressing adenovirus directly to the airways of fetal sheep in utero

using ultrasound-guided percutaneous injection of the trachea in the

fetal chest, " scientists in England report.

" Injection of adenoviral particles to the fetal airways was not

associated with mortality and resulted in low-level expression in the

peripheral airways. However, complexation of the virus with DEAE

dextran, which confers a positive charge to the virus, and pretreatment

of the airways with Na-caprate, which opens tight junctions, increased

transgene expression, and a combination of these two enhancers resulted

in widespread and efficient gene transfer of the fetal trachea and

bronchial tree, " wrote D. Peebles and colleagues, Imperial College of

Science, Technology and Medicine, Department of Cell &   Molecular

Biology.

" Using a percutaneous ultrasound-guided injection technique, we have

clearly demonstrated proof of principle for substantial transgene

delivery to the fetal airways providing levels of gene expression that

could be relevant for a therapeutic application of CFTR expressing

vectors, " researchers concluded.

Peebles and colleagues published their study in Gene Therapy (Widespread

and efficient marker gene expression in the airway epithelia of fetal

sheep after minimally invasive tracheal application of recombinant

adenovirus in utero. Gene Therapy, 2004;11(1):70-78).

Becki

Life is not measured by the number of breaths we take, but by the moments

that take our breath away.

Listed for Lungs 1/14/04

at

Mayo Clinic ville,Fla.

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