A Half-Century History of Applications of Antisense Oligonucleotides in Medicine, Agriculture and Forestry: We Should Continue the Journey.

Antisense oligonucleotides (ASO), short single-stranded polymers based on DNA or RNA chemistries and synthesized in vitro, regulate gene expression by binding in a sequence-specific manner to an RNA target. The functional activity and selectivity in the action of ASOs largely depends on the combination of nitrogenous bases in a target sequence. This simple and natural property of nucleic acids provides an attractive route by which scientists can create different ASO-based techniques. Over the last 50 years, planned and realized applications in the field of antisense and nucleic acid nanotechnologies have produced astonishing results and posed new challenges for further developments, exemplifying the essence of the post-genomic era. Today the majority of ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake. This review critically analyzes some successful cases using the antisense approach in medicine to address severe diseases, such as Duchenne muscular dystrophy and spinal muscular atrophy, and suggests some prospective directions for future research. We also examine in detail the elaboration of unmodified insect-specific DNA insecticides and RNA preparations in the areas of agriculture and forestry, a relatively new branch of ASO that allows circumvention of the use of non-selective chemical insecticides. When considering the variety of successful ASO modifications with an efficient signal-to-noise ratio of action, coupled with the affordability of in vitro oligonucleotide synthesis and post-synthesis procedures, we predict that the next half-century will produce a fruitful yield of tools created from effective ASO-based end products.

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia : The role played by two neglected protagonists.

In 1957, Professor Daniel Bovet received the Nobel Prize in Physiology or Medicine for his studies on various compounds including the muscle relaxants gallamine and succinylcholine that became very useful in anaesthesia. Textbooks credit Professor Bovet for the discovery of these drugs. However, although he indeed did discover their pharmacological character, the actual syntheses were made by Ernest Fourneau and Reid Hunt, respectively; sadly, these two scientists have largely been ignored. In this paper, a brief biography of Bovet is presented along with some of his more notable accomplishments. Particular emphasis has been placed on gallamine and succinylcholine along with their history. In an attempt to undo the "injustice" dealt to both Fourneau and Hunt, brief accounts of their history, story and character are provided.

Botulinum toxin drugs: brief history and outlook.

The global botulinum toxin (BT) market is currently undergoing rapid changes: this may be the time to review the history and the future of BT drug development. Since the early 1990s Botox(®) and Dysport(®) dominated the international BT market. Later, Myobloc(®)/NeuroBloc(®), a liquid BT type B drug, came out, but failed. Xeomin(®) is the latest major BT drug. It features removal of complexing proteins and improved neurotoxin purity. Several new BT drugs are coming out of Korea, China and Russia. Scientific challenges for BT drug development include modification of BT's duration of action, its transdermal transport and the design of BT hybrid drugs for specific target tissues. The increased competition will change the global BT market fundamentally and a re-organisation according to large indication groups, such as therapeutic and cosmetic applications, might occur.

Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc.

In some patients treated with botulinum toxin (BT), antibodies are produced in association with certain treatment parameters, patient characteristics and immunological properties of the BT preparation used. Therapeutic BT preparations are comprised of botulinum neurotoxin, non-toxic proteins and excipients. Antibodies formed against botulinum neurotoxin can block BT's biological activity. The antigenicity of a BT preparation depends on the amount of botulinum neurotoxin presented to the immune system. This amount is determined by the specific biological activity, the relationship between the biological activity and the amount of botulinum neurotoxin contained in the preparation. For Botox the specific biological activity is 60 MU-EV/ng neurotoxin, for Dysport 100 MU-EV/ng neurotoxin and for Myobloc/NeuroBloc 5 MU-EV/ng neurotoxin. For Myobloc/NeuroBloc this translates into an antibody-induced therapy failure rate of 44% in patients treated for cervical dystonia, whereas for BT type A preparations this figure is approximately 5%. No obvious differences in antigenicity of BT type A preparations have been detected thus far. For the current formulation of Botox, the rate of antibody-induced therapy failure is reportedly less than 1%. To determine the antigenicity of different BT preparations in more detail, prospective studies on large series of unbiased patients with sensitive and specific BT antibody tests are necessary.

Development of botulinum toxin therapy.

Justinius Kerner collected data on 230 cases of botulism in the 1820s, suggested the therapeutic use of toxin, and gave a remarkably complete and accurate description of clinical botulism: its symptoms, time course, and the physical findings that the tear fluid disappears, the skin is dry, the eye, gut, and somatic muscles are paralyzed, and mucus and saliva secretion is suppressed. These effects are the clinical targets of botulinum therapy today. Inspired by Drachman's use of toxin to safely paralyze the hind limb in chicks, we worked out the procedures for its safe medical application and licensure from 1972 to 1989, applying it first to correct strabismus, blepharospasm, leg muscle spasm, and torticollis. This list is now extended by others to well over 100 uses. For many years, blepharospasm patients returning for injection around the eyes and upper face would mention as a joke that they were "back to get the wrinkles out." Working in aesthetic dermatology and ophthalmology, Alistair and Jean Carruthers could envision the intentional cosmetic application of botulinum toxin, probably its greatest single use today.

History of the clinical use of botulinum toxin A and B.

The history of the cosmetic use of botulinum toxin (BTX) must begin with the clinical use of BTX in humans. This came out of Alan Scott's work, which was initially an attempt to find a nonsurgical treatment for some forms of strabismus. Alan Scott put together the idea of Ed Maumenee to use BTX to affect extraocular muscles, Art Jampolsky's electromyographic control delivery system, and Ed Schantz' work on the purification of BTX.

Botulinum toxin type A: history and current cosmetic use in the upper face.

This article reviews the cosmetic use of botulinum toxin in upper face from both the historic and clinical viewpoints. The published literature and our current experience are outlined. Botulinum toxin type A in the upper face has become an extremely popular cosmetic procedure and is outstandingly safe.

Botulinum toxin type A: history and current cosmetic use in the upper face.

This article reviews the cosmetic use of botulinum toxin in upper face from both the historic and clinical viewpoints. The published literature and our current experience are outlined. Botulinum toxin type A in the upper face has become an extremely poplular cosmetic procedure and is outstandingly safe.