4,223,041 4,489,097 4,513,008 4,613,501 4,767,788 4,806,352 4,828,912 4,841,023 4,853,978 4,897,304 7/1989 9/1980 12/1984 4/1985 9/1986 8/1988 2/1989 5/1989 6/1989 8/1989 1/1989 Kinsolving .......................... 514/560 Carroll ................................ 424/322 Stone ................................... 514/557 Revici et al. ... 514/703 Horowitz ... ... 424/89 Diana .................................. 514/574 Cantrell . ... 514/937 Hossain ..... ... 428/289 Horowitz .. ... 530/351 Stockum ................................. 2/167 Hossain ............................... 428/289 USOO5434182A

Candida-associated stomatitis is a common problem in patients wearing dentures, especially the institutionalized elderly. Regular topical antifungal therapy is often not very effective. New treatments for candidal overgrowth in the mouths of edentulous people are needed, preferably using agents not similar to conventional anticandidal agents, to avoid the buildup of resistance. Antimicrobial lipids, such as fatty acids and their monoglycerides, are known to have activity against Candida, and the monoglyceride monocaprin is the most effective. The aim of this study was to perform a clinical trial to determine the effect of a denture adhesive containing 3% monocaprin on Candida-associated denture stomatitis.

Halldor Thormar*, Hilmar Hilmarsson and Gudmundur Bergsson Faculty of Life and Environmental Sciences, University of Iceland, Reykjavik, Iceland Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland * Address correspondence to this author at the Faculty of Life and Environmental Sciences, University of Iceland, Sturlugata 7, 108 Reykjavik, Iceland; Tel: 354-525-4602; Fax: 354-525-4069; E-mail: halldort@hi.is.

A pharmaceutical formulation was designed which reduces the viral load of RSV in the nasal mucosa of rats after application immediately before inoculation and then daily for 4 days. The formulation did not cause irritation in the mucosal membranes or any other ill effects in intranasally treated rats. The formulation is composed of lauric acid and monocaprin as virucidal lipids, propylene glycol as a solvent, a polysorbate as a surfactant and Carbopol 974P, which has bioadhesive properties causing the formulation to adhere to mucosal membranes. Formulations without lipids were also found to exhibit antiviral activity in the nasal mucosa although apparently less than the formulation with lipids which caused a significant reduction in the viral load compared with controls receiving saline (P < 0.01). The formulation may have potential as a nasal spray to suppress or ameliorate respiratory infections by RSV and other enveloped viruses.

Maedi and visna are contagious sheep diseases which were introduced into Iceland in 1933 by imported sheep of Karakul breed. Maedi, a slowly progressing pneumonia, and the central nervous system disease visna were shown to be transmissible in sheep and most likely caused by a virus. In 1957, visna virus was isolated in tissue culture from sheep brain and maedi virus was isolated the following year from sheep lungs. Both viruses showed similar cytopathic effect in tissue culture. Electron microscope studies of ultrathin sections from visna virus infected cells demonstrated spherical particles, 70-100 nm in diameter, which were formed by budding from the cell membrane. Later studies showed identical particles in maedi virus infected cultures. These, and several other comparative studies, strongly indicated that maedi and visna were caused by strains of the same virus, later named maedi-visna virus (MVV). Comparative studies in tissue culture suggested that MVV was related to RNA tumor viruses of animals, the oncornaviruses. This was later supported by the finding that MVV is an RNA virus. A few months after reverse transcriptase was demonstrated in oncornaviruses, the enzyme was also found in MVV virions. Thus, MVV was classified as a retrovirus together with the oncornaviruses. However, MVV is not oncogenic in vivo or in vitro and was in 1975 placed in a subgroup of retroviruses named lentiviruses, which cause cytopathic effect in vitro and slowly progressing inflammatory disease in animals, but are nononcogenic. In the early 1980s, the causative agent of AIDS was found to be a non-oncogenic retrovirus and was classified as a lentivirus. Thus, HIV became the first human lentivirus.

For a long time it was a common practice to add subtherapeutic amounts of antibiotics, such as tetracycline, to the feeds of livestock to promote growth and improve productivity. When antibiotic resistance in foodborne human pathogens was reported, this practice was either banned or voluntarily abandoned in many countries. The task of controlling the intestinal microflora in food animals, in the absence of antibiotics, is two-fold. First, to modulate the composition and number of commensal bacteria in the gastrointestinal tract so that it is as favorable as possible to the health and productivity of the animal. Second, to reduce asymptomatic intestinal colonization by pathogenic bacteria in the animals to lower the possibility of foodborne transmission to humans. Unfortunately, the knowledge of what constitutes a healthy, balanced intestinal microflora is still incomplete. This makes the task of favorably changing its composition difficult. However, modulation by means of natural feed supplements has been successfully practised for a number of years, the most important being probiotics, prebiotics, bacteriocins, organic acids, enzymes, bioactive phytochemicals, antimicrobial peptides, lipids and bacteriophages. A number of patents and patent applications have been published recently describing new supplements of various types. Many new compounds can therefore be expected to enter the market in the near future.

BACKGROUND:Current treatment of herpes labialis is usually with topical antiviral drugs and early drug administration is required for effectiveness. Monocaprin, a 1-monoglyceride of capric acid, has high microbicidal activity in vitro and efficiently inactivates herpes simplex virus. Tetracyclines are inhibitors of matrix metalloproteinases that are part of the inflammatory response and contribute to the breakdown of tissue in ulcers. The study objective was to investigate the antiviral and wound-healing effect of a hydrogel containing either monocaprin or a combination of monocaprin and a low dose of doxycycline in vivo against herpes labialis.METHODS:Subjects were divided into two groups: (i) with prodromal symptoms of herpes labialis; (ii) with a vesicle. Both groups applied the hydrogel five times a day for five days. Test formulations were: (i) hydrogel containing monocaprin and doxycycline (MCD), (ii) hydrogel containing only monocaprin and (iii) placebo hydrogel. Formulations were distributed randomly to subjects within each group. Subjects recorded treatment results in a 6-day diary and a 7-day follow-up diary.RESULTS:For the MCD group the mean time to healing was 5.5 days (prodromal) and 5.3 days (vesicles/ulceration) or significantly shorter than for the placebo groups (7.25 and 7.5 days respectively; P < 0.05). Pain relief was significantly more with MCD (combining both the prodromal and vesicle groups) than with the monocaprin and placebo groups (P = 0.0114).CONCLUSION:Combining monocaprin with low-dose doxycycline offers an effective treatment for herpes labialiss, significantly reducing time to healing and pain compared with the placebo and monocaprin alone.

Objectives. A long-term collaboration between Departments of Odontology and Pharmacy at the University of Iceland aimed to develop useful new formulations for treating some common oral conditions. Two main active ingredients have been tested: (1) low-dose doxycycline and (2) monocaprin.

Emulsions of glycerol monocaprate (monocaprin) kill a variety of pathogenic bacteria and viruses in suspension. In this study the microbicidal activity of monocaprin against enterobacteria was tested on contaminated hard surfaces. Surfaces were contaminated with nutrient broth or meat juice containing large numbers of Escherichia coli or Salmonella enteritidis. They were then treated with acidified monocaprin emulsions and the surviving bacteria counted. Monocaprin killed S. enteritidis in chicken meat juice on plastic cutting boards and reduced the number of viable E. coli and S. enteritidis by more than 5 logo in 2 min on a laminated plastic kitchen counter contaminated with nutrient broth. Monocaprin rapidly killed E. coli on glass, stainless steel, laminated plastic, glazed ceramic tiles and polypropylene boards. It was most effective on glass and stainless steel and more effective on dry than on wet surfaces. It was concluded that acidified monocaprin emulsions reduce contamination by pathogenic enterbacteria on hard surfaces. They may be useful as sanitizers in the home, and possibly in public places, where contaminated surfaces are a potential source of transmission of pathogens to humans. Cleaning with monocaprin emulsions may therefore be a means to improve hygiene and infection control. (C) 2011 Elsevier Ltd. All rights reserved.

1. A previous study has shown that emulsions of monocaprin in citrate lactate buffer at pH 4 center dot 1-4 center dot 3 are highly active in killing Campylobacter in water, where they reduce viable bacterial counts by more than 6 log10 colony forming units (cfu) in 1 min at a concentration of 1 center dot 25 mM (0 center dot 03%). 2. The present study was carried out to evaluate whether monocaprin emulsions could be used to kill Campylobacter on raw poultry. 3. It was shown that immersion of naturally contaminated chicken legs in 20 mM (0 center dot 5%) monocaprin emulsion at pH 4 center dot 1 for 1 min at 20 degrees C reduced the number of Campylobacter by 2 center dot 0 to 2 center dot 7 log10 cfu. Pre-chill dipping of whole carcases into 20 mM monocaprin emulsion in the slaughterhouse also caused a significant reduction in Campylobacter contamination. 4. Immersion in monocaprin emulsions at pH 4 center dot 1 was also assessed as a means to reduce the number of psychrotrophic spoilage bacteria. There were lower psychrotrophic bacteria counts on treated chicken parts than on untreated controls after storage at 3 degrees C for up to 14 d. 5. Immersion in emulsions of monocaprin, which is a natural lipid classified as GRAS, may be a feasible method to reduce the number of Campylobacter and spoilage bacteria on raw poultry. This method could reduce the risk of human exposure to Campylobacter, and at the same time increase the shelf-life of poultry products.

Soaps are sodium or potassium salts of natural fatty acids and have been used for cleaning for thousands of years. They are surface acting agents and their cleaning activity depends on their amphiphilic nature which makes it possible for soapy water to remove dirt, such as oil, grease and water-insoluble proteins, from soiled surfaces. In the process, various types of bacteria are physically removed from the surface together with the dirt which serves as medium for bacterial growth. In the last decade of the 19th century and first decades of the 20th century numerous studies were done on the killing of pathogenic bacteria by various natural soaps. In this pre-antibiotic era soaps were considered useful to fight bacterial infections. During and after the Second World War various types of inexpensive and easily manufactured synthetic detergents were developed which gradually replaced natural soaps as general cleaners. Similar to natural soaps, some of the synthetic detergents killed microbes. However, in many cases commercial detergents, for example soaps used to wash the hands, contain antimicrobial chemicals as additives. More recently, it has been attempted to use certain fatty acids and monoglycerides as disinfectants of foodborne bacteria on meat and vegetables. Glycerol monocaprate (monocaprin), a 1- monoglyceride of the 10-carbon saturated capric acid, has proved particularly active in killing Campylobacter, and also Salmonella and Escherichia coli at low pH. Monocaprin emulsions have been found to retain their antimicrobial activity after addition to liquid soaps, such as washing-up liquids. They could therefore be used as antibacterial additives to synthetic soaps and used as sanitizing cleaners in the home, and in various settings. Compared with other compounds which have been used as sanitizers or disinfectants, monocaprin, either in emulsions in water or in liquid soaps, may be an attractive choice because it is derived from natural sources and is both environmentally safe and harmless to the body in concentrations which kill bacteria.

Aims:Contamination in the kitchen with foodborne bacteria is a risk factor in human exposure to these pathogens, an important route being transfer of bacteria from contaminated cutting boards and other surfaces to humans. The aim of this study was to test microbicidal emulsions of glycerol monocaprate (monocaprin) against Campylobacter on contaminated cutting boards.Methods and Results:Plastic and wooden cutting boards, soiled with meat juice heavily contaminated with Campylobacter, were treated for 2 min with emulsions of monocaprin (MC) made in water or in buffer at low pH. Viable Campylobacter counts were reduced below the detectable level on plastic board surfaces after treatment with MC emulsions with or without 1 center dot 25% washing-up liquids (WUL). The counts were also greatly reduced on wooden boards (P < 0 center dot 05).Conclusions:Monocaprin emulsions and mixtures of MC emulsions and WUL may be useful as sanitizers/disinfectants in kitchens and in other food preparing and processing facilities.Significance and Impact of the Study:Cleaning with MC emulsions with or without WUL may reduce the risk of human exposure to Campylobacter.

This review covers studies of the antibacterial effect of lipids carried out between 1881 and 1960. The studies in the last two decades of the 19th century and in the early 1900s focussed on the germicidal action of soaps, which had been used for cleaning by mankind for thousands of years. The first study indicating that soaps are toxic to bacteria was published in 1881 by Robert Koch who observed an inhibiting effect of potassium soap on the growth of anthrax bacilli. His work was followed by a number of studies on the germicidal action of different commercial soaps under a variety of conditions to determine their potential as general disinfectants. The results of these studies were somewhat conflicting, but cholera and diphtheria bacilli were found to be easily killed by most soaps, whereas typhoid bacilli and particularly coli bacteria and staphylococci were resistant. The conflicting results were thought to be caused by a difference in the composition of the commercial soaps used by the various investigators. After 1910, the studies therefore focussed on purified fatty acids and their potassium and sodium salts, i.e. the main components of commercial soaps, in the hope to determine whether or not a soap could be used as a disinfectant for a certain bacterium. These studies confirmed that free alkali were not the active ingredients in soaps but rather the neutral salts of fatty acids. The studies also showed that lipids and proteins, such as serum albumin, inhibited the germicidal action of soaps. This was of practical importance, for example for disinfection of bacteria in bodily fluids. In later studies, mostly after 1930, the diverse actions of fatty acids and their alkali salts were emphasized. These actions ranged from stimulation or inhibition of bacterial growth, depending on the bacterium and the concentration of fatty acids, to killing of the bacterium. Inhibition of sporulation of aerobic bacteria or spore germination of anaerobic bacteria was also observed. The difference between bacteriostatic and bactericidal actions was emphasized and a number of studies were carried out in the period from 1911 to the late 1940s to determine the nature of bacterial killing by fatty acids and soaps. In a number of studies, beginning as early as 1905, lipid extracts from leukocytes and lymphoid tissues, and particularly from inflammatory foci, were found to be bactericidal, suggesting a possible role of lipids in host defense against bacteria and in recovery from infection. This led to studies of a possible application for bactericidal fatty acids and their salts in cleaning of infected wounds and for use in wet dressings for wounds and abscesses. In the 1920s and 1930s there was a considerable interest in the therapeutic treatment of chaulmoogra oil for leprosy and of unsaturated fatty acids from cod liver oil for tuberculosis. With the advent of antibiotics in the 1940s and 1950s the interest in fatty acids and other lipids as antibacterial agents decreased greatly, at least temporarily, whereas there was a new interest in their effect on viruses in the 1960s.

In contrast to the adaptive immune system, which is best known for production of specific antibodies, the innate immune system responds immediately to invading pathogens in a non-specific way and constitutes the first line of host defense against pathogenic bacteria, viruses, fungi and protozoa. It is mediated both by cells and by non-cellular factors which either kill the pathogens or inhibit their growth. Among the best known non-cellular components of the innate immune system are proteins, such as lysozyme and lactoferrin, as well as the antimicrobial peptides defensins and cathelicidins. They interact with the cells of the innate immune system, both non-phagocytic cells and phagocytic leukocytes, such as macrophages. It has long been suspected that lipids may be a factor in this multifactorial and multifunctional host defense system of animals. Antimicrobial lipids, particularly fatty acids, are present in the skin and in mucosal membranes of the lungs, as well as in the gastrointestinal tract where they are commonly found in infants as breakdown products of breast milk triglycerides. Several studies indicate that antimicrobial lipids play an active role in the host defense against pathogenic microorganisms in skin and mucosa and that they are truly a part of the innate immune system. Recent studies support this notion and suggest that they may interact with antimicrobial peptides.

Lipids such as fatty alcohols, free fatty acids and monoglycerides of fatty acids are known to be potent antimicrobial/microbicidal agents in vitro and to kill enveloped viruses, Gram-positive and Gram-negative bacteria and fungi on contact. For over half a century several studies have tried to answer the question of whether or not lipids play a role in the natural host defense against pathogens. A comprehensive review is given of these studies, particularly concerning infections in skin and in mucosal membranes of the respiratory tract, and of the role of lipids in the antimicrobial activity of breast milk. Based on studies of the microbicidal activities of lipids, both in vitro and in vivo, the possibility of using such lipids as active ingredients in prophylactic and therapeutic dosage forms is considered and examples are given of studies of such pharmaceutical dosage forms in experimental animal models and in clinical trials.

Recent studies have shown that some lipids and fatty alcohols have microbicidal activities against a broad variety of pathogens. In this study, virucidal activities of fatty acids, monoglycerides and fatty alcohols were tested against respiratory syncytial virus (RSV) and human parainfluenza virus type 2 (HPIV2) at different concentrations, times and pH levels. The most active compounds were mixed with milk products and fruit juices and the mixtures tested for virucidal effects. The aim was to determine which compounds are the most active against these respiratory viruses and could possibly be used in pharmaceutical formulations or as additives to milk products or juice. Several compounds caused a significant inactivation of virus, and there was generally a good agreement between the activities against RSV and parainfluenza virus. By changing the pH from 7 to 4.2, the virucidal activities of some of the compounds were greatly increased, i.e., they inactivated virus in a shorter time and at lower concentrations. The most active compound tested was 1-monoglyceride of capric acid, monocaprin, which also showed activity against influenza A virus and significant virucidal activities after addition to milk products and fruit juices, even at a concentration as low as 0.06-0.12%. The significant virucidal activities of fatty alcohols and lipids on RSV and parainfluenza virus demonstrated in this in vitro study raise the question of the feasibility of using such compounds as ingredients in pharmaceutical dosage forms against respiratory infections caused by these viruses, and possibly other paramyxo- and myxoviruses.

ABSTRACT Of 11 fatty acids and monoglycerides tested against Campylobacter jejuni, the 1-monoglyceride of capric acid (monocaprin) was the most active in killing the bacterium. Various monocaprin-in-water emulsions were prepared which were stable after storage at room temperature for many months and which retained their microbicidal activity. A procedure was developed to manufacture up to 500 ml of 200 mM preconcentrated emulsions of monocaprin in tap water. The concentrates were clear and remained stable for at least 12 months. They were active against C. jejuni upon 160- to 200-fold dilution in tap water and caused a >6- to 7-log10 reduction in viable bacterial count in 1 min at room temperature. The addition of 0.8% Tween 40 to the concentrates as an emulsifying agent did not change the microbicidal activity. Emulsions of monocaprin killed a variety of Campylobacter isolates from humans and poultry and also killed strains of Campylobacter coli and Campylobacter lari, indicating a broad anticampylobacter activity. Emulsions of 1.25 mM monocaprin in citrate-lactate buffer at pH 4 to 5 caused a >6- to 7-log10 reduction in viable bacterial counts of Salmonella spp. and Escherichia coli in 10 min. C. jejuni was also more susceptible to monocaprin emulsions at low pH. The addition of 5 and 10 mM monocaprin emulsions to Campylobacter-spiked chicken feed significantly reduced the bacterial contamination. These results are discussed in view of the possible utilization of monocaprin emulsions in controlling the spread of food-borne bacteria from poultry to humans.