The purpose of this review was to describe the new therapeutic alternatives, particularly in the post antibiotic era, and review the most relevant chemical properties of the compounds and their spectrum of activity, emphasizing their mechanisms of action and resistance as substitutes to antibiotics.
Chapter One: Introduction
The origin of the word antibiotic comes from Greek, anti means against, and bios, life. Antibacterial are natural, semisynthetic or synthetic substances that at low concentrations inhibit the growth or cause the death of bacteria (Vaseeharan & Ramasamy, 2003). But they are popularly known to all as antibiotics, but in reality, these are only the substances produced naturally by some microorganisms. Since ancient times humans have used organic compounds for the treatment of infectious diseases such as extract some plants and fungi of some cheeses. The term antibiotics literally means against life; in this case, against microbes. There are many types of antibiotics: antibacterial, antiviral, antifungal and antiparasitic. Some drugs are effective against several organisms; these are called broad-spectrum antibiotics. Others are only effective against a few organisms and are called narrow-spectrum antibiotics. The most commonly used antibiotics are antibacterial (Vaseeharan & Ramasamy, 2003)
In the nineteenth century, the French prestigious Louis Pasteur discovered that certain saprophytic bacteria could destroy Anthrax bacteria. In 1900, German bacteriologist Rudolf von Emmerich isolated a substance that could destroy the germs causing cholera and diphtheria in a test tube, but could not apply in the treatment of disease. You can tell the story of antibiotics as such begins in 1928, when a British scientist named Alexander Fleming discovered penicillin. However, we must not forget the contribution of Paul Ehrlich in the early twentieth century salvarsan for the treatment of syphilis (1909).
Ehrlich studied the relationship between chemical composition of the drugs and their mode of action on the body and on target cells which were directed. Among its objectives was to find specific products that have affinity for pathogens and thus spoke of magic bullets, ie act on the causative agent of the disease without harming the host. The idea of killing microorganisms using chemicals Ehrlich predated. Unna, in 1886, used the ichthyol and resorcinol in dermatology; Koch, meanwhile, used the mercuric chloride; Biebrich (1882), the scarlet; Laveran, Koch and Shiga -is used the atoxyl in 1860 by Béchamp, to treat trypanosomiasis (Wahab et al 2015).
After many studies, with dozens of chemicals and rigorous use of the scientific method, Ehrlich began the work of converting atoxyl a toxic to the pathogen that had little or no effect on the host organism (ill) (Wahab et al 2015). In this work the compound 606 emerged, which I named the salvarsan or arsenic saves, which was used to treat syphilis. It was observed that the compound produced certain side effects, so Ehrich was criticized by some opponents. Although they tried to retain the product until you have tested on hundreds of patients, Ehrlich could not avoid the growing demand of the new drug. Salvarsan had other enemies: the Russian Orthodox Church, for example, considered that venereal diseases were not treated because they were God’s punishment for immorality (Wahab et al 2015). On the other hand, the German police did not support marketing salvarsan to prevent prostitution. It took four years for Ehrlich replaces the 606 by 914 or neosalvarsan, a more soluble product, easy to use and did not lose efficacy.
Years later, in September 1928, a British scientist Alexander Fleming was conducting several experiments in his laboratory when the twenty-second day, after inspecting their crops before destroying the colony fortuitously observed a fungus had grown spontaneously, as a contaminant, in one of the Petri dish seeded with Staphylococcus aureus (Ganz & Gerber, 2015). Fleming noted plates and later found that the bacterial colonies that were around the fungus (Penicillium notatum) were transparent because bacterial death had occurred. Specifically, the genus Penicillium produces a natural substance with antibacterial effects which was called penicillin. At first, his fellow scientists underestimated Fleming’s discovery, but during World War antibiotic acquired interest. Ernst Boris Chain chemical and Howard Florey developed a purification method which allowed penicillin synthesis and marketing. Also were the first to use in humans (Ganz & Gerber, 2015).
The discovery of penicillin marked a before and after in the treatment of infectious diseases. It was described as a casual and casualty, which was surrounded by a romantic and attractive legend. However, very few people like Fleming had the knowledge to interpret the biological activity of the fungus and scientific curiosity and practical interest to pursue the subject (Li et al 2015).
1.2. Research Aim
The aim of this paper is to analyse the possible replacements for antibiotics in post-antibiotic era.
1.3. Research Objectives
The objectives of this research include:
- To develop an understanding of the history of antibiotics
- To analyse the various developments in the field of microorganisms/antibiotics
- To examine the substitute for antibiotics
Chapter Two: Literature Review
2.1. The discovery of antibiotics: history and evolution
Many discoveries have to do with chance and luck, although the latter requires the insight of the observer. The discovery of antibiotics is no exception to this axiom. It is a young Scotsman, Alexander Fleming, whom should such a feat (Li et al 2015). The story says that investigated in a hospital laboratory Saint Mary of London, how to fight infectious diseases and above all, how to eliminate pathogenic bacteria. He had had his hour of random-success noting that a culture of Staphylococcus aureus lysate had a tear to fall out (Lorch, 1999). He discovered the antiseptic role of lysozyme and its presence in several natural exudates (tears, mucus, etc.). As this compound was not sufficiently active therapeutic agent, he continued his studies and that was how it was in 1928 planting these same bacteria in a petri dish, but went on vacation and forgot. A his return two weeks later plate, besides the expected colonies showed the presence of an invading fungus. It had contaminated the experiment! Instead of throwing away his plate, he began to observe (Wang et al 2015).
Around the fungus were no colonies and only in the most remote places were the fungus colonies. He suspected that the fungus had spread an inhibitory substance. That was how the first antibiotic (AB) was discovered and named penicillin by the fungus Penicillium notatum (and then P. chrysogenum), producers of said compound (Lorch, 1999). But it is the subsequent work by Howard Florey and Ernst Chain which allow purifying penicillin. His enormous therapeutic profile only was launched during the Second World War. There were needs to fight infections from numerous mutilations which prompted the pharmaceutical industry, mainly in the US (Eli Lilly, Pfizer Squibb, Merck, Lederle), and academic to undertake the study of this substance institutions. They spoke of the greatest miracle and millions of lives were saved. In 1945, the Swedish Academy awarded the Nobel Prize in Medicine for his three important discoverers (Fleming, Chain and Florey) (Lorch, 1999).
1940 – 1970 was the golden period of the discovery of new antibiotics, whether natural or synthetic (Gewirtz, 1999).
Currently, penicillin is best known antibiotic, and has been used to treat many infectious diseases, such as syphilis, gonorrhea, tetanus and scarlet fever. It is noteworthy that with the passage of time and the structure after the discovery of penicillin, a beta-lactam ring composed of atoms bonded to four other atoms thiazolidine five, could be obtained new synthetic and semisynthetic penicillin. So the group of antibiotics called beta-lactams arose (Gewirtz, 1999).
Continuing with the story of antibiotics, Dubos (student of Waksman) in 1939 found tyrothricin composed of two polypeptides, the tirocina and gramicidin, which had antibacterial properties. There was used the purified substance was produced bacteria to inhibit the growth of other (Gewirtz, 1999). In 1944, Selman Waksman, American biologist instituted a research program whose purpose was to isolate substances would later call antibiotics. Few graduate and doctoral students, Waksman developed analysis techniques for a variety of soil and organic matter. He performed and studied crops if inhibited colony growth of pathogenic bacteria. His investigations were in actinomycetes, which were the most known microorganisms. In a decade were isolated and characterized ten antibiotics, three of which were successful in clinic: actinomycin, streptomycin, and neomycin (Gewirtz, 1999).
Streptomycin was especially important to be an active bacteriostatic and bactericidal selective agent against gram-positive and gram-negative bacteria. The name streptomycin comes from an old name of the actinomycetes: streptococci. This new substance was effective for treatment of pulmonary tuberculosis. Since then other Streptomyces species neomycin (1949) and kanamycin (1957) were obtained. To enhance the antibacterial activity and reduce the toxicity was continued investigating and thus emerged: tobramycin (1967), amikacin (1972), dibekacin (1971) and netilmicin (1975) accept the first which are semisynthetic. From different species of the genus Micromonospora were obtained gentamicin (1958) and sisomicin (1978) (Campieri & Gionchetti, 1999). 1957 also marked the beginning of the antibiotic therapy combination and mixtures of aminoglycosides with other agents were found to have a large and powerful to control infections in immune compromised individuals, who had many infections spectrum (Campieri & Gionchetti, 1999).
Furthermore, in 1950 in research laboratories in France, were synthesized a group of compounds including nitroimidazolic subsequently highlighted metronidazole. The latter antibiotic was effective against Trichomonas vaginalis (trichomoniasis causative parasite, a type of vaginitis, which is a sexually transmitted disease) (Campieri & Gionchetti, 1999).
In early 1970, during the study of soil organisms, for inhibitors of peptidoglycan synthesis, imipenem, which led to a new class of broad-spectrum antibiotics, carbapenems is discovered. It was a nuvo chapter in the history of beta-lactam antibiotics, since it was observed that certain pathogens produce substances with different lactam ring (Prantera et al 2002).
Today, not only have not been able to completely eradicate infectious diseases, but show an emerging trend, among other things, the development of resistance by microorganisms to antibiotics. Serious diseases that once killed thousands of young people each year have been almost eliminated in many parts of the world thanks to the widespread use of childhood vaccines (Prantera et al 2002).
Much like the discovery of antimicrobial drugs (antibiotics) was one of the most significant medical achievements of the 20th century several types of antimicrobials: antibacterial drugs, antiviral, antifungal and antiparasitic (Although antibacterial often known by the general term antibiotics, we use the more accurate term). Of course, antimicrobials are not panaceas that can cure all diseases. If they are used at the right time they can cure many severe and potentially fatal diseases (Prantera et al 2002).
Antibacterial are specifically designed to treat bacterial infections. Billions of microscopic bacteria normally live on the skin, the digestive system and in our mouths and throats. Most are harmless to humans, but some are pathogenic (disease-causing) and can cause ear infections, throat, and skin and other body parts. In the era before antibiotics, in the early 1900s, people had no drugs against these common germs and as a result, human suffering was enormous. Although the body’s immune system that fights diseases often can successfully attack bacterial infections, sometimes germs (microbes) are too strong and your child can get sick. E.g (Dierick et al 2002).
- Before antibiotics, 90% of children who were infected with bacterial meningitis were dying.Among children who survived, most had serious and lasting disabilities ranging from deafness to mental retardation.
- The throat infections were sometimes fatal disease and ear infections are sometimes passed from the ear to the brain, causing serious problems.
- Other serious infections from tuberculosis to pneumonia and whooping cough were caused by aggressive bacteria that reproduced at extraordinary speed and caused serious illness and sometimes death.
2.2. The emergence of penicillin
With the discovery of penicillin and the beginning of the era of antibiotics, the body’s own defense gained a powerful ally. In the 1920s, British scientist Alexander Fleming was working in his laboratory at St. Mary’s Hospital in London when, almost by accident, discovered a substance of natural growth that could attack certain bacteria. In one of his experiments in 1928, Fleming observed that colonies of the common bacteria Staphylococcus aureus had been exhausted or removed by a mould that grew on the same plate or petri dish. He determined that mould elaborated a substance that could dissolve bacteria. He called this substance penicillin, the name of the Penicillium mould that produces it. Fleming et al conducted a series of experiments in the following two decades using penicillin taking crop mould showing its ability to destroy infectious bacteria (Dierick et al 2002).
Soon, other researchers from Europe and the United States began to recreate experiments Fleming. They could produce enough penicillin to test it on animals and then in humans. Since 1941, found that even low levels of penicillin cured severe infections and saved many lives. For their discoveries, Alexander Fleming won the Nobel Prize in Physiology and Medicine (Syal et al 2015).
Drug companies were very interested in this discovery and began to produce penicillin for commercial purposes. Rather it was used to treat soldiers during World War II, healing wound infections in the battlefield and pneumonia. From mid to late 1940s, it became widely accessible to the general public. The headlines called it the miracle drug (although no medication that really deserves that description) (Syal et al 2015).
With the success of penicillin, began the race to produce other antibiotics. Currently, paediatricians and other physicians can choose from dozens of antibiotics on the market and are prescribed in very high quantities. In the United States each year are made at least 150 million medical prescriptions for antibiotics, many of them children.
2.3. Problems with antibiotics
The success of antibiotics has been impressive. At the same time, by the same emotion has been attenuated by a phenomenon called antibiotic resistance. This is a problem that arose shortly after the introduction of penicillin and now threatens the usefulness of this important drug (Rojas et al 2006).
Almost from the beginning, doctors noticed that in some cases, penicillin was not useful against certain strains of Staphylococcus aureus (bacteria that cause skin infections).Since then, the problem of resistance has grown and involving other bacteria and antibiotics. This is a public health problem. Increasingly, it has become harder to treat certain serious infections, forcing doctors to prescribe a second or even third antibiotic when the first treatment does not work (Rojas et al 2006).
In view of this growing resistance to antibiotics, many doctors have become much more careful when prescribing these drugs. In fact, a recent survey conducted in physicians’ offices, published in JAMA: The Journal of the American Medical Association in 2002 showed that doctors reduced the number of prescriptions of antibiotics prescribed to children about common respiratory infections by 40% during the 1990s (Rojas et al 2006).
Antibiotics should be used wisely and only as directed by the paediatrician. If these rules are followed, the healing properties of these substances are retained for your child and for generations to come (Rojas et al 2006).
2.4. People are becoming more resistant to antibiotics
When a child is sick, parents worry. Even if you have only a mild cold it becomes irritable and cranky or an earache that only hurts a little; these moments can be very stressful. Of course, you want to give the best possible treatment. For many parents, this means go to the paediatrician and leave the clinic with a prescription for antibiotics. But it is not necessarily what will happen during the doctor’s visit. After examining his small, the paediatrician can tell you based on your child’s symptoms or perhaps the results of any tests, antibiotics are simply not necessary (Fritts & Waldroup, 2003). Many parents are surprised by this decision. After all, antibiotics are powerful drugs that have eased the pain and suffering of humans for decades. They have even saved lives. But many doctors do not go to these prescriptions as fast as they used to. In recent years, they are realizing that there are disadvantages in choosing antibiotics if these drugs are used when not needed or taken incorrectly, can actually put your child in a higher health risk. Yes, antibiotics should be prescribed and used with caution or diminish its potential benefits for all (Fritts & Waldroup, 2003).
The World Health Organization (WHO) warns that resistance to antibiotics has become a serious threat to public health worldwide. In a study presented by WHO in which 114 countries have participated, reveals the resistors are a reality in all regions of the world and does not distinguish between rich and poor countries. The drugs are no longer effective because the bacteria that cause infections undergo changes and become immune to treatment. And much of the blame for this transformation is the misuse of antibiotics (He et al 2015).
The world faces a post antibiotic era where infections are common and minor injuries that have been treatable decades ago are now life threatening. Effective antibiotics have been one of the pillars that have allowed us to live longer with health and benefit of modern medicine (He et al 2015). If we do not take significant steps to improve the prevention of infections and do not change our way of producing, prescribe and use antibiotics, the world will suffer a progressive loss of these global public health goods whose impact will be devastating. Since the development of penicillin almost 90 years, antibiotics have become increasingly important in the treatment of bacterial infections, and in recent years, the overuse of antibiotics has caused the emergence of bacteria resistant to these drugs. However, in recent days two separate investigations have announced the creation of two drugs that could be an alternative to antibiotics (He et al 2015):
On the one hand the Dutch biotechnology company, Micreos, has developed a drug composed mainly of an enzyme, endolysin, which kills the superbug MRSA specifically. Furthermore, Swiss researchers at the University of Bern have developed a substance effective against bacterial toxins.
In an experiment with a small number of patients, the Micreos laboratories, showed that endolysins based medicine is effective in eradicating the ‘superbug’ MRSA, staph Staphylococcus aureus, a widespread pathogen that colonizes the skin and the airway mucous of human and which is resistant to methicillin, usually antibiotic effective against these bacteria. Endolysins are synthesized by the bacteriophage enzymes, a type of virus that kills only bacteria specifically, being harmless for the other cells (He et al 2015).
The new drug is available as a cream for skin infections, and doctors believe it is unlikely that bacteria develop immunity to this new treatment. Now hope to develop a pill or an injectable version of the medication in the next five years (He et al 2015).
In parallel the University of Bern (Switzerland) has developed a substance that also represents an effective alternative to antibiotics. This is a kind of bait for bacteria designed from nanoparticles with artificial lipid-based, called liposomes. This bait acts as a decoy to catch those getting bacterial toxins, kidnap and neutralize them completely. With no toxins the bacteria become helpless and can be easily removed by cells of the immune system.
According to the study published in Nature Biotechnology, the new substance has been successfully tested in mice with sepsis. After administration of liposomes, rodents were cured and did not require any additional antibiotic treatment.
2.5. New alternatives to antibiotics
Scientists at the University of Bern in Switzerland developed a new substance that would help combat severe bacterial infections and thus solve the problem of antibiotic resistance.
According to the study published in the journal Nature Biotechnology, the compound was created from artificial lipid nanoparticles and functions as bait to trap and neutralize toxins immunity. They have made irresistible bait for bacterial toxins, said research leader as per the researcher. He explained that once attracted bacteria can be easily removed without danger to the host cells (Gruenberg et al 2004).
Meanwhile, Annette Draeger, also author of the study, explained that although not directly attack bacteria, liposomes do not promote the development of bacterial resistance adds. The substance was tested in laboratory mice, which survived without additional antibiotic treatment. Scientists from a Dutch biotech company also created a substitute for antibiotics that could reduce infections resistant to medication. According to experts, treatment may eradicate MRSA, the invulnerable Staphylococcus aureus. Currently, antibiotics are the best weapons to combat diseases caused by microorganisms. One of the best known worldwide is penicillin, discovered over 60 years ago (Gruenberg et al 2004).
Chapter Three: Methodology
The secondary research for this study began a few months before the actual one in the form of pilot study analysing Possible Replacements for Antibiotics in Post-Antibiotic Era. This chapter focuses on the research methodology, design and procedures that are determined to complete the study goals. In the particular chapter, validity and reliability of the research purpose and research goals are considered relying on the research design, problem statement, research question, and population, informed consent, sampling frame, confidentiality, instrumentation and data collection. The adopted methodology for this research is secondary.
Procedure for Recruitment, and Data Collection Using Secondary Data
The literature responding for the research development was then informed of the initial study and interested literature was coordinated in a manner of trust and confidentiality through online means of communication as well. In order to have more searches for the online procedure and availing searches for the research modulation, several other emails were sent for the cause in another round because persuasion of that sort was made to believe and communicated in a feasible and assisting manner.
Inclusion and Exclusion Criteria for Secondary Research
All research searches had the option to withdraw from the study at any time without any obligation and penalty. The results of the study may be published, but the names of research searches will not be used. The main purpose of this research is to create an understanding within the literature about Possible Replacements for Antibiotics in Post-Antibiotic Erain a long run which is why portability and derivation of literature from such backgrounds and memberships is vital; creating a balanced amount of discussion within the searches was only possible with the help of credibility and a fair responses to the database systems.
Instrumentation and Operationalization of Constructs
Keyword search is the first step when it comes to talking about research methods about epidemiology programs because there are multiple implications and considerations to make when things like literature information and derivation of information from prevailing information are involved. The stock level developments are shown and described within the literature review and keyword search is important to know about the things which are coming in the orderly manner and the ones which will be implied to sustain a continuous production level and services along with the dealings and several other management plans.
Chapter Four: Result and Analysis
4.1. Liposomes: Alternate to Antibiotics
The liposomes are extremely small vesicles (nanometers) mainly composed of phospholipid bilayer organized. These vesicles contain an internal aqueous phase and are suspended in an external aqueous phase. The liposome is a system, namely a permeable complex system, and, from a thermodynamic point of view, a structure is metastable. In both its structure and its composition bilayer phospholipid these vesicles basically have a similar structure, if not identical, to that of the cell membrane and membranes of cellular organelles (Baqui et al 2015).
For preparing lipids are used basically phospholipids natural, synthetic or other analogous compounds. These molecules, phospholipids, are mainly characterized by a hydrophilic part and a lipophilic, and because the hydrated bilayers tend to associate forming. These phospholipid bilayers by power management in properly and become right amount vesicles, i.e. in liposomes (Baqui et al 2015).
Liposomes are classified by size into small and large, and the number of bilayers in uni, oligo or multilamellar. Each type has its own method of production as well as its own APPLICA potential. In pharmaceutical preparations, the most widely used, its general features are small unilamellar liposomes (40-250 nm), the other plurilamellar types, oligo and multilamellar, have specific and concrete applications. The oligolamellar, in my case, by its nature, the necessary instrumentation, high lipid concentration allowing preparations, and raw materials of relatively low price, are mainly used in industrial or techniques different type applications such as in the dyeing of wool (Shasha, Sharon & Inbar, 2004).
The multilamellar due to the large number lipid phase and in proportion to the small amount of aqueous phase was successfully used to produce a sustained release, even months, mainly lipophilic active ingredients, in places of difficult access to the active substances or uncomfortable applying them, such as intraocular injection are antiviruses, intrathecal injection moulding antibiotics, anti-inflammatory intra-articular injection. For its special relationship with the immune system also been used as vaccine adjuvants (Shasha, Sharon & Inbar, 2004).
For different types of liposome used various techniques or methods of production and compositions, both along the encapsulated active ingredient and the aqueous phase used will determine the structure, characteristics and behaviour thereof.
4.1.3. Uses and applications
While at first the liposomes were developed as model membranes and used for studies and related her experiences, characteristics, composition, behaviour in certain agents such as surfactants, membrane proteins, and sensed soon developed other applications thereof, particularly as a vector or carrier of active ingredients, whether pharmaceutical, cosmetic or dietary, plus some other industrial or technical applications of various kinds. For ease of presentation and explanation of the different applications liposomes can be divided basically in medical or biological applications and no medical or biological or technical applications (van et al 2015).
4.1.4. Medical or biological applications
Liposomes are mainly used for transporting active ingredients or drugs of the more selective as possible by increasing the efficiency and lowering, especially its unwanted effects thereof toxicity. Size and physicochemical characteristics make these structures or vesicles circulate, penetrate and diffuse into the tissues easily, releasing the active ingredient encapsulated therein in a controlled and effective. This causes the kinetics of the active principle in liposomal form is very different from the same product in its free form or in conventional dosage forms (M’Sadeq et al 2015).
This change in the pharmacokinetics of the active ingredient have a major impact on the pharmaco dynamic characteristics thereof which almost always result in an overall improvement in the product activity and decreased toxicity or undesirable effects. The structure and physicochemical characteristics of liposomes can incorporate active ingredients separately or together, both hydrosoluble and liposoluble. Liposoluble active ingredients are incorporated into the lipid bilayer phase or while the water-soluble are incorporated primarily in the inner aqueous phase of the liposome and in the external aqueous phase. The portion of dissolved active ingredient in the external aqueous phase of the liposome, if necessary, can be removed by various filtration or separation techniques (M’Sadeq et al 2015).
However in the case of water-soluble products have found very few that only incorporated in either internal or external aqueous phase, i.e. very few active molecules or purely hydrophilic or water-soluble. In varying degrees, almost all of them, in addition to external and internal aqueous phase, are also incorporated into the lipid phase, showing their status or degree of lipophilicity. In most actives the degree of hydronephrosis or lipophilicity is conditioned or is seriously affected by the pH of the medium. In the case of different salts of the same molecule, the type of salt may also affect the appearance significantly. Liposomes are often used to prolong the action, improve absorption, changing the route of administration or simply to solubilize or stabilize a given active substance or a set of them (M’Sadeq et al 2015).
Generally the bioavailability of the substances encapsulated in liposomes is increased significantly increasing efficiency, intensity and duration of its effects. These vesicles due to its high stability and flexibility in vitro and in vivo have a large adaptability to environments of different polarity and therefore have the ability to cross or spread both skin barrier as the blood brain barrier, gastric / intestinal etc. without losing its structural integrity (Dewi et al 2015).
These improvements in activity and potency of active encapsulated in liposomes principle entails that, in most cases, doses of the same can and / or should be reduced when these are used in this way. In this, the ratio amount of amount of active ingredient per liposomes also plays an important role. There have been many trials and tests with different compositions, different kinds incorporated components, sophisticated technological and manoeuvres in order to increase or improve the specificity of such liposomal particle and thereby enhance the therapeutic efficacy of the active ingredients in them or by them vehicular encapsulated (Dewi et al 2015).
In addition to transport as specifically as possible an asset to the tissue or cells target organ principle, have also made significant efforts to control the type of interaction that is established between the target cell and the liposome, i.e., fusion, adsorption, endocytosis etc., as this will also determine significantly the kinetics and activity thereof. Examples of this are antitumor anchoring the liposome surface to ensure that these antibodies adhere to the tumour cells and thus improve the effectiveness of certain anti-cancer treatments, or, incorporating fusogenic lipids and / or the composition thermolabile liposome to occur more easily the fusion of the liposomal and cell membrane (Fernández et al 2015).
Many of the undesirable effects of the active substance are reduced dramatically by encapsulation in liposomes, to even disappear, increasing tolerance of them and reducing their overall toxicity. A very good example of this we observe with our formulation of morphine hydrochloride as a liposomal because she failed to make the LD 50 in mice because the volume of injectate exceeded the allowed limit pharmacological practice; however the analgesic activity of the same increased very significantly. Liposomes as such may be administered by any of the routes own medicine, their physicochemical characteristics, its analogy with the cell membrane makes these structures are totally biocompatible and biodegradable bio camouflaged and thus applicable for all routes (Fernández et al 2015).
The large capacity of penetration and diffusion through different tissues and organs make them ideal for all applications and preparations, e.g. dermatological topical formulations, ophthalmic, oral, and injectable, inhalation, intranasal, otic (Kalyvas et al 2015). As mentioned earlier, liposomes, both its structure and its composition are non-toxic and completely metabolized in vivo. Unlike conventional, injectable, topical, etc… pharmaceutical preparations incorporating solvents, dispersants or other media, which are often problematic condition as alcohols, polyols and other organic solvents, saturated fats, detergents the liposomal preparations, meanwhile, provide phospholipids, mainly phosphatidylcholine and water and per se are substances of great structural value, metabolic, nutritional, and even therapeutic, for all organs and tissues (Kalyvas et al 2015).
Many unstable and susceptible to degradation during the storage of the product, such as Vitamin C or other sensitive to oxidative processes, substances are markedly protected by incorporating or encapsulating active ingredients in liposomes. The structure and characteristics of these molecules protect active ingredient from oxidation and other degradative processes. This protective effect on the liposome active ingredient in vitro is translatable or extendable on the stability in vivo of the same, for example, the metabolism of some drugs can be slowed by encapsulation in liposomes, also digesting some active peptide orally administered character can be avoided by the same route with the same technology, etc (Morgun et al 2015).
Besides the type of disease or injury (Morgun et al 2015), the magnitude of the improvements in activity of an active ingredient in the liposomal form against its conventional form depends on the physicochemical properties of the liposome set / active principle incorporated, factor which is determined by the technique of and preparing the liposome composition as well as the characteristics of the molecule of the active principle.
By acting liposomes as isolated and independent entities is important to consider both the number of particles or liposomes as the ratio liposomes number / amount of active ingredient to be administered for the treatment of a particular disease or condition for a particular route because both factors significantly influence the outcome and will condition the significance of therapy. In addition to active ingredients in solid or liquid form in the liposome can also be encapsulated gases or gaseous active ingredients such as oxygen, nitrous oxide, ozone, halothane, etc. For very different applications these are incorporated into the lipid phase of the structure and are transported and transferred to recipient cells (Morgun et al 2015).
The pharmaceutical formulation of liposomal final product, aqueous or lotion, gel, emulsion, emulgel, suspension etc., is of paramount importance, as this will also determine significantly the effectiveness and outcome of all liposomal products. This is especially important for topical formulations, in particular topical cutaneous.
The final dosage form liposomes ideal for application by any route, including topically, is in aqueous suspension, lotion or serum, or other potential forms as emulsions or gels are, affect the ability of diffusion or penetration thereof and / or also to its stability, wasting product in either case the advantages obtained or acquired incorporation or encapsulation in liposomes (Borkowski et al 2015).
This is true for all except in those cases topical formulations whose action is to be superficial, mainly on the stratum corneum of the skin but also in other tissues or organs, basically looking for a protective, barrier effect of high density and homogeneity, either to water, sun, air, etc.
4.1.5. Frequently medical or biological applications
The active pharmaceutical ingredients more often encapsulated to date in order to improve their therapeutic properties have been antifungal, antineoplastic, immunosuppressive agents, antibiotics, hormones, anti-inflammatories, analgesics, contrast media for different diagnostic techniques, diagnostic kits (Borkowski et al 2015).
In addition, liposomes are also used, for the same reasons and with the same general claims or objectives for veterinary applications as well as in many cosmetics and dietary blockbuster products.
The cosmetics industry is currently using or producing as many products as liposomal or containing liposomes, these being very different type and quality, generally low, and therefore, the cosmetic industry is partly to blame the discredit that liposomes have suffered from their marketing, finding no customers in products advertised benefits and / or expected by them (Borkowski et al 2015).
4.2. Liposomes without active ingredient, therapeutic possibilities
The liposomes per se, as structures without active principle, can be used or applied in different processes and systems with different interests or goals, some of great biological importance and therapeutic efficacy. As isolated entities such as membrane surface or interface, the liposomes interact with the environment in general, many times resulting in an effect or result of such interaction activity or meeting (Wang et al 2015).
Molecules, ions, viruses, bacteria, or other cells, may interact with the liposome, as well as, certain molecules may be in the lipid interface and interact and / or react with, in both results, an activity or an effect more or less intense or relevant as a result of this interaction or encounter.
The structure bilayer cover liposomal analogous to the cell membrane, besides having a restorative effect on the membranes of the diseased cells, as a lure, is capable of absorbing more or less important part of aggression or thereof mediators produced in certain processes or diseases, producing a dilution effect thereof and, barring the liposome, would membranes intended for different cells or tissues involved producing their harmful effect or injury (Wang et al 2015).
This activity by the liposome without active principle becomes relevant in certain processes such as the inflammation, hypertension, and muscle spasms, training sperm different poisonings where efficacy is similar and even surpasses the drug for the treatment of these pathologies.
Moreover, different molecules of all types can be found in the liposomal membrane and interact and / or react with one another or not, in this case acting as a liposome processor, helping to solve certain problems or pathological situations (van et al 2015).
The interaction of the structure liposomal certain molecules or ions, mainly metallic character, leads to a powerful chelating effect or kidnapper thereof by the liposome that produces or carries a significant decrease in their activity or toxicity.
Character amphiphilic, hydrophilic and lipophilic while the bilayer phospholipid along with the internal aqueous phase has such a structure makes the liposome have a very wide range of solvent or dispersant and ability to incorporate in their structure and support a large number and variety of substances or molecules (van et al 2015).
Different molecules both soluble and water-soluble can be incorporated together without any problem to the structure liposomal to be subsequently removed by hepato / biliary or urinary tract. Disease or highly diverse processes can be treated, in whole or in part, this way of dilution with liposomes without active ingredient which means a form of passive therapy to fight the disease.
The high solvent capacity of the empty liposome may be used to enhance or improve the activity of many active molecules or administered in its classical pharmaceutical forms, regardless of the liposome. In this case the inclusion of the active liposome take place in vivo and can be very useful to improve pharmacokinetic problematic aspects of many molecules, such as the passage of the blood brain barrier, diffusion bone tissue, etc (Syal et al 2015).
These general effects of liposome per se also have the liposomes with active ingredient incorporated so, in most cases, the benefit provided by the transported active substance must be added as inherent to the liposome particle surface membrane or interface, carrier,…
The structure of the cell membrane or liposomal incorporates and is the interface that determines, allows or gives rise to life on the biological side, like the interface in general leads to all existence. Biological membranes are the hardware main life and therefore liposome delivery is a way of managing processors, support structures, entities or help in improving healing of most processes.
Therefore, and as example, incorporation or management interface as such liposome in a medium or a patient, increases the possibility that reactions occur in which events occur, increasing overall metabolic activity, making life easier that being (Morgun et al 2015).
The order said structure means is absorbed and integrated by the body and transformed or availed through the countless ways dissipation or conversion that this structure has at all levels, from the structural to molecular, bills or actions very beneficial they can serve as adjuvant or active substance to act synergistically in the treatment of many injuries, diseases or conditions.
For example, mental disorders of very different kinds, from the schizoid delirium until memory loss of different origin are corrected wholly or partly in varying degrees with the simple administration of empty liposomes, administration of phosphatidylcholine structured like membrane cell. By increasing the overall membrane surface and be outstanding based these exchanges and interactions, the problem usually located in an area or point is relative and diluted in them and throughout the body (Morgun et al 2015).
The order, coherence transported by them is used by the body through its multiple forms or pathways of transformation, to bring order to restore consistency to structures or systems that have been lost.
4.3. Lipid nanoparticles: an alternative to antibiotics
Since the development of penicillin almost 90 years, antibiotics have remained as star treatment of bacterial infections. But what happens when the infection comes from bacteria with antibiotic-resistant strains?
Once the antibiotics no longer protect against bacterial infection, pneumonia can be deadly, says the World Health Organization (WHO).
A discovery made by researchers at the University of Bern (Switzerland) have developed an effective alternative to antibiotics, says a recent study published in the journal Nature Biotechnology.
4.3.1. Fatal Attraction
This would bebait designed from artificial lipid nanoparticles made and called liposomes which closely resemble the host cell membrane. These liposomes act like sponges with bacterial toxins and are able to attract and trap them and redirect the host cells and limiting its destructive effect. No toxins, bacteria become helpless and can be eliminated from the host immune system, explains the researcher. The big plus bonus, as described Levitin is that can help treat people infected with multiple pathogens. They act as a broad-spectrum antimicrobial agent without generating drug-resistant strains. In clinical medicine, the liposomes are used to enter specific medication in the body of patients. In this therapy, however, unlike the (drug) antimicrobial, the liposome is to pathogen not direct, avoiding the development of a bacterial resistance (M’Sadeq et al 2015).
4.4. Plasmas: potential substitutes for antibiotics
German scientists have analysed how attacks the atmospheric pressure plasma bacterial infections, cellular and molecular level. Knowing your operation will avoid the side effects of their use, increasingly widespread. The researchers note that, in a decade, plasmas could replace antibiotics (Fernández et al 2015).
Since studies have shown that plasmas destroy bacteria very efficiently, they are increasingly considered as alternative to chemical disinfectants and potentially also to antibiotics. Now, biology, physics and chemical plasma in Ruhr University Bochum (RUB) in Germany have struggled to figure out how to achieve these effect plasmas. Their results are published in the Journal of the Royal Society Interface. In general, atmospheric pressure cold plasma to attack the cell envelope proteins and DNA of prokaryotic microorganisms (including bacteria found) (Baqui et al 2015). This attack is too big to repair mechanisms and stress response systems bacterial challenge, explains Professor Julia Bandow, RUB researcher in the press release from the university. Hence the efficiency of plasmas for treating infections. But to develop plasmas for specific applications, for example, to treat chronic wounds or to disinfect the root canal of the tooth, it is important to understand how they affect plasmas cells, so that undesired side effects are avoided Bandow further explained (Baqui et al 2015).
4.4.1. Components and effects
Depending on its specific composition, plasmas may contain different components such as ions, radicals or light in the ultraviolet spectrum, that is, UV photons. Until now, scientists did not know to what extent it contributes each of these components of the mixture to the antibacterial effect. Bandow team analysed the effect of UV photons and reactive particles, namely radicals and ozone, both the cellular and the level of individual biomolecules level, ie, DNA and protein. It was thus found that, at the cellular level, the reactive particles were most effective because destroying the cell envelope (Baqui et al 2015). At the molecular level, two components were effective plasma: Both UV reactive particles such as DNA damage; and also deactivate reactive protein particles. Sanitizers within decade plasmas at atmospheric pressure and are being used as surgical instruments, for example, extraction of nasal and intestinal polyps. But its properties as disinfectants may also be of interest in medical applications. In ten years, the bacteria may have developed resistance to all antibiotics that are available to us today, explains Julia Bandow. Without antibiotics, surgery would be impossible due to high rates of infection (Baqui et al 2015).
4.5. Phage Therapy: Antibiotics substitute
The emergence of bacteria increasingly resistant to antibiotics, in hospitals and in general practice, pushes scientists to explore new therapeutic approaches. Among them is phage therapy that uses virus eater’s bacteria. No one has forgotten the tragic story of Guillaume Depardieu, who had had to resort to the amputation of his leg after the attack of Staphylococcus aureus resistant to antibiotics. Well, if the actor was born in Georgia, perhaps this would it never happened! Indeed, in this country, doctors apply against bacteria old military adage: The enemy of my enemy is my friend.
Bacteria do have natural enemies. Name: bacteriophages, viruses harmless to humans, but can eat bacteria or more precisely to destroy them. The idea of using them to fight against bacterial infections is also not new. Discovered in 1915, bacteriophages have even experienced their heyday in the 1920s some pharmaceutical companies marketing then the preparations of bacteriophages to treat dysentery and cholera.
4.6. Bacteriophages dethroned by antibiotics
But with the advent of antibiotics – inert chemical molecules much easier to manufacture, to standardize and distribute large quantities – this strategy was abandoned. Except in certain countries of the former Soviet bloc, both for economic and ideological reasons. In Georgia, a research institute, the Eliava Institute, is dedicated. In this country, the use of bacteriophages is common and it is likely that the majority of the population has already benefited at least once in his life, whether to treat conjunctivitis, ear infection or an infected wound by a staph, says Dr. Lawrence Debarbieux subject expert at the Pasteur Institute. In Russia and Georgia, bacteriophages solutions are even counter in pharmacies added Dr. Olivier Patey, head of infectious diseases at the Villeneuve-Saint-Georges hospital (Dewi et al 2015).
The lack of scientific publications in line with Western standards that bacteriophages are still not recognized as drugs in Europe or the United States. Bacteriophages do not meet the European standards of the drug and are, in fact, unauthorized, laments Dr. Patey. This has not prevented some European doctors to practice their wild use.
At Villeneuve-Saint-Georges hospital, they treated four or five patients with bone and joint infections and for whom the only alternative was amputation. All recovered and avoided amputation, says the doctor. But despite this success, the team of Dr. Patey stopped the experiment there are two years. We preferred to wait until the regulation is changing, he says. Risk, he admits, to see developing a new kind of medical tourism to countries of Eastern Europe (He et al 2015).
For its part, Western research seems to be interested in new bacteriophages. While loans (including from the US Army) flock to the Eliava Institute, some French researchers, English or American it also very interested. Among them, Dr. Lawrence Debarbieux new bacteriophages isolated from water collected in the sewers of Paris! These help to treat and even prevent the onset of lung infections in mice exposed to the bacterium Pseudomonas aeruginosa, which is known to proliferate in the lungs of patients with cystic fibrosis.
Improving the lives of people with cystic fibrosis, treat bone and joint infections, pulmonary or ENT, or prevent gangrene on the feet of diabetics, the possible applications are numerous, lists Dr. Patey. But for now, clinical trials on humans are rare.
The first Phase II trial (i.e. the penultimate stage of clinical trials before marketing a drug) date of 2009. Led by an English team, he helped successfully treat ear infections caused by the bacteria Pseudomonas aeruginosa. Following these encouraging results, the British company will soon start Ampliphi the last phase of clinical trials. In Bangladesh, the Nestlé Foundation, meanwhile, launched a Phase II clinical trial of to measure the effectiveness of an antidiarrheal oral rehydration solution containing bacteriophages. The preliminary safety results have just been published and are very encouraging; the efficacy results should be known within two years (Dierick et al 2002).
In the food, sprays based sprayable bacteriophages on cheese to neutralize Listeria (bacteria responsible for listeriosis, an infectious disease) are sold in the United States. A veterinary drug against staphylococcus is also used there (Dierick et al 2002). Knowing that the misuse of antibiotics in livestock is also responsible for the emergence of resistant bacteria, bacteriophages veterinary use is a track not to be overlooked. But it will develop standards and regulations so that the mishap with known antibiotics is not repeated.
4.7. The future substitute for antibiotics, bacteriophages
The bacteriophages (also called phage -from φαγετον Greek (phageton), ‘food / eating’) are viruses that infect bacteria exclusively.
Phages are ubiquitous and can be found in various populations of bacteria both in the soil and in the intestinal flora of the animals. One of the more crowded environments phage and other viruses is seawater.
The use of bacteriophages (phages) as therapeutics discovery dates back to early last century. The widespread emergence of bacterial resistance to antibiotics bound to the technological advances that allow the preparation of purified phages and better molecular understanding of these has led to reconsider the work in the countries of the former Soviet Union and propose the use of phages, viruses that infect bacteria, as authentic therapeutic alternative (Borkowski et al 2015).
The scientists used a close relative of Escherichia coli, the bacterium that commonly causes food poisoning and gastrointestinal infections in humans, called Citrobacter rodentium, which has exactly the same gastrointestinal effects in mice. They were able to treat infected with a cocktail of bacteriophages obtained on the river Cam that attacks the Citrobacter rodentium mice. Currently researchers are optimizing the selection of the viruses by DNA analysis to utilize phage with different perfiles. This is called phage therapy as mentioned earlier.
Phage therapy has been used since the 1940s as an alternative to antibiotics for treating bacterial infections (Borkowski et al 2015).
The emergence of bacterial resistance to antibiotics bound to the technological advances that allow the preparation of purified phages and better molecular understanding has led to propose the use of phages as a therapeutic alternative.
Bacteriophages or phage are viruses that invade bacterial cells and, in the case of lytic phages, disrupt bacterial metabolism and lyse bacteria. Phage therapy is the therapeutic use of lytic bacteriophages to treat infections caused by pathogenic bacteria.
It has been predicted that we may have returned to the pre-antibiotic era. In what is agreed on is that both the use of phages as any of the phage products, we face new and promising therapies that used along with antibiotics, can provide a very effective means to combat the problem of the appearance of bacteria resistant to the arsenal of available antibiotic.
4.8. Natural alternatives to antibiotics
Taking antibiotics so controlled especially necessary cases; it may be the best option but use them constantly as a means to overcome a health crisis can become a problem because, without realizing it, the body creates resistance and when they do his work on a much-needed case because they have no effect. Therefore, natural alternatives at our hands are the best antibiotics that can take uncontrollably as always fight infection without side effects (Gruenberg et al 2004).
Antibiotics are needed in rare cases and prescription but as any chemical, helps improve some things in our body but sometimes we hurt others, for example, our defense are completely weak and causes a significant imbalance in the general body. However, if we choose to maintain a healthy and strong body with natural products we will not be forced to use them in extreme cases (Gruenberg et al 2004).
Sometimes infect infection or common diseases are inevitable and should befall, it is useful to know what other natural alternatives available to us to decide what is best for our health.
Thus, we can create our own personal first aid kit at home with authentic natural antibiotics safe, economical, healthy and natural way. All will benefit because they do not present any risk to health, have no side effects, i.e., do not cause allergic reactions or anything like that; beneficial microorganisms adhere strictly to the body, for example, forming the intestinal flora; they are not dangerous by its accumulation and not subject to an expiration date and, of course, are inexpensive and easy to acquire, do not require a prescription or endless and complicated prospects (Gruenberg et al 2004).
4.8.1. Natural Antibiotics
Among the many options that nature puts at our disposal to enjoy good health and a faster healing and less risky, are the following (Prantera et al 2002):
- Garlic: the king of natural antibiotics for his long list of beneficial qualities for the body, always raw, of course. Without a doubt, the best natural bactericide and antiviral. Ideal for absolutely everything, but especially for internal treatment of respiratory infections and the excretory system.
- Onion: the same family as garlic is presented as a powerful natural antibiotic. It is a good disinfectant and is used mainly in respiratory infections (flu, bronchitis, pharyngitis).
- Echinacea: widespread and well known for their large capsules antimicrobial properties against bacteria, fungi and viruses. It is considered a genuine alternative to chemical antibiotics.
- Ginger: its antibacterial power eliminates bacteria and treats stomach ulcers successfully. It is widely used in cases of gastroenteritis.
- Tomillet: a plant rich in antiviral properties, which is a strong antibacterial although not kill bacteria, at least contributes to not propagate. Help nicely heal wounds.
- Romero: contains over 40 antibacterial principles and over 20 antivirals. It is very common use in teas and help fight pathogens of respiratory and intestinal diseases.
Chapter Five: Conclusion
Interestingly, in themselves, their transformations or expressions, as it had observed in biological models, not always follow the same path or pattern of dissipation or conversion and also it does not always expressed in a unique effect, action or direction.
This very large and diverse understanding or understanding from many types and levels of structures systems or entities, made me see and understand what the primary incorporated into the liposomal membrane, in this interface, message and the importance, the unimaginable possibilities that this structure can have.
Wool dyeing, tanning, paper, dyes and flavours for the food industry laundering, aquaculture feed, gas and water purification, chemical synthesis, energy production are some examples of the many industrial applications that these structures may have.
In the media and non-biological systems, stability and behaviour of liposomes shows great strength, flexibility, adaptability, versatility and versatility of being able to incorporate these processes very different and hard physicochemical conditions such as temperature, ionic strength of pHs, pressure.
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