Management of Acute and Chronic Open Wounds: The Importance of Moist Environment in Optimal Wound Healing Pp-179-195
Bishara
S. Atiyeh, John Ioannovich, Christian A. Al-Amm and Kusai A. El-Musa
Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis Pp-197-225
E.K.
Schroeder, O.N. de Souza, D.S. Santos, J.S. Blanchard, and L.A. Basso
Encapsulating DNA within Biodegradable Polymeric Microparticles Pp-227-235
Corinne
S. Lengsfeld, Mark C. Manning, and Theodore W. Randolph
Engineering Antibodies for Therapy Pp-237-256
Leonard
G. Presta
Localised Delivery of Therapeutic Agents to CNS Malignancies: Old and New Approaches Pp-257-273
Tracy-Ann
Read, Frits Thorsen and Rolf Bjerkvig
Modulating Poly (ADP-Ribose) Polymerase Activity: Potential for the Prevention and Therapy of Pathogenic Situations Involving DNA Damage and Oxidative Stress Pp-275-283
Patrice
Decker and Sylviane Muller
Bishara
S. Atiyeh, John Ioannovich, Christian A. Al-Amm and Kusai A. El-Musa
The history of wound care and management closely parallels that of military surgery which has laid down the principles and dictated the practices of wound cleansing, debridement and coverage. From a treatment standpoint, there are essentially two types of wounds: those characterized by loss of tissue and those in which no tissue has been lost. In the event of tissue loss it is critical to determine whether vital structures such as bone, tendons, nerves and vessels have been exposed. It is also important to determine the amount of soft tissue contusion and contamination. In any case primary wound healing by early closure either primarily or with the help of grafts or flaps is preferred to secondary healing and wound contraction with subsequent contractures which interfere with range of motion and function.
Whether the wound is acute or chronic, essential principles of wound care must be observed in order to avoid wound sepsis and achieve rapid and optimal wound healing.
- Tissues must be handled gently.
- Caustic solutions capable of sterilizing the skin should never be applied to the wound. It is desirable never to put anything in the wound that cannot be tolerated comfortably in the conjunctival sac.
- All devitalized tissues must be debrided either hydrodynamically, chemically, mechanically or surgically.
- All dead space must be obliterated
- Exposed vital structures must be covered by well vascularized tissues.
An
essential part of any wound management protocol is wound dressing. It cannot be
too strongly emphasized that a wound dressing may have a profound influence on
healing particularly of secondary type healing, a critical feature being the
extent to which such dressing restricts the evaporation of water from the wound
surface. A review of available dressing materials is reported with emphasis on
the newly developed concept of moist environment for optimal healing. A
practical guide for dressing selection is also proposed.
[Back to top] Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis
E.K.
Schroeder, O.N. de Souza, D.S. Santos, J.S. Blanchard, and L.A. Basso
Tuberculosis resurged in the late 1980s and now kills more than 2 million people a year. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multidrug- resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat Mycobacterium tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are a-alkyl, b-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, a-methyl ketone, or a-methyl methylethers groups. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straight-chain saturated fatty acids to provide the a-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. In addition, pyrazinamide was shown to inhibit fatty acid synthase type I which, in turn, provides precursors for fatty acid elongation to long-chain mycolic acids by fatty acid synthase II. Here we review the biosynthesis of mycolic acids and the mechanism of action of antimicrobial agents that act upon this pathway. In addition, we describe molecular modeling studies on InhA, the bona-fide target for isoniazid, which should improve our understanding of the amino acid residues involved in the enzyme’s mechanism of action and, accordingly, provide a rational approach to the design of new drugs.
[Back
to top] Encapsulating DNA within
Biodegradable Polymeric Microparticles
Corinne
S. Lengsfeld, Mark C. Manning, and Theodore W. Randolph
In
order for genetic medicines to become viable commercial products, the active
form of the drug (e.g., DNA) must be able to reach the site of action and
remain there long enough to accomplish its intended function. Encapsulation of
plasmid DNA into biodegradable microspheres is one approach towards solving
this challenge. This review describes the primary methods for satisfactorily
entrapping intact DNA into biodegradable polymeric matrices. In particular, the
materials, processes, and equipment required for each encapsulation method are
described in detail. The resulting microspheres could be used for parenteral,
oral, and inhalation therapy.
[Back to
top] Engineering
Antibodies for Therapy
Leonard
G. Presta
With
eleven therapeutic antibodies approved worldwide and many more in clinical
trials, research on antibody engineering has continued to escalate and expand.
This review covers recent progress in generation of antibodies by ex vivo
methods, systems for screening these, and the quest for higher affinity, more
stable, optimally biodistributed antibody fragments, especially for solid
tumors. The latest developments in engineering antibodies for removal or
enhancement of effector functions (antibody-dependent cellular cytotoxicity
(ADCC), phagosytosis, complement fixation (CDC) and halflife) through protein
alteration or carbohydrate optimization may now enable generation of superior
antibody therapeutics. Antibody conjugates, including immunotoxins and
immunocytokines, as well as multivalent and multispecific antibodies confer
expanded utility of therapeutic antibodies. Finally, research into the IgA/FcaRI system has now provided an additional route to therapeutic
antibodies.
[Back to top] Localised Delivery of Therapeutic Agents to CNS Malignancies: Old and New Approaches
Tracy-Ann
Read, Frits Thorsen and Rolf Bjerkvig
Despite
advances in neuro-imaging, neurosurgery, radiation therapy, and chemotherapy,
limited progress has been made in the treatment of patients with high-grade
astrocytomas. Primary brain tumours are considered to be among the most
difficult neoplasms to treat which is largely due to the invasive nature of
these tumours and the complexity of the organ in which they arise. In an
attempt to overcome some of the limitations of systemic delivery of anticancer
drugs, several methods of localised delivery have been developed. In this
article we briefly review some of the current literature on systems for
localised delivery of therapeutic agents to brain tumors, which consists of
osmotic mini-pumps, infusion pumps (convectionenhanced delivery), and cell
grafting. Furthermore, special emphasis is made on bio-degradable polymers,
which is at present the best characterised system of local delivery to brain
tumors, along with a promising novel delivery system, based on non-degradable
polymer encapsulated cell therapy.
[Back to top] Modulating Poly (ADP-Ribose) Polymerase Activity: Potential for the Prevention and Therapy of Pathogenic Situations Involving DNA Damage and Oxidative Stress
Patrice
Decker and Sylviane Muller
Poly
(ADP-ribose) polymerase is a zinc-finger DNA-binding enzyme which detects and
signals DNA strand breaks generated either directly during base excision
repair, or indirectly by genotoxic agents such as oxygen radicals. In response
to genotoxic injury, PARP catalyses the synthesis of poly (ADP-ribose), from
its substrate b-NAD+ and this polymer is covalently attached to several nuclear
proteins and PARP itself. As a result, PARP converts DNA breaks into
intracellular signals which activate DNA repair programs or cell death options.
Several studies have also shown that PARP is involved in either necrosis and
subsequent inflammation or apoptosis. Although this enzyme is not indispensable
during the latter cell death program, it has been demonstrated that PARP plays
a facilitating role in this process. PARP is activated at an intermediate stage
of apoptosis and is then cleaved and inactivated at a late stage by apoptotic
proteases, namely caspase-3/CPP-32/Yama/apopain and caspase-7. This cleavage
prevents necrosis during apoptosis, avoiding inflammation. All these functions,
and the observation that PARP is an abundant and highly conserved enzyme,
suggest that this enzyme plays a pivotal role, particularly in the maintenance
of genomic DNA stability, apoptosis and in the response to oxidative stress.
Since these situations are found in cancer, inflammation, autoimmunity (such as
diabetes), myocardial dysfunction, certain infections, ageing and
radiation/chemical exposure, attempts have been made to modulate PARP activity.
With regard to the increasing interest towards PARP, the aim of this review is
to explain the cellular role of PARP and the advantages of modulating its
activity in diverse preventive or therapeutic strategies.