Phytochemistry, 2001 Dec, 58(7), 1107 - 11 Taraxastane-type triterpenoids from Saussurea petrovii; Dai J et al.; Two taraxastane triterpenoids, i.e . taraxast-20-ene-3beta,30-diol (1) and 20alpha,21alpha-epoxy-taraxastane-3beta,22alpha-diol (2), as well as four known triterpenes taraxast-20(30)ene-3beta,21alpha-diol (3), taraxast-20(30)-ene-3beta-ol (4), taraxast-20-ene-3beta-ol (5) and taraxastane-3beta,20alpha-diol (6) were isolated from the Chinese medicinal plant Saussurea petrovii . Their structures were elucidated by spectroscopic methods . These compounds, especially 1 and 2, exhibit significant antitumor and antibacterial activity. Int Arch Allergy Immunol, 2001 Oct, 126(2), 173 - 8 Equal allergenic potency of beta-lactam antibiotics produced by chemical or enzymatic manufacturing--mouse IgE test; Coenen TM et al.; BACKGROUND: Cephalexin and amoxicillin are semisynthetic beta-lactam antibiotics with a broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms . Both antibiotics are produced by a new 'green' process in which enzyme technology is used to combine the intermediate structure and the side chain in an aqueous medium to yield cephalexin or amoxicillin, thus avoiding the use of several chemical reagents and volatile organic solvents . As a result of the enzyme technology a new residual protein impurity has been identified . To check for the sensitizing capacity of the residual protein, a mouse IgE test was used to detect differences in the production of specific IgE by chemical or enzymatic preparations of the antibiotics . METHODS: Balb/c female mice were immunized intraperitoneally with alum and conjugates of different amoxicillins or cephalexins with ovalbumin (OVA) . After 16 days, the amoxicillin mice were injected with one half the original amount of antigen . After 19-23 days, the sera were tested for specific IgE by the passive cutaneous anaphylaxis assay in Sprague-Dawley rats . The greatest dilution of sera which resulted in a positive response was the titer of specific IgE . RESULTS: No significant differences were found between the titers of specific IgE caused by the chemically and enzymatically produced beta-lactam antibiotics, indicating that the antibiotics are equal in allergenicity . CONCLUSIONS: The data show that a residual level of 35 ppm protein did not affect the allergenic potency of these beta-lactam antibiotics as determined by the mouse allergenicity model . Trends Microbiol, 2001 Dec, 9(12), 611 - 7 Exploiting genomics to discover new antibiotics; McDevitt D et al.; There is an urgent need to develop new classes of antibiotics to tackle the increase in resistance in many common bacterial pathogens . One strategy to develop new antibiotics is to identify and exploit new molecular targets and this strategy is being driven by the wealth of new genome sequence information now available . Additionally, new technologies have been developed to validate new antibacterial targets, for example, new technologies have been developed to enable rapid determination of whether a gene is essential and to assess the transcription status of a putative target during infection . As a result, many novel validated targets have now been identified and for some, appropriate high-throughput screens against diverse compound collections have been carried out . Novel antibiotic leads are emerging from these genomics-derived targeted screens and the challenge now is to optimize and develop these leads to become part of the next generation of antibiotics. FEMS Microbiol Lett, 2001 Nov 27, 205(1), 1 - 7 Macrolide antibiotics and pulmonary inflammation; Hoyt JC et al.; Many clinically effective therapeutic agents can exhibit localized and systemic effects that are manifestly different from their intended primary pharmacological mode of action . Macrolide antibiotics such as erythromycin and its derivatives are no exception . In addition to their antibacterial action, this class of antibiotics exhibits anti-inflammatory activity in a variety of airway diseases such as asthma and diffuse panbronchiolitis that is separate and distinct from a direct antibacterial action . A variety of erythromycin derivatives have been shown to be clinically beneficial in these airway diseases . The anti-inflammatory activities of these macrolide antibiotics are becoming a research topic of intense interest . Recent work in this field has led to the understanding of the various physiological, cellular and molecular processes of the inflammatory response that are inhibited or suppressed by these compounds . This review presents a brief summary of the fascinating recent work in this active research area. Adv Exp Med Biol, 2001, 493, 207 - 14 Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation; Cabral GA et al.; Activated brain microglial cells release inflammatory mediators such as nitric oxide (NO) that may play important roles in central nervous system antibacterial, antiviral, and antitumor activities . However, excessive release of these factors has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury . Recent studies using the rat animal model indicate that select cannabinoids may modulate production of these inflammatory factors . Treatment of neonatal rat brain cortical microglial cells with the cannabinoid paired enantiomers CP55940 and CP56667 resulted in a stereoselective differential effect on inducible NO production . The analog CP55940 exerted a dose-dependent inhibition of interferon gamma (IFNy)/bacterial lipopolysaccharide (LPS)-inducible NO production which was significantly greater than that exerted by CP56667 . Pretreatment of microglial cells with the CB1 cannabinoid receptor-selective antagonist SR141716A reversed this CP55940-mediated inhibition . MRT-PCR demonstrated the presence of CB1 receptor mRNA within microglial cells consistent with the presence of CB1 receptors . Collectively, these results indicate that the cannabinoid analog CP55940 selectively inhibits inducible NO production by microglial cells and that this inhibition is effected, at least in part, through the CB1 receptor. Anal Biochem, 2001 Dec 1, 299(1), 31 - 6 A method for identification of inhibitors of the phosphorylation reactions of bacterial response regulator proteins using (31)P nuclear magnetic resonance spectroscopy; Hubbard JA et al.; Bacterial response regulators are attractive targets for antibacterial drug development, yet random screening against these targets has failed as yet to identify chemicals that constitute viable leads . Alternative methods to provide leads for drug development based on identification and optimization of low affinity ligands from NMR screens have been described . However, leads from these processes still require verification in a bioassay, which is often problematic if compounds have unfavorable optical and solubility properties . A simple method, based on using NMR to observe the activity of the target, is described . It has the advantages of being able to characterize both low affinity leads and a wider selection of compounds in a structure activity relationships series, without the problems affecting a fluorescence assay . In this example we use (31)P to monitor the turnover of a bacterial response regulator, but the generic approach could be applied to other nuclei and thus a range of biological systems. Z Naturforsch {C}, 2001 Sep-Oct, 56(9-10), 731 - 8 Composition and antibacterial activity of the essential oils from Satureja wiedemanniana (Lallem.) Velen; Baser KH et al.; Satureja wiedemanniana (Lallem.) Velen (Lamiaceae) is an endemic species of Turkey . Aerial parts of the plant collected from eleven different localities in Turkey were subjected to hydrodistillation to yield essential oils which were analysed by a GC/MS system . Carvacrol, thymol, p-cymene and gamma-terpinene were found as the main constituents . Antibacterial evaluation of the oils was also carried out. Eur J Surg Suppl, 2001, (586), 82 - 8 Helicobacter pylori: today's treatment, and possible future treatment; Trust TJ et al.; Helicobacter pylori induces chronic superficial gastritis which in some patients may lead to peptic ulcer disease, while a subset of infected individuals develop gastric cancer or gastric lymphoma . Consensus guidelines recommend that patients with a known H . pylori infection receive eradication treatment . Successful treatment requires that antibiotics be used in combination with acid suppressants or bismuth, and although the list of effective antibacterials is short, regimens such as amoxicillin and clarithromycin or metronidazole and clarithromycin with the proton pump inhibitor omeprazole have achieved eradication rates of approximately 90% in trials . However lower eradication rates are probably more common, and strains resistant to clarithromycin or metronidazole, or both, are of concern . Stable amoxycillin resistance has also been reported . Efforts are underway to discover and develop novel therapeutics, both H . pylori specific antibacterial drugs and a therapeutic vaccine . Impetus to these efforts has been provided by the availability of the genome sequences of two different H . pylori isolates . In the case of drug discovery, a genome-based strategy facilitates the expeditious selection of novel lethal targets not used by today's antibiotics, providing the opportunity to identify novel classes of antibacterials . Vaccine discovery and development has largely focused on a small number of antigens selected by conventional means . Recent reports that mucosal and serum antibody titers do not appear to be essential for protection against H . pylori in murine models suggest that that a wider range of H . pylori proteins than those previously considered may be able to induce protective immunity . Progress towards development of new H . pylori therapeutics is discussed. Zhonghua Wai Ke Za Zhi, 1998 Feb, 36(2), 110 - 2 {The relationship between severe burn injury and systemic inflammatory response syndrome}; Sun Y et al.; OBJECTIVE: To study course of systemic inflammatory response syndrome (SIRS) . METHODS: The relationship was observed between SIRS and the effect of burn injury on cellular and humoral immunity between survivors . Nonsurvivors were also compared . The gastric mucosal pHi was measured . RESULTS: The SIRS initiated 22 hours after burn injury and peaked 3 days to 7 days postburn . Compared to the survivors significan increase of content of TNF and decrease of content of G-CSF were detected in the nonsurvivors serum . Obvious immunosuppression could be found . In patients with SIRS accompanied with infection or organ failure, marked increase of mortality was seen . The value of pHi was very low . CONCLUSION: Severe burn injury can lead to the release of massive inflammatory mediators . The second insult such as infection can further amplify the process leading to a vicious cycle of inflammation which cause tissue damage and immunosuppression . To prevent MODS, early diagnosis and treatment including organ supply, use of antibacterial agents, oxygen supply and immunity therapy were necesary. Zhong Yao Cai, 2001 Aug, 24(8), 568 - 9 {Studies on chemical constituents of mycelium of fungus Cephalosporium sp . AL031(I)}; Bi Y et al.; Five compounds were isolated from the mycelium of the fungus Cephalosporium sp . AL031 whose metabolites have been proven to possess antifungal and antibacterial activities . Based on the spectral data and elemental analysis, they were identified as ergosterol(I), 2,4,6-octatrienoic acid(II), succinic acid(III), uracil(IV), and D-mannitol(V) . All of these compounds were obtained from the culture of this fungus for the first time. J Invest Dermatol, 2001 Nov, 117(5), 1206 - 11 Quinolone-photoconjugated major histocompatibility complex class II-binding peptides with lysine are antigenic for T cells mediating murine quinolone photoallergy; Tokura Y et al.; Fluoroquinolone antibacterial agents cause photosensitivity dermatitis as an adverse effect and can function immunologically as photohapten . In a murine model of quinolone photoallergy, Langerhans cells are photomodified with a systemically given quinolone upon ultraviolet A irradiation of skin and thus present photohaptenic moieties to sensitize and restimulate T cells . The aim of this study is to determine the site of peptides/proteins photobound to quinolones and to assess the T cell antigenicity of quinolone-photocoupled peptides using Langerhans cells as photoadduct-presenting cells . On an amino acid composition analysis, lysine was preferentially degraded in bovine serum albumin that was ultraviolet A-conjugated with a representative quinolone ofloxacin . An affinity chromatographic study using a quinolone photoadduct-specific monoclonal antibody as ligand demonstrated preferential photocoupling of ofloxacin with a lysine-containing peptide . CD4+ T cells were purified from lymph nodes of BALB/c mice sensitized subcutaneously with ofloxacin-photomodified epidermal cells and from those sensitized epicutaneously via barrier-disrupted skin with a major histocompatibility complex class II (I-Ad)-binding, ofloxacin-photoconjugated peptide . These immune T cells proliferated in vitro in response to Langerhans cells loaded with class II-binding, lysine-containing peptides when photomodified with ofloxacin . Furthermore, epicutaneous application of the ofloxacin-photoconjugated peptide was able to prime mice for subsequent elicitation of photoallergy evoked with systemic ofloxacin and ultraviolet A light . This study suggests that lysine affords quinolone photocoupling of peptides and quinolone-photomodified peptides on class II molecules stimulate pathogenetic T cells in quinolone photoallergy. Antimicrob Agents Chemother, 2001 Dec, 45(12), 3616 - 22 In vitro antibacterial activities of AF 3013, the active metabolite of prulifloxacin, against nosocomial and community Italian isolates; Montanari MP et al.; AF 3013, the active metabolite of prulifloxacin, was tested to determine its inhibitory and bactericidal activities against 396 nosocomial and 258 community Italian isolates . Compared with that of ciprofloxacin, its activity (assessed in MIC and minimal bactericidal concentration tests) was generally similar or greater against gram-positive bacteria and greater against gram-negative bacteria . In time-kill assays using selected isolates, its bactericidal activity was comparable to that of ciprofloxacin. Enferm Infecc Microbiol Clin, 2001 Nov, 19(9), 422 - 7 {Infection in patients with neutropenia that undergo an autologous peripheral blood stem cell transplant due to breast cancer}; Palau J et al.; BACKGROUND: The extent and duration of neutropenia and the characteristics of the underlying disease are determinant factors for the prognosis of febrile syndromes . Despite the fact that traditionally the peripheral blood stem cell transplantation (PBSCT) were considered to cause high risk neutropenia, in all probability the neutropenia observed in the PBSCT in some solid tumours could be considered moderate risk . Febrile episodes in patients with these characteristics were evaluated . METHODS: We prospectively analysed 132 autologus PBSCT in patients with breast cancer (1994-1999).Conditioning regime: STAMP V . Antibacterial prophylaxis: ofloxacin (400 mg/12 hrs PO) . Classification of the febrile syndrome: bacteremia, microbiologically documented infection withut bacteremia, clinical infection and a fever of unknown origin . RESULTS: 122 patients had a fever (92%), mean age: 45 years (range: 27-61) . There were 32 (26%) bacteremias, 13 (11%) microbiologically documented infections without bacteremia and 54 (44%) clinical infections . The mean number of days with a neutrophil count of <1x109/1 was 14 (range: 11-20) . In the 74 patients (61%) that had a granulocyte colony stimulating factor (G-CSF), the mean number of days to reach a 0,5x109/I neutrophil count (7,6) and the average number of days in hospital (26) were significantly less . There was a main infectious point in 80 patients (65%): the most frequent being oropharynx in 33 cases (46%) and digestive in 29 cases (41%) . 48 gram negative (GN) 29 gram positive (GP) bacteria were isolated (71% of the GN's were resistant to ofloxacin) . Between 1997-1999 the GN/GP ratio was 2,3 . There were no deaths related to the infection . CONCLUSIONS: Given the excellent evolution of our patients we can consider their neutropenia to be moderate or low risk, and they are a long way from the death rates caused by infections published by other types of hemopoietic transplants . The predominance of GN over the last few years and their limited sensitivity to quinolones means that their prophylactic use in these patients should be reconsidered. Trans R Soc Trop Med Hyg, 2001 Sep-Oct, 95(5), 524 - 8 Therapeutic responses to antibacterial drugs in vivax malaria; Pukrittayakamee S et al.; Some antibacterial drugs have antimalarial activity that can be exploited for the prevention or treatment of malaria . Monotherapy with tetracycline, doxycycline, clindamycin or azithromycin was assessed in 1995-98 in 92 adult patients in Thailand with Plasmodium vivax malaria . All patients recovered following treatment and the early therapeutic responses were similar among the 4 groups . The overall median fever clearance time was 57 h and the mean (SD) overall time to parasite clearance was 134 (48) h . Of 66 patients who completed a 28-day follow-up, reappearances of vivax infection occurred in 27 patients (41%) from all groups; delayed appearances of falciparum malaria occurred in 6 patients (9%), only from the azithromycin group . The overall mean (SD) time to reappearance of P . vivax was 23 (5) days and time taken for detection of falciparum malaria was 13 (4) days after starting treatment for vivax malaria . The 28-day cumulative cure rates of clindamycin (n = 12), tetracycline (n = 18) and doxycycline (n = 18) groups were similar (P > or = 0.14) and all were significantly higher compared to the azithromycin group (n = 18; P < or = 0.04) . The intervals until vivax reappearance were also significantly shorter in the azithromycin group {mean (SD) = 21 (6) vs 25 (3) days, P < 0.05} suggesting that some of these were recrudescences . The apparent success rate (no subsequent appearances of either vivax or falciparum infection) was significantly lower for the azithromycin group (11%) compared to the other groups (34-78%; P < 0.01) . In current antibacterial treatment regimens, short-course azithromycin has inferior antimalarial activity compared to clindamycin or the tetracyclines. Plant Physiol, 2001 Nov, 127(3), 711 - 9 Rapid isolation of monoclonal antibodies . Monitoring enzymes in the phytochelatin synthesis pathway; Li Y et al.; Genomics projects have identified thousands of interesting new genes whose protein products need to be examined at the tissue, subcellular, and molecular levels . Furthermore, modern metabolic engineering requires accurate control of expression levels of multiple enzymes in complex pathways . The lack of specific immune reagents for characterization and monitoring of these numerous proteins limits all proteomic and metabolic engineering projects . We describe a rapid method of isolating monoclonal antibodies that required only sequence information from GenBank . We show that large synthetic peptides were highly immunogenic in mice and crude protein extracts were effective sources of antigen, thus eliminating the time-consuming step of purifying the target proteins for antibody production . A case study was made of the three-enzyme pathway for the synthesis of phytochelatins . Enzyme-linked immunosorbent assays and western blots with the recombinant proteins in crude extracts demonstrated that the monoclonal antibodies produced to synthetic peptides were highly specific for the different target proteins, gamma-glutamyl cysteine synthetase, glutathione synthetase, and phytochelatin synthase . Moreover, immunofluorescence localization studies with antibacterial gamma-glutamyl cysteine synthetase and antiglutathione synthetase antibodies demonstrated that these immune reagents reacted strongly with their respective target proteins in chemically fixed cells from transgenic plants . This approach enables research to progress rapidly from the genomic sequence of poorly characterized target genes, to protein-specific antibodies, to functional studies. Am J Clin Dermatol, 2001, 2(4), 219 - 27 Clinical applications for maggots in wound care; Mumcuoglu KY; Maggot debridement therapy (MDT) was first introduced in the US in 1931 and was routinely used there until mid-1940s in over 300 hospitals . With the advent of antibacterials, maggot therapy became rare until the early 1990s, when it was re-introduced first in the US, and later in Israel, the UK, Germany, Sweden, Switzerland, Ukraine and Thailand . Sterile maggots of the green bottle fly, Lucilia (Phaenicia) sericata, are used for MDT . Up to 1000 maggots are introduced in the wound and left for 1 to 3 days . MDT could be used for any kind of purulent, sloughy wound on the skin, independent of the underlying diseases or the location on the body for ambulatory as well as for hospitalized patients . One of the major advantages of MDT is that the maggots separate the necrotic tissue from the living tissue, making a surgical debridement easier . In 80 to 95% of the cases, a complete or significant debridement of the wound is achieved . As therapy progresses, new layers of healthy tissue are formed over the wounds . The offensive odor emanating from the necrotic tissue and the intense pain accompanying the wound decrease significantly . In a significant number of patients, an immediate amputation can be prevented as a result of MDT . In other cases, a more proximal amputation could be avoided . It is also possible that in patients with deep wounds, where septicemia is a serious threat, this can be prevented as a result of MDT . The majority of patients do not complain of any major discomfort during the treatment . Psychological and esthetic considerations are obvious . Maggots can occasionally cause a tickling or itching sensation . Approximately 20 to 25% of the patients with superficial, painful wounds, complain of increased pain during treatment with maggots, and are treated with analgesics . MDT has been proven to be an effective method for cleaning chronic wounds and initiating granulation . It is a simple, efficient, well tolerated and cost-effective tool for the treatment of wounds and ulcers, which do not respond to conventional treatment and surgical intervention. Value Health, 2001 Sep-Oct, 4(5), 370 - 5 The excess cost of acute exacerbations of chronic bronchitis in patients aged 45 and older in England and Wales; McGuire A et al.; INTRODUCTION: Chronic Bronchitis is a serious and costly health problem . Prevalence is estimated at 45 per 10,000 persons in the United Kingdom . Approximately 120,000 Pounds would be saved for every 100 hospital admissions avoided . A reduction in acute exacerbations of chronic bronchitis (AECB), treatment failures, and subsequent hospital admission could have a significant impact on the burden of AECB borne by secondary care facilities in the UK National Health Service (NHS) . OBJECTIVE: The aim of this study is to provide an economic assessment of the direct cost to the health care system associated with the management of chronic bronchitis and its acute exacerbations . DESIGN: A prevalence-based, excess-cost-of-illness analysis is undertaken from the perspective of the UK NHS . Disease prevalence data, primary health care resource utilization, hospital inpatient and outpatient resource utilization, and costs of health care were taken from a variety of data sources, including a large UK national survey of general practice (GP) consultations, the General Practice Research Database, a survey from a single NHS hospital trust, and the national health-care resource and cost statistics . RESULTS: From 1994 to 1995, approximately 233,000 cases of chronic bronchitis were detected in the persons aged 45 and older in the United Kingdom . Prevalence peaked at 204 per 10,000 in the group of subjects aged 75 to 84 years . During that same period, the total excess cost of primary care associated with AECB was calculated at 35.7 million Pounds . The largest component of primary care costs was the excess cost of all prescription medicines, which totaled 27.8 million Pounds . The excess cost attributed to antibacterial and respiratory prescription medications alone was estimated at 9 million Pounds . Excess costs attributed to GP consultations and hospital emergency room visits were 6.5 million Pounds and 1.3 million Pounds, respectively . The excess costs arising from inpatient hospital episodes included 8.3 million Pounds for hospital admissions, 660,000 Pounds for outpatient costs, and 225,000 Pounds for day care . CONCLUSIONS: These results suggest that improving the management of AECB with the objective of reducing the number of AECB treatment failures and the associated hospital admissions could significantly reduce expenditures by the UK NHS. Rev Esp Quimioter, 2001 Jun, 14(2), 165 - 71 {Effect of anti-inflammatory drugs, alone and combined with ofloxacin, on the respiratory burst of human polymorphonuclear leukocytes}; Cabrera E et al.; The antibacterial activity of polymorphonuclear leukocytes (PMNs) is based on the production of superoxide anion and H(2)O(2) in the respiratory burst and can be impaired in different ways . The combination of an antibacterial agent and an antiinflammatory drug is quite common in immunodepressed patients whose respiratory burst of PMN could be impaired . In this study we examine in vitro the effect of pretreating (35 degrees C for 30 min) PMNs with the antiinflammatory drugs dexamethasone (0.4, 4 and 40 microgram/ml), methylprednisolone (0.37, 3.7 and 37 microgram/ ml), hydrocortisone (0.048, 0.48 and 4.8 microgram/ml), betamethasone (0.1, 1, 5 and 10 mg/ml), phenylbutazone (1000 microgram/ml) and acetylsalicylic acid (25, 250, 2500 microgram/ml) alone, and combined with 10 mg/ml of ofloxacin on the respiratory burst . Superoxide anion was measured by the cytochrome c reduction microtechnique and H(2)O(2) by phenol red . The antiinflammatory drugs alone decreased the production of H(2)O(2) (except dexamethasone and methylprednisolone) and superoxide anion (except betamethasone) from 15-45%, depending on the antiinflammatory drug and concentration, while ofloxacin increased the production of superoxide anion (20.2 +/- 6.7%) . The combination of antiinflammatory drugs with ofloxacin neutralizes the inhibitory effect of the former on the respiratory burst of PMNs . It is therefore important to know the effect of drugs on the respiratory burst in order to choose those that have the same therapeutic effect without interfering with PMN functions. Dev Cell, 2001 Oct, 1(4), 503 - 14 Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis; Georgel P et al.; We report the molecular characterization of the immune deficiency (imd) gene, which controls antibacterial defense in Drosophila . imd encodes a protein with a death domain similar to that of mammalian RIP (receptor interacting protein), a protein that plays a role in both NF-kappaB activation and apoptosis . We show that imd functions upstream of the DmIKK signalosome and the caspase DREDD in the control of antibacterial peptide genes . Strikingly, overexpression of imd leads to constitutive transcription of these genes and to apoptosis, and both effects are blocked by coexpression of the caspase inhibitor P35 . We also show that imd is involved in the apoptotic response to UV irradiation . These data raise the possibility that antibacterial response and apoptosis share common control elements in Drosophila. Am J Clin Dermatol, 2001, 2(1), 21 - 5 Laser removal of tattoos; Kuperman-Beade M et al.; Tattoos are placed for different reasons . A technique for tattoo removal which produces selective removal of each tattoo pigment, with minimal risk of scarring, is needed . Nonspecific methods have a high incidence of scarring, textural, and pigmentary alterations compared with the use of Q-switched lasers . With new advances in Q-switched laser technology, tattoo removal can be achieved with minimal risk of scarring and permanent pigmentary alteration . There are five types of tattoos: amateur, professional, cosmetic, medicinal, and traumatic . Amateur tattoos require less treatment sessions than professional multicolored tattoos . Other factors to consider when evaluating tattoos for removal are: location, age and the skin type of the patient . Treatment should begin by obtaining a pre-operative history . Since treatment with the Q-switched lasers is painful, use of a local injection with lidocaine or topical anaesthesia cream may be used prior to laser treatment . Topical broad-spectrum antibacterial ointment is applied immediately following the procedure . Three types of lasers are currently used for tattoo removal: Q-switched ruby laser (694 nm), Q-switched Nd:YAG laser (532 nm, 1064 nm), and Q-switched alexandrite laser (755 nm) . The Q-switched ruby and alexandrite lasers are useful for removing black, blue and green pigments . The Q-switched 532 nm Nd:YAG laser can be used to remove red pigments and the 1064 nm Nd:YAG laser is used for removal of black and blue pigments . The most common adverse effects following laser tattoo treatment with the Q-switched ruby laser include textural change, scarring, and pigmentary alteration . Transient hypopigmentation and textural changes have been reported in up to 50 and 12%, respectively, of patients treated with the Q-switched alexandrite laser . Hyperpigmentation and textural changes are infrequent adverse effects of the Q-switched Nd:YAG laser and the incidence of hypopigmentary changes is much lower than with the ruby laser . The development of localized and generalized allergic reactions is an unusual complication following tattoo removal with the Q-switched ruby and Nd:YAG lasers . Since many wavelengths are needed to treat multicolored tattoos, not one laser system can be used alone to remove all the available inks and combination of inks . While laser tattoo removal is not perfect, we have come a long way since the advent of Q-switched lasers . Current research is focusing on newer picosecond lasers, which may be more successful than the Q-switched lasers in the removal of the new vibrant tattoo links. Am J Clin Dermatol, 2000 Nov-Dec, 1(6), 349 - 60 Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis; Fritsch PO et al.; Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare (occurring in approximately 2 to 3 people/million population/year in Europe and the US), life-threatening, intolerance reaction of the skin . It is most often caused by drugs (most commonly sulfonamides, nonsteroidal anti-inflammatory drugs, antimalarials, anticonvulsants, and allopurinol) . SJS/TEN is characterized by a macular exanthema ('atypical targets') which focusses on the face, neck, and the central trunk regions . Lesions show rapid confluence, a positive Nikolsky's sign, and quickly result in widespread detachment of the epidermis and erosions . Mucosal, conjunctival, and anogenital mucous membranes are prominently involved . Histopathology shows satellite cell necrosis in the early stages progressing to full thickness necrosis of the epidermis, contrasting with rather inconspicuous inflammatory infiltrates of the dermis . Damage to the skin is thought to be mediated by cytotoxic T lymphocytes and mononuclear cells which induce apoptosis in keratinocytes expressing drug-derived antigens at their surfaces . No guidelines for the treatment of SJS/TEN exist since no controlled clinical trials have ever been performed . The controversy over whether systemic corticosteroids should be used to curtail progression is still unresolved; while many authors agree that corticosteroids do in fact suppress progression, it is obvious that they also greatly enhance the risk of infection, the complication which most frequently leads to a fatal outcome . It appears reasonable to only administer corticosteroids in the phase of progression and to withdraw them as soon as possible, and to add antibacterials for prophylaxis . Recently, in a small series of patients, intravenous immunoglobulins were presumed to be effective by the blockade of lytic Fas ligand-mediated apoptosis in SJS/TEN . However, these results have to be confirmed by large clinical trials . Supportive treatment and monitoring of vital functions is of utmost importance in SJS/TEN, and out-patient treatment is unacceptable . Recovery is usually slow, depending on the extent and severity and the presence of complications, and may take 3 to 6 weeks . Skin lesions heal without scars as a rule, but scarring of mucosal sites is a frequent late complication, potentially leading to blindness, obliteration of the fornices and anogenital strictures . There is no reliable laboratory test to determine the offending drug; diagnosis rests on the patient's history and the empirical risk of drugs to elicit skin SJS/TEN . Provocation tests are not indicated since re-exposure is likely to elicit a new episode of SJS/TEN of increased severity. Am J Clin Dermatol, 2000 Mar-Apr, 1(2), 81 - 8 alpha-Hydroxy acid-based cosmetic procedures . Guidelines for patient management; Tung RC et al.; alpha-Hydroxy acid (AHA) peels and home regimens have recently been recognized as important adjunctive therapy in a variety of conditions including photodamage, actinic damage, melasma, hyperpigmentation disorders, acne, and rosacea . Overall in our experience and in the literature, AHAs have a proven level of safety and efficacy in a variety of skin types . Although their exact mechanism of action is unknown, it has been demonstrated that AHAs improve these disorders by thinning the stratum corneum, promoting epidermolysis, dispersing basal layer melanin, and increasing collagen synthesis within the dermis . In patients with photodamage, AHA peels and topical products are often combined with retinoids and other antioxidants for maximum benefit . Similarly, synergistic effects of fluorouracil and glycolic acid are observed in the treatment of diffuse actinic keratoses . For patients with melasma, AHA peels and combination products containing bleaching agents such as hydroquinone, kojic acid, and glycolic acid seem to have increased efficacy . Acne and rosacea patients can see improved results when standard regimens like antibacterials and topical retinoids are supplemented with AHA peels and lotions . However, care should always be taken prior to commencing treatment with AHA peels and topical products . By obtaining a thorough history and physical examination, the physician will identify any specific factors like medications, prior procedures and medical conditions which can affect the outcome of the peel . During the interview, there should be open discussion of patient questions and concerns so that realistic expectations can be made . Pre- and post-peel regimens should also be reviewed in full as patient compliance is essential to ensure the success of a series of AHA peels. Am J Clin Dermatol, 2000 May-Jun, 1(3), 191 - 9 Topical metronidazole . A review of its use in rosacea; McClellan KJ et al.; Topical application of the antibacterial agent metronidazole is effective in the treatment of moderate to severe rosacea, although its mechanism of action has yet to be clearly established . Metronidazole preparations (0.75 and 1% cream, 0.75% gel and 0.75% lotion) were significantly more effective than placebo in patients with moderate to severe rosacea when administered to the affected area once or twice daily for 7 to 12 weeks . The mean number of papules and pustules decreased by between 48 and 65.1% during the treatment period . Reductions were fairly consistent regardless of formulation, strength or application frequency and were significant compared with placebo (p < 0.05) . In 1 study, most of the overall effects of metronidazole were observed within the first 3 weeks . Although data are limited, topical metronidazole appears to improve inflammatory lesions and erythema as effectively as oral tetracyclines . Like tetracyclines, however, metronidazole has no effect on telangiectasia . Metronidazole 0.75% gel seems to be effective in maintaining remission of rosacea symptoms in patients successfully treated with both oral tetracycline and topical metronidazole . In the only study, 77% of patients treated with metronidazole gel compared with 58% of placebo recipients (p < 0.05) remained in remission 6 months after the tetracycline was stopped . The effects of topical metronidazole preparations on rosacea symptoms are palliative, not curative, but preliminary data suggest that relapse rates after cessation of therapy are no worse than those after cessation of oral oxytetracycline . Topical metronidazole formulations are generally well tolerated locally, with stinging, dryness, burning and itching reported in < or = 2% of patients . Because minimal concentrations of metronidazole are absorbed after topical administration, systemic adverse events and drug interactions seen with oral or intravenous metronidazole are unlikely . CONCLUSIONS: Topical metronidazole formulations are significantly more effective than placebo when used in the initial treatment of patients with moderate to severe rosacea . Furthermore, limited evidence suggests that the use of topical metronidazole alone may be as effective as oral tetracyclines against the disorder's inflammatory component . Therefore, for those patients with a preference for topical rather than oral therapy, the use of a topical metronidazole formulation must be a consideration. Eur J Clin Pharmacol, 2001 Sep, 57(6-7), 547 - 51 Use of systemic anti-infective agents in Iran during 1997-1998; Ansari F; OBJECTIVE: Conduction of standardized national drug utilization review to investigate the pattern of systemic anti-infective agent use in Iran . METHODS: The wholesale data were used . The Anatomical Therapeutic Chemical (ATC) classification and the defined daily dose (DDD) methodology was employed . Data were presented as DDD/1,000 inhabitants"day . Results were compared using national drug statistics of Norway, Sweden, and Denmark . RESULTS: The overall sales of systemic anti-infective agents was 43.5 DDD/1,000 inhabitants/day . The parenteral form of drug accounted for 4.20% and broad-spectrum systemic antibacterial agents accounted for 86.2% . The three most commonly used agents, accounting for 74.1% of total sales, were amoxicillin, co-trimoxazole, and ampicillin . Seven kinds of anti-infective agents (17% of total available agents) accounted for 90% of antibacterial use, with dominance of broad-spectrum agents . Comparison showed differences in pattern and intensity of use . The sales of systemic anti-infective agents in general, particularly antibacterials and anti-tuberclotics, were greater in Iran than in three European countries . Broad-spectrum antibacterial agents accounted for a larger proportion of total sales in Iran . CONCLUSION: The high use of systemic antibacterial agents in general, particularly broad-spectrum agents, suggest the possibility of irrational prescribing, higher prescribed daily doses than DDDs, and a drug wastage . This survey, as a first attempt, provided an overview of anti-infective use in Iran . Thus, it may serve as a basis for further investigative studies and advanced drug policies. Vestn Otorinolaringol, 2001, (5), 29 - 32 {Comparative clinical efficacy and tolerance of cefuroxime axetil (zinnat) and ceftibuten (cedex) in patients with acute sinusitis}; Otvagin IV et al.; The aim of the study was to substantiate clinically and microbiologically administration of such oral cephalosporins as cefuroxime axetil and ceftibuten in acute sinusitis . The spectrum of causative agents of acute sinusitis was determined, most common pathogens were identified and their sensitivity to antibiotics was tested . The conclusion is made that cephalosporins of the II-III generation meet the requirements to antibacterial drugs for treatment of acute sinusitis. Eur J Pharmacol, 2001 Oct 19, 429(1-3), 209 - 29 Anti-inflammatory effects of macrolide antibiotics; Culic O et al.; Macrolides are widely used as antibacterial drugs . Clinical and experimental data, however, indicate that they also modulate inflammatory responses, both contributing to the treatment of infective diseases and opening new opportunities for the therapy of other inflammatory conditions . Considerable evidence, mainly from in vitro studies, suggests that leukocytes and neutrophils in particular, are important targets for modulatory effects of macrolides on host defense responses . This underlies the use of the 14-membered macrolide erythromycin for the therapy of diffuse panbronchiolitis . A variety of other inflammatory mediators and processes are also modulated by macrolides, suggesting that the therapeutic indications for these drugs may be extended significantly in future. J Pharm Pharmacol, 2001 Oct, 53(10), 1303 - 10 Human lactoferrin: a novel therapeutic with broad spectrum potential; Weinberg ED; Lactoferrin (Lf), a natural defence iron-binding protein, has been found to possess antibacterial, antimycotic, antiviral, antineoplastic and anti-inflammatory activity . The protein is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervico-vaginal mucus and seminal fluid . Additionally, Lf is a major constituent of the secondary specific granules of circulating polymorphonuclear neutrophils (PMNs) . The apoprotein is released on degranulation of the PMNs in septic areas . A principal function of Lf is that of scavenging free iron in fluids and inflamed areas so as to suppress free radical-mediated damage and decrease the availability of the metal to invading microbial and neoplastic cells . Mechanisms of action of Lf in addition to iron deprivation are also described . Administration of exogenous human or bovine Lf to hosts with various infected or inflamed sites has resulted in some prophylactic or therapeutic effects . However, an adverse response to the protein might occur if it were to stimulate antibody production or if it were to provide iron to the invading pathogen . The recombinant form of human Lf has become available and development of the product for use in a wide range of medical conditions can now be anticipated. Stomatologiia (Mosk), 2001, 80(5), 22 - 5 {Insulating polymeric film in comprehensive prevention of complications of mandibular fractures}; Korotkikh NG et al.; A method for prevention of inflammatory complications of mandibular fractures making use of insulating polymer-based bioactive film was studied on 48 mice . Antibacterial and osteoregeneratory activities of the therapeutic film were assessed. Stomatologiia (Mosk), 2001, 80(5), 14 - 7 {Ozone therapy of chronic mandibular osteomyelitis}; Agapov VS et al.; Clinical picture, bacterial passage, and immune status were studied in patients with chronic traumatic and chronic odontogenic mandibular osteomyelitis . The deepest disorders of biocenosis and the highest incidence of immunodeficiencies were observed in patients with chronic odontogenic osteomyelitis . Local and total ozone therapy is suggested for antibacterial and immunomodulating treatment . Medical ozone exposure promoted more complete and rapid normalization of nonspecific resistance and T-cellular immunity, thus accelerating clinical cure and reducing the incidence of complications. Aust Dent J, 2001 Sep, 46(3), 166 - 73 Oral hygiene measures and promotion: review and considerations; Choo A et al.; Current mechanical and chemotherapeutic approaches to oral hygiene aim to modify the oral microflora to promote healthy periodontal and dental tissues . Current oral hygiene measures, appropriately used and in conjunction with regular professional care, are capable of virtually preventing caries and most periodontal disease and maintaining oral health . Toothbrushing and flossing are most commonly used, although interdental brushes and wooden sticks can offer advantages in periodontally involved dentitions . Chewing sugar-free gums as a salivary stimulant is a promising caries-preventive measure . Despite new products and design modifications, mechanical measures require manual dexterity and cognitive ability . Chemotherapeutic supplementation of mechanical measures using dentifrices, mouthrinses, gels and chewing gums as delivery vehicles can improve oral hygiene . The list includes anticalculus, antibacterial and cariostatic agents . For the population at large to make effective use of these oral hygiene measures, oral hygiene promotion needs to be implemented . Considerations include the role of parents, school and the media for children and the workplace, social environments . nursing homes and trained carers for adults and the elderly . Community oral hygiene promotion must attempt to maximise opportunities for oral health for all and reduce inequalities by removing financial and other barriers . Oral health approaches should be tailored to lifestyles and abilities of children, adults and the elderly in order to enable them to make decisions to improve personal oral hygiene and oral health. J Ethnopharmacol, 2001 Dec, 78(2-3), 133 - 7 Immunomodulatory activity of alcoholic extract of Mangifera indica L . in mice; Makare N et al.; Mangifera indica Linn, a plant widely used in the traditional medicinal systems of India, has been reported to possess antiviral, antibacterial and anti-inflammatory activities . In the present study, the alcoholic extract of stem bark of Mangifera indica Linn (Extract I containing mangiferin 2.6%), has been investigated for its effect on cell mediated and humoral components of the immune system in mice . Administration of test extract I produced increase in humoral antibody (HA) titre and delayed type hypersensitivity (DTH) in mice . It is concluded that test extract I is a promising drug with immunostimulant properties. Indian J Biochem Biophys, 2001 Jun, 38(3), 142 - 8 Effects of salt and denaturant on structure of the amino terminal alpha-helical segment of an antibacterial peptide dermaseptin and its binding to model membranes; Thennarasu S et al.; The amino terminal 1-18 domain of dermaseptin s is an important determinant of its structure as well as the antibacterial activity . A thorough investigation on the structure of the 18-residue peptide (D18) and its binding to model membranes in presence of salt and denaturant guanidinium chloride has been carried out . In presence of salt, there is an increase in the fraction of peptide molecules in helical conformation . In presence of the denaturant, D18 is unordered, but addition of the structure-promoting solvent trifluoroethanol results in a transition to the helical conformation . In presence of denaturant, the peptide is unordered, but binding to lipid vesicles is not abolished . Investigation of model membrane permeabilizing ability of the peptide in solutions containing various proportions of sodium chloride and guanidinium chloride indicates that vesicle permeabilization parallels extent of binding . The peptide thus binds to lipid vesicles in an unfolded state . Since the peptide has propensity to fold into a helical conformation, lipid induced transition to a helical structure occurs, followed by membrane permeabilization as a result of pore formation. Arch Toxicol, 2001 Sep, 75(7), 395 - 9 Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice; Shimoda K et al.; We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation . Retinal degeneration was induced at 40 mg/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation . We then examined the incidence of retinal degeneration with various periods of UVA irradiation in BALB/c mice given a single intravenous administration of 40 mg/kg sitafloxacin . Retinal degeneration occurred in all the groups receiving UVA irradiation immediately after sitafloxacin administration, whereas no retinal degeneration occurred in the groups receiving UVA irradiation starting 30 min or later after administration . In addition, we examined both the retinal degeneration and auricular inflammation in BALB/c mice given a 7-day repeated administration of sitafloxacin at 1, 3.3 and 10 mg/kg per day, which never induce retinal or auricular change by a single administration . Retinal degeneration was not induced at any dose level, although auricular skin inflammation was augmented by repeated administration . These results suggest that the occurrence of retinal degeneration depends on maximum ocular sitafloxacin concentration during UVA irradiation, whereas the severity of auricular inflammation is directly proportional to the total decrease in area under the drug concentration curve for auricular sitafloxacin under UVA irradiation . This difference between retinal degeneration and auricular inflammation may derive from their respective mechanisms of pathogenesis. Clin Diagn Lab Immunol, 2001 Nov, 8(6), 1044 - 8 STAT4 is required for antibacterial defense but enhances mortality during polymicrobial sepsis; Godshall CJ et al.; The signal transducer and activator of transcription factor 4 (STAT4) pathway mediates the intracellular effects of interleukin-12 (IL-12), leading to the production of gamma interferon, induction of a T helper type 1 response, and increased natural killer cell cytotoxicity . The purpose of this study was to determine the role of the STAT4 pathway during polymicrobial peritonitis in the cecal ligation and puncture (CLP) model . CLP was performed on STAT4-deficient (STAT4(-/-)) and wild-type control (BALB/c) mice . At 4 h after CLP, STAT4(-/-) mice had significantly higher bacterial counts in the peritoneal lavage fluid, liver, and blood . This difference persisted for 18 h in the peritoneal lavage fluid and blood . Neutrophil migration to the site of infection and into remote tissues was unaffected . Despite higher bacterial counts locally and systemically, STAT4(-/-) mice had a lower mortality rate than BALB/c controls . In contrast, blockade of IL-12 in BALB/c mice was detrimental to host survival . A blunted serum IL-12 response at 18 h after CLP was exhibited in STAT4(-/-) mice . These results suggest several critical roles for the STAT4 pathway in the resolution of polymicrobial infections . Additionally, the disparate effects observed with IL-12 blockade and STAT4 deficiency on host survival suggest that IL-12 may activate alternate pathways promoting survival. Pharm Res, 2001 Sep, 18(9), 1310 - 4 Penetration of cefaclor into the interstitial space fluid of skeletal muscle and lung tissue in rats; De La Pena A et al.; PURPOSE: To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model . METHODS: Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v . bolus doses of 50 and 75 mg/kg cefaclor . Unbound muscle concentrations were also measured after a primed, continuous i.v . infusion at an infusion rate of 0.3 mg/kg/min . RESULTS: The cefaclor half-life in plasma, muscle and lung was approximately 1 h . Unbound cefaclor concentrations in muscle and lung were found to be virtually identical . A 2-compartment body model was fitted to the data with a tissue penetration factor (AUC(tissue(unbound)))/AUC(plasma(unbound))) of approximately 0.26 independent of dose, tissue and mode of administration . CONCLUSIONS: Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma . Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy . Instead, therapeutically active levels of cefaclor at the site of action should be taken into account . Microdialysis allows direct measurement of these unbound concentrations. J Pharm Biomed Anal, 2002 Jan 1, 27(1-2), 133 - 42 Spectrophotometric determination of ciprofloxacin, enrofloxacin and pefloxacin through charge transfer complex formation; Mostafa S et al.; A spectrophotometric method was described for the determination of the antibacterial quinolone derivatives, ciprofloxacin, enrofloxacin and pefloxacin through charge transfer complex formation with three different acceptors . Chloranilic acid (CL) was utilized for their determination, forming charge transfer complex with lambdamax 520 nm . The proposed method was applied for determination of Ciprocin tablets, Enroxil oral solution, Peflacin ampoules and Peflacin tablets, with mean percentage accuracies, 99.58+/-1.25,99.94+/-0.96,100.91+/-1.59 and 99.86+/-1.003 . Also, tetracyanoethylene (TCNE) was utilized in the determination of the concerned compounds forming charge transfer complexes with maximum absorbances at lambdamax 335 nm for ciprofloxacin and at lambdamax 290 nm for both enrofloxacin and pefloxacin . The procedure was applied for determination of Ciprocin tablets, Enroxil 10% oral solution, Peflacine tablets and Peflacine ampoules with mean percentage accuracies 99.40+/-1.27,99.95+/-0.90,98.98+/-1.565 and 99.88+/-0.998, respectively . Also, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was utilized for determination of pefloxacin forming charge transfer complex with maximum absorbance at lambdamax 460 nm . The procedure was applied for determination of peflacine tablets and peflacine ampoules with mean percentage accuracies 100.40+/-0.76 and 99.91+/-0.623, respectively . Statistical analysis of the obtained results showed no significant difference between the proposed method and other official and reported methods as evident from the t-test and variance ratio. Farmaco, 2001 Sep, 56(9), 665 - 75 Synthesis and antibacterial activity of 2-substituted 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids; Jung JC et al.; A series of 2-substituted 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was prepared and evaluated for antibacterial activity . The 6-fluoro-2-methyl-1-prenyl-1,4-dihydro-7-(3,5-dimethylpiperazinyl)-4-oxo-3-quinolinecarboxylic acid (14f) exhibited the most potent antibacterial activity against gram-positive bacteria among the total 32 derivatives . The synthetic strategies involve the use of well known keto ester condensation of benzoyl chloride and reductive cyclization of intermediates (4a-d) to afford 4-hydroxy-1,2-dihydro-2-oxo-quinoline derivatives (5a,b) or 1-hydroxy-1,4-dihydro-4-oxo-quinoline derivatives (6a,b). Adv Immunol, 2001, 79, 225 - 59 Regulation of antibacterial and antifungal innate immunity in fruitflies and humans; Williams MJ; Insects have been very successful in adapting to their environment, and the ability of the insect immune system to detect and elicit the appropriate response against various invading pathogens has helped in this success . Unlike the vertebrate immune system, which consists of both innate and adaptive components, insect immunity probably consists entirely of an innate immune response, as no evidence of an adaptive response has been found . The innate immune response is described as either a reaction against "lack of self," or the interaction between host germline-encoded receptors and molecules unique to a particular class of invading organisms . Once the invading organism is recognized, the host immune response can be activated via signaling pathways that lead to the appropriate reaction . This review endeavors to put forth how through genetic, molecular, and biochemical studies of the fruit fly Drosophila melanogaster, as well as other insects, it is now understood that aspects of the insect and vertebrate innate immune system are very similar. Acta Crystallogr D Biol Crystallogr, 2001 Nov, 57(Pt 11), 1677 - 9 Epub 2001 Oct 25. Expression, purification, crystallization and preliminary X-ray analysis of the cathelicidin motif of the protegrin-3 precursor; Sanchez JF et al.; Numerous precursors of antibacterial peptides with unrelated sequences share a similar prosequence which belongs to the cathelicidin family of proteins . The three-dimensional structure of this cathelicidin motif, which contains two disulfide bonds, has not yet been reported . The cathelicidin motif (ProS) of the protegrin-3 precursor was overexpressed in Escherichia coli as a His-tagged protein . The His(6) tag was removed by thrombin cleavage . ProS was purified to homogeneity and single crystals were obtained by the hanging-drop vapour-diffusion method at pH 3-4 . Preliminary X-ray diffraction analysis indicated that these crystals belong to the hexagonal space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 51.42, c = 134.25 A . These crystals diffracted beyond 2.75 A (1.9 A at ESRF) and contain one molecule per asymmetric unit. Bioorg Med Chem Lett, 2001 Nov 19, 11(22), 2931 - 4 Enols as potent antibacterial agents; Thorarensen A et al.; This paper describes the discovery of alpha-trifluoroketoacetamides as potent antibacterial agents against Gram-positive organisms . The initial SAR indicates that the aryl ethyl side chain is essential in maintaining antibacterial activity . The SAR observations have been utilized to design a bioisostere for the alpha-trifluoroketoacetamide with good activity against Gram-positive organisms. Fitoterapia, 2001 Nov, 72(7), 810 - 7 Sudanese plants used in folkloric medicine: screening for antibacterial activity . Part X; Elegami AA et al.; The results of the screening for antibacterial activity of 30 medicinal plants from north, east and central Sudan are reported. Fitoterapia, 2001 Nov, 72(7), 807 - 9 Antibacterial activity of Caesalpinia bonducella seeds; Saeed MA et al.; The methanol extract and four triterpenoids isolated from the seeds of Caesalpinia bonducella showed a wide range of inhibiting activity against both gram-positive and gram-negative bacteria. Biosci Biotechnol Biochem, 2001 Sep, 65(9), 1965 - 9 The relationship between a leaf-rolling moth (Dactylioglypha tonica) and fungi covering the cocoon; Imamura N et al.; To discover the relationship between a leaf-rolling moth and the fungi densely covering its cocoons, the rolled nest leaves were collected in two districts in Japan and antibacterial properties of the fungi were examined . Cocoons and fungi isolated from the nest were classified into 5 categories by the growth stages of the insects, and 7 categories based on taxonomic properties and pigment productivity, respectively . The dominant genus was Penicillium in each location . However, the composition of the fungal categories was different and seemed to depend on their circumstances . From all cocoons with larvae, the strains that belonged to the same fungal category and produced the same antibiotic (deoxyherqueinone) were isolated . From these results, the species-specific relationship between the insect and fungi or fungal products was considered to be not extremely tight, and it was suggested the period of the larval spinning of the cocoon is a key stage of this unique relationship. J Org Chem, 1999 Jul 23, 64(15), 5388 - 5395 Photoinduced C-F Bond Cleavage in Some Fluorinated 7-Amino-4-quinolone-3-carboxylic Acids; Fasani E et al.; The photochemistry of some fluorinated 7-amino-4-quinolone-3-carboxylic acids used in therapy as antibacterials and known to be phototoxic has been investigated in water . All of them undergo heterolytic defluorination, and this appears to be a path for the generation of aryl cations in solution . 6-Fluoro derivatives such as norfloxacin (Phi(dec) = 0.06) and enoxacin (Phi(dec) = 0.13) give the corresponding phenols . Insertion of an electron-donating substituent makes defluorination inefficient; thus, ofloxacin, an 8-alkoxy derivative, is found to be rather photostable (Phi(dec) = 0.001) and reacts in part via a process different from defluorination (degradation of the N-alkyl side chain) . With a 6,8-difluoro derivative, lomefloxacin, the reaction is more efficient (Phi = 0.55) and selective for position 8 . Contrary to the previous cases, the aryl cation undergoes insertion in the neighboring N-ethyl group rather than solvent addition (a carbene-like chemistry) . With all of the above fluoroquinolones an intensive triplet-triplet absorption is detected and is quenched by sulfite (k(q) = (1-5) x 10(8) M(-)(1) s(-)(1)) . Under this condition, reductive defluorination via the radical anion takes place . The relation of the above chemistry to the phototoxicity of these drugs is commented upon briefly. J Org Chem, 1997 Nov 14, 62(23), 8177 - 8181 Solid-Phase Synthesis of beta-Sultams; Gordeev MF et al.; Solid-phase synthesis of beta-sultams amenable for construction of sulfonyl beta-lactam analogue combinatorial libraries is reported . Imine intermediates generated from polymer-immobilized amino acids and aldehydes are reacted with (chlorosulfonyl)acetates in the presence of pyridine to afford the solid-phase-tethered beta-sultam products . The latter can be released from support by acidic cleavage (TFA) or photocleavage, depending on the nature of the linker employed (acid-labile or photolabile linkers) . Immobilized 4-(9-fluorenyl)methoxycarbonyl beta-sultams are further functionalized on supports to afford, upon cleavage, the respective carboxy and amido thiazetidine derivatives . The method can be employed in production of beta-sultam libraries for identification of new antibacterial agents. J Org Chem, 1996 Jun 14, 61(12), 3983 - 3986 Solid-Phase Total Synthesis of Bacitracin A; Lee J et al.; An efficient solid-phase method for the total synthesis of bacitracin A is reported . This work was undertaken in order to provide a general means of probing the intriguing mode of action of the bacitracins and exploring their potential for use against emerging drug-resistant pathogens . The synthetic approach to bacitracin A involves three key features: (1) linkage to the solid support through the side chain of the L-asparaginyl residue at position 12 (L-Asn(12)), (2) cyclization through amide bond formation between the alpha-carboxyl of L-Asn(12) and the side chain amino group of L-Lys(8), and (3) postcyclization addition of the N-terminal thiazoline dipeptide as a single unit . To initiate the synthesis, Fmoc L-Asp(OH)-OAllyl was attached to a PAL resin . The chain of bacitracin A was elaborated in the C-to-N direction by sequential piperidine deprotection/HBTU-mediated coupling cycles with Fmoc D-Asp(OtBu)-OH, Fmoc L-His(Trt)-OH, Fmoc D-Phe-OH, Fmoc L-Ile-OH, Fmoc D-Orn(Boc)-OH, Fmoc L-Lys(Aloc)-OH, Fmoc L-Ile-OH, Fmoc D-Glu(OtBu)-OH, and Fmoc L-Leu-OH . The allyl ester and allyl carbamate protecting groups of L-Asn(12) and L-Lys(8), respectively, were simultaneously and selectively removed by treating the peptide-resin with palladium tetrakis(triphenylphosphine), acetic acid, and triethylamine . Cyclization was effected by PyBOP/HOBT under the pseudo high-dilution conditions afforded by attachment to the solid support . After removal of the N-terminal Fmoc group, the cyclized peptide was coupled with 2-{1'(S)-(tert-butyloxycarbonylamino)-2'(R)-methylbutyl}-4(R)-carboxy-Delta(2)-thiazoline (1) . The synthetic peptide was deprotected and cleaved from the solid support under acidic conditions and then purified by reverse-phase HPLC . The synthetic material exhibited an ion in the FAB-MS at m/z 1422.7, consistent with the molecular weight calculated for the parent ion of bacitracin A (MH(+) = C(73)H(84)N(10)O(23)Cl(2), 1422.7 g/mol) . It was also indistinguishable from authentic bacitracin A by high-field (1)H NMR and displayed antibacterial activity equal to that of the natural product, thus confirming its identity as bacitracin A . The overall yield for the solid-phase synthesis was 24%. Drug Saf, 2001, 24(11), 843 - 53 Preventing and managing drug-induced anaphylaxis; Drain KL et al.; Drug-induced anaphylaxis and anaphylactoid reactions have increased in frequency with more widespread use of pharmaceutical agents . Anaphylaxis is a systemic, severe immediate hypersensitivity reaction caused by immunoglobulin (Ig) E-mediated immunological release of mediators of mast cells and basophils . An anaphylactoid reaction is an event similar to anaphylaxis but is not mediated by IgE . The incidence of anaphylactic or anaphylactoid reactions differs amongst classes of medications . Antibacterials are the most usual offenders, and penicillins are the most studied . Other compounds commonly causing reactions include non-steroidal anti-inflammatory drugs, anaesthetics, muscle relaxants, latex and radiocontrast media . Prevention, if possible, is the purpose of detailed patient history taking and physical examination . Simple strategies can be employed to decrease the risk of anaphylaxis . These include consideration of the route of drug administration, identification of patients with known causes of anaphylaxis, and the knowledge that certain medications cross react and are contraindicated in those with known history of anaphylaxis . Tests are available, and include IgE-specific skin tests and radioallergosorbent tests . Penicillins are the only compounds whose antigenic determinants are well documented, it is therefore difficult to determine the negative predictive value of other compounds tested . Oral challenge remains an alternative, though entails risk . Desensitisation procedures, as well as gradual dose escalation protocols, are available and can be implemented based on patient history and diagnostic testing . The management of anaphylaxis is based on control of the airway, breathing and circulation . Treatment consists of epinephrine (adrenaline) and supportive measures . Rapid diagnosis and intervention are important in these life-threatening reactions . After stabilisation, all individuals with a documented history of anaphylaxis require a Medic-Alert bracelet or necklace, and an identification card for their wallet or purse. Pharmacotherapy, 2001 Oct, 21(10 Pt 2), 224S - 232S Mechanism of action of and resistance to quinolones; Bearden DT et al.; A topoisomerase was identified as the bacterial target site for quinolone action in the late 1970s . Since that time, further study identified two bacterial topoisomerases, DNA gyrase and topoisomerase IV, as sites of antibacterial activity DNA gyrase appears to be the primary quinolone target for gram-negative bacteria . Topoisomerase IV appears to be the preferential target in gram-positive organisms, but this varies with the drug . Three mechanisms of resistance against quinolones are mutations of topoisomerases, decreased membrane permeability, and active drug efflux . Although these mechanisms occur singly, several resistance factors are often required to produce clinically applicable increases in minimum inhibitory concentrations . Appropriate drug selection and dosage and prudent human and veterinary interventions are important factors in controlling the emergence of resistance. Pathol Biol (Paris), 2001 Sep, 49(7), 576 - 82 {Chronic experimental bacteremia in Yucatan micropigs}; Peter JD et al.; The Yucatan micropig has been used to develop an experimental model of chronic bacteremia . This animal exhibits clinical and biological characteristics that are close to those in humans, and the pharmacokinetic behaviours of many classes of drugs in this model are similar to those in man . Six adult female were intravenously inoculated with a mean Escherichia coli inoculum of 5.1 x 10(9) bacteria . During five days of spontaneous evolution, the medical follow-up includes biological, clinical and bacteriological parameters . A systemic inflammatory syndrome, a sepsis, an organ insufficiency and positive blood cultures mimic the human disease . In all animals there is an adynamia, a lack of motor coordination, an anorexia, a tachypnea, a fever, a leuconeutropenia followed by an hyperleucocytosis, an anemia, a thrombopenia, an acute tubulonephritis and an elevated sedimentation rate . In some cases, there is an increase of the C reactive protein, in others, an increase of IL-6 and IL-8 . At day five, all animals are alive, and five micropigs have positive blood cultures . This chronic, reproducible model is thus suitable for further antibacterial treatments evaluations. Caries Res, 2001 Sep-Oct, 35(5), 331 - 7 The effects of benzoate and fluoride on dental caries in intact and desalivated rats; Davis BA et al.; The decline in prevalence of dental caries in some segments of the population has been attributed mainly to extensive exposure to fluoride . Over the past decades, the use of fluoridated products has increased . During the same period, the consumption of food preservatives such as benzoates and sorbates has also increased substantially . Benzoates, in vitro, possess antibacterial properties similar to those of fluoride and in combination with fluoride could affect caries development . In the present study we explored the effects of sodium benzoate and fluoride in combination and alone on dental caries in our animal model . The results showed a combination of benzoate and fluoride reduced caries activity more effectively in rodents fed a cariogenic diet ad libitum than fluoride alone (p = 0.038). Rev Hist Pharm (Paris), 1997, 45(314), 171 - 8 {A hundred years pharmaceutical research performed in the Rhône-Poulenc groups}; Barral E; The main discoveries performed by scientists working the Rhone-Poulenc groups are listed, from 1895, date of the creation of Societe chimique des usines du Rhone, to 1996 . Analgesics, hypnotics, drugs useful for surgery, Tropical diseases, antihistaminics, neuroleptics, antibacterial agents, drugs acting in the cardio-vascular system, anti-cancer agents and drugs discovered by companies who joined the groups are briefly presented . Biotechnologies are also evoked. Nord Medicinhist Arsb . 1996;:81-90. {The history of toothcleaning}; Hanstrom L et al.; A short historical review of toothcleaning with primitive and manufactured toothbrushes, toothpicks and thread of waxed silk . Mouthrinses, toothpowders or soaps and toothpastes and chewing gums composed of ingredients from nature are presented . Antibacterial and pharmacological effects are discussed. Genetics, 2001 Oct, 159(2), 659 - 71 Evidence for recurrent paralogous gene conversion and exceptional allelic divergence in the Attacin genes of Drosophila melanogaster; Lazzaro BP et al.; Insects produce a limited variety of antibacterial peptides to combat a wide diversity of pathogens . These peptides are often conserved across evolutionarily distant taxa, but little is known about the level and structure of polymorphism within species . We have surveyed naturally occurring genetic variation in the promoter and coding regions of three Attacin antibacterial peptide genes from 12 lines of Drosophila melanogaster . These genes exhibit high levels of silent nucleotide variations (1-3% per nucleotide heterozygosity), but are not excessively polymorphic at the amino acid level . There is extensive variation in the Attacin promoters, some of which may affect transcriptional efficiency, and one line carries a deletion in the Attacin A coding region that renders this gene nonfunctional . Two of the genes, Attacins A and B, are arranged in tandem and show evidence of repeated interlocus gene conversion . Attacin C, more divergent and located 1.3 Mbp upstream of Attacins A and B, does not appear to have been involved in such exchanges . All three genes are characterized by divergent haplotypes, and one Attacin AB allele appears to have recently increased rapidly in frequency in the population. J Am Coll Nutr, 2001 Oct, 20(5 Suppl), 389S - 395S; discussion 396S-397S Antiinflammatory activities of lactoferrin; Conneely OM; Lactoferrin is a non-heme iron binding glycoprotein produced during lactation and by epithelial cells at mucosal surfaces . The protein is a prominent component of the first line of mammalian host defense and its expression is upregulated in response to inflammatory stimuli . In this paper, the antibacterial and immune modulatory properties of lactoferrin that contribute to host defense are reviewed . In addition, the results of recent preclinical and clinical studies demonstrating that lactoferrin acts as an inhibitor of dermal inflammatory cytokine production are summarized . The results indicate that lactoferrin may act as a potent anti-inflammatory protein at local sites of inflammation including the respiratory and gastrointestinal tracts. Dev Comp Immunol, 2001 Oct-Dec, 25(8-9), 827 - 39 Innate host defense mechanisms of fish against viruses and bacteria; Ellis AE; The integumental defenses provide a physical and chemical barrier to the attachment and penetration of microbes . Besides the entrapping and sloughing of microbes in the mucus, the latter contains many antibacterial substances including anti-bacterial peptides, lysozyme, lectins and proteases.The gastro-intestinal tract is a hostile environment of acids, bile salts and enzymes able to inactivate and digest many viruses and bacteria . In most cases the integumental defenses are sufficient to protect against even quite virulent organisms which often only produce disease when the integument has been physically damaged . If a microbe gains access to the tissues of the fish, it is met with an array of soluble and cellular defenses . The complement system, present in the blood plasma, plays a central role in recognising bacteria and its activated products may lyse the bacterial cells, initiate inflammation, induce the influx of phagocytes and enhance their phagocytic activity . Complement can be activated directly by bacterial products and constituents and also indirectly by other factors, principally C-reactive protein and lectins, which can also bind to the bacterial surface . Plasma also contains a number of factors which inhibit bacterial growth(e.g . transferrin and anti-proteases) or which are bactericidal e.g . lysozyme . Following the infection of fish with virus pathogens, infected cells produce interferon . This induces antiviral defenses in neighbouring cells which are then protected from becoming infected . Anti-viral cytotoxic cells are able to lyse virally infected cells and thus reduce the rate of multiplication of virus within them . Innate defenses thus provide a pre-existing and fast-acting system of protection which is non-specific and relatively temperature-independent and thus has several advantages over the slow-acting and temperature-dependent specific immune responses. J Food Prot, 2001 Oct, 64(10), 1579 - 83 Heated scallop-shell powder slurry treatment of shredded cabbage; Sawai J et al.; The main component of scallop-shell powder is calcium carbonate (CaCO3) . Through heat treatment, CaCO3 in the shell is converted to CaO, which exhibits antibacterial activity . The disinfecting effect of heated scallop-shell powder on shredded cabbage was investigated for various powder concentrations (0.1 to 1.0 g dm(-3)) and treatment temperatures (10 to 40 degrees C) . Scallop-shell powder treatment was found to reduce the aerobic bacteria count in cabbage, with increasing effectiveness at higher powder concentrations and treatment temperatures . Coliforms were completely eliminated within 5 min with as little as 0.1 g dm(-3) powder treatment . During storage at 4 degrees C, aerobic bacterial counts did not increase after powder treatment, whereas counts increased with water-washing or sodium hypochlorite treatment at 200 microg dm(-3) . The inactivation pattern of bacterial cells in shredded cabbage involved an accelerated decline followed by an extended tail at powder concentrations of 0.1 and 0.5 g dm(-3) . We postulate that a fraction of bacterial cells in the initial population becomes tolerant to the shell powder . A proposed model accurately predicts the reducing bacterial counts on shredded cabbage by scallop-shell powder treatment . The decrease in the L-ascorbic acid content of shredded cabbage was approximately 20 to 30% for scallop-shell powder treatment at 0.1 and 0.5 g dm(-3) (20 degrees C), which is almost identical to that by sodium hypochlorite treatment at 200 micorg dm(-3). Farmaco, 2001 Aug, 56(8), 565 - 70 Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial and anticancer screening studies--part I; Holla BS et al.; A series of 7-arylidene-6-(2,4-dichloro-5-fluorophenyl)-3-substituted-1,2,4-triazolo{3,4-b}-1,3,4-thiadiazines (3) were prepared by the condensation of 4-amino-5-mercapto-3-substituted-1,2,4-triazoles (1) and 3-aryl-1-(2,4-dichloro-5-fluorophenyl)-2-bromo-2-propen-1-one (2) . An alternative route for the synthesis of the title compound 3 has been described . The newly synthesised compounds were characterised on the basis of N-analyses, IR, 1H NMR and mass spectral data . Some of the newly synthesised compounds were tested for their antibacterial activities against Gram + ve and Gram - ve bacteria . Among the tested compounds 3n showed the highest degree of antibacterial activity against S . aureus and evaluation of the LD50 value of this compound was carried out . Some of the newly synthesised compounds were also screened for their anticancer activities . Among these, compounds 3b, 3g, 3n and 3p are found to be active against NCI-H460 (lung), MCF7 (breast), SF 268 (CNS) in the preliminary anticancer screening studies . Further, 60-cell-line anticancer studies of these compounds were carried out . The results of such studies are discussed in this paper. Farmaco, 2001 Aug, 56(8), 549 - 54 Synthesis and biological evaluation of some differently substituted 9,10-anthracenediones; Cardia MC et al.; 9,10-Anthracenedione derivatives are known to exhibit a quite potent anticancer activity . It has also been reported that these compounds can be effectively employed in both antibacterial and antitrypanosomal therapy . Anthraquinones also exhibit some undesirable side effects, like cardiotoxicity . So many interactions seem to demonstrate that 9,10-anthracenediones strongly interact with a number of biological sites . In this paper we wish to report on the synthesis and the pharmaceutical activity of some newly synthesised derivatives containing the anthraquinone pharmacophore. Nucleic Acids Res, 2001 Oct 15, 29(20), 4224 - 30 The topoisomerase II poison clerocidin alkylates non-paired guanines of DNA: implications for irreversible stimulation of DNA cleavage; Gatto B et al.; Clerocidin, a diterpenoid with antibacterial and antitumor activity, stimulates in vitro DNA cleavage mediated by mammalian and bacterial topoisomerase (topo) II . Different from the classical topoisomerase poisons, clerocidin-stimulated breaks at guanines immediately preceding the sites of DNA cleavage are not resealed upon heat or salt treatment . To understand the mechanism of irreversible trapping of the topo II-cleavable complex, we have investigated the reactivity of clerocidin per se towards DNA . We show here that the drug is able to nick negatively supercoiled plasmids . DNA cleavage by clerocidin in enzyme-free medium is due to the ability of the drug to form covalent adducts with guanines . Indeed, clerocidin was able to specifically react with short oligonucleotides when the guanines were unpaired and exposed as in bulges or in the single-strand form . The clerocidin epoxy group attacks the nitrogen at position 7 of guanines, leading to strand scission at the modified site . Our findings also demonstrate that trapping of topoisomerases by clerocidin is specific for type II enzymes . The guanine-alkylating ability of clerocidin suggests an unprecedented mechanism of topo II poisoning, according to which the enzyme renders the drug reactive toward DNA by distorting the double-helical structure of the nucleic acid at the cleavage site. Eur J Med Chem, 2001 Jul-Aug, 36(7-8), 615 - 25 Synthesis and antibacterial screening of hydrazones, Schiff and Mannich bases of isatin derivatives; Sridhar SK et al.; Schiff bases and hydrazones of substituted isatins (1-28) were prepared by reacting isatin and aromatic primary amines/hydrazines . A new series of the corresponding N-Mannich base (29-35) was synthesised by reacting them with formaldehyde and diphenyl amine . The chemical structures were confirmed by means of 1H-NMR, IR spectral data and elemental analysis . The compounds were screened for antibacterial activity against seven Gram (+) and seven Gram (-) standard and pathological bacterial strains by the paper disc diffusion technique . The minimum inhibitory concentrations of the active compounds were determined . 1-Diphenyl amino-methyl-3-(4-bromo phenylimino)-1,3-dihydro-indol-3-one (30) and 3-(4-bromo phenylimino)-5-nitro-1,3-dihydro-indol-3-one (13) were found to be the most active compounds of the series . Mannich bases exhibited higher activity than the corresponding Schiff bases. Chem Res Toxicol, 2001 Oct, 14(10), 1453 - 64 Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds; Pattison DI et al.; Hypochlorous acid (HOCl) is a potent oxidant, which is produced in vivo by activated phagocytes . This compound is an important antibacterial agent, but excessive or misplaced production has been implicated in a number of human diseases, including atherosclerosis, arthritis, and some cancers . Proteins are major targets for this oxidant, and such reaction results in side-chain modification, backbone fragmentation, and cross-linking . Despite a wealth of qualitative data for such reactions, little absolute kinetic data is available to rationalize the in vitro and in vivo data . In this study, absolute second-order rate constants for the reactions of HOCl with protein side chains, model compounds, and backbone amide (peptide) bonds have been determined at physiological pH values . The reactivity of HOCl with potential reactive sites in proteins is summarized by the series: Met (3.8 x 10(7) M(-1) x s(-1)) > Cys (3.0 x 10(7) M(-1) x s(-1)) >> cystine (1.6 x 10(5) M(-1) x s(-1)) approximately His (1.0 x 10(5) M(-1) x s(-1)) approximately alpha-amino (1.0 x 10(5) M(-1) x s(-1)) > Trp (1.1 x 10(4) M(-1) x s(-1)) > Lys (5.0 x 10(3) M(-1) x s(-1)) >> Tyr (44 M(-1) x s(-1)) approximately Arg (26 M(-1) x s(-1)) > backbone amides (10-10(-3) M(-1) x s(-1)) > Gln(0.03 M(-1) x s(-1)) approximately Asn (0.03 M(-1) x s(-1)) . The rate constants for reaction of HOCl with backbone amides (peptide bonds) vary by 4 orders of magnitude with uncharged peptide bonds reacting more readily with HOCl than those in a charged environment . These kinetic parameters have been used in computer modeling of the reactions of HOCl with human serum albumin, apolipoprotein-A1 and free amino acids in plasma at different molar excesses . These models are useful tools for predicting, and reconciling, experimental data obtained in HOCl-induced oxidations and allow estimations to be made as to the flux of HOCl to which proteins are exposed in vivo. Cell Stress Chaperones, 2001 Apr, 6(2), 148 - 52 Activation of human monocyte cell line U937 via cell surface calreticulin; Cho JH et al.; U937 cells were found to be activated by an antibacterial peptide, KLKLLLLLKLK-NH2 (L5), to generate superoxide anion (O2-)-like peripheral neutrophils . However, the state of cell surface calreticulin, a possible receptor for L5, was suggested to differ between neutrophils and U937 cells . Unlike the former, the latter ones were activated by anti-C-domain peptide antibody of calreticulin even in the absence of L5 and generated O2- in a GTP-binding protein (G-protein)-dependent manner. Dtsch Tierarztl Wochenschr, 2001 Sep, 108(9), 393 - 6 Pharmacodisposition of thiamphenicol in rabbits; el-Aty AM et al.; The pharmacokinetic parameters of thiamphenicol (TAP) were studied in New Zealand white rabbits . Five rabbits were each given thiamphenicol as a single 30 mg/kg of body weight dosage by intravenous (i.v.), intramuscular (i.m.) and oral routes . Serum antibacterial concentrations were determined for 72 h after dosing . Compartmental modeling of the i.v . administration indicated that a 2-compartment open model best described the disposition of thiamphenicol in rabbits . Serum thiamphenicol concentrations after i.m . and oral dosing were best described by a 1- and 2-compartment model, respectively . Overall elimination half-lives for i.v., i.m . and oral routes of administration were 1.39, 2.45, and 1.44 h, respectively . The half-life of absorption for oral dosing was 1.2 times the half-life of absorption after i.m . dosing (0.49 h vs 0.40 h) . The calculated time to maximal serum concentration was 1.25 h after i.m . dosing and 1.17 h after oral administration . The calculated serum concentrations at these times were 80.4 and 69.8 micrograms/ml, respectively . Mean residence time's were 1.89 h for i.v . injection, 2.78 h for i.m . dosing and 4.11 h for oral administration . Thiamphenicol was widely distributed in the rabbit as suggested by the volume of distribution value at steady state of 1.47 l/kg calculated from the i.v . study . Bioavailability was 101.4% after i.m . dosing and 64.2% for oral absorption. J Biomol Screen, 2000 Dec, 5(6), 435 - 40 Isolation of peptide ligands that inhibit glutamate racemase activity from a random phage display library; Kim WC et al.; Several new antibacterial agents are currently being developed in response to the emergence of bacterial resistance to existing antibiotic substances . The new agents include compounds that interfere with bacterial membrane function . The peptidoglycan component of the bacterial cell wall is synthesized by glutamate racemase, and this enzyme is responsible for the biosynthesis of d-glutamate, which is an essential component of cell wall peptidoglycan . In this study, we screened a phage display library expressing random dodecapeptides on the surface of bacteriophage against an Escherichia coli glutamate racemase, and isolated specific peptide sequences that bind to the enzyme . Twenty-seven positive phage clones were analyzed, and seven different peptide sequences were obtained . Among them, the peptide sequence His-Pro-Trp-His-Lys-Lys-His-Pro-Asp-Arg-Lys-Thr was found most frequently, suggesting that this peptide might have the highest affinity to glutamate racemase . The positive phage clones and HPWHKKHPDRKT synthetic peptide were able to inhibit glutamate racemase activity in vitro, implying that our peptide inhibitors may be utilized for the molecular design of new potential antibacterial agents targeting cell wall synthesis. Pharmacoeconomics, 2001, 19(8), 831 - 43 Cost effectiveness in Canada of a multidrug prepackaged regimen (Hp-PAC)+ for Helicobacter pylori eradication; Agro K et al.; OBJECTIVE: To assess the cost effectiveness of a multidrug prepackaged regimen for Helicobacter pylori, the Hp-PAC (lansoprazole 30mg, clarithromycin 500 mg, amoxicillin 1 g, all twice daily), relative to alternative pharmacological strategies in the management of confirmed duodenal ulcer over a 1-year period from 2 perspectives: (i) a strict healthcare payer perspective (Ontario Ministry of Health) excluding the patient copayment; and (ii) a healthcare payer perspective including the patient copayment . DESIGN: A decision-analytical model was developed to estimate expected per patient costs {1998 Canadian dollars ($ Can)}, weeks without ulcer and symptomatic ulcer recurrences for the Hp-PAC compared with: proton pump inhibitor (PPI)-clarithromycin-amoxicillin (PPI-CA), PPI-clarithromycin-metronidazole (PPI-CM), PPI-amoxicillin-metronidazole (PPI-AM) and ranitidine-bismuthmetronidazole-tetracycline (RAN-BMT) . MAIN OUTCOME MEASURES AND RESULTS: All PPI-based regimens had higher expected costs but better outcomes relative to RAN-BMT . From a strict healthcare payer perspective, PPI-CM ($Can 209) yielded lower expected costs than PPI-CA ($Can 221) and slightly lower costs than Hp-PAC ($Can 211) . However, these 3 regimens all shared identical outcomes (51.2 weeks without ulcer) . When the current Ontario, Canada, $Can 2 patient copayment was added to the dispensing fee, Hp-PAC yielded lower costs ($Can 214) than PPI-CM ($Can 216) . CONCLUSION: From a strict healthcare payer perspective, Hp-PAC is weakly dominated by PPI-CM with an incremental cost effectiveness (relative to RAN-BMT) of $Can 5.77 per ulcer week averted . When the patient copayment is added to this perspective, Hp-PAC weakly dominates PPI-CM ($Can 5 per ulcer week averted) . Regardless of perspective, Hp-PAC and PPI-CM differed by only $Can 2 per patient over 1 year and the expected time without ulcer was 51.2 weeks for both . More data on the clinical and statistical differences in H . pylori eradication with Hp-PAC and PPI-CM would be useful . This analysis does not in clude the possible advantage of Hp-PAC in terms of compliance and antibacterial resistance. Yao Xue Xue Bao, 1997 Nov, 32(11), 844 - 51 {Studies on pyridonecarboxylic acids as antibacterial agents . XII . Synthesis and antibacterial activity of 6-chloro-1-cyclopropyl-7-(1-piperazinyl)-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid and analogues}; Li XH et al.; Sixteen pyridonecarboxylic acids, characterized by having a chlorine atom and a cyclopropyl group at the 6- and 1-position respectively, substituted amino groups at the 7-position, and some substituted groups (chloro, nitro, amino, dimethylamino) at the 8-position, were synthesized . In vitro antibacterial activities of these compounds were tested . The fluoroquinolones ciprofloxacin and norfloxacin were included for comparative purposes . The results showed that both 11 Ca and 11 Cc were 4-8 times more active than ciprofloxacin and norfloxacin against S . aureus-15 in vitro, but with the same activity as ciprofloxacin against E . coli-22 and P . aeruginosa-29. Curr Med Res Opin, 1999, 15 Suppl 1, S1 - 45 A critical analysis of the pharmacology of AZT and its use in AIDS; Papadopulos-Eleopulos E et al.; The triphosphorylated form of the nucleoside analogue 3'-azido-3'-deoxythymidine (Zidovudine, AZT) is claimed to interrupt the HIV replication cycle by a selective inhibition of viral reverse transcriptase, thereby preventing the formation of new proviral DNA in permissive, uninfected cells . Given that initial HIV infection of an individual instigates abundant HIV replication from inception until death, and that the life of infected T-cells is only several days, the administration of AZT should lead both in vitro and in vivo (i) to decreased formation of proviral DNA; and thus (ii) to decreased frequencies of 'HIV isolation' (detection of p24 or reverse transcription or both) in stimulated cultures/cocultures of T-cells from seropositive individuals; (iii) to decreased synthesis of HIV p24 and RNA ('antigenaemia', 'plasma viraemia', 'viral load') ultimately resulting in low or absent levels of all three parameters; and (iv) to a perfect and direct correlation between all these parameters . A critical analysis of the presently available data shows that no such evidence exists, an outcome not unexpected given the pharmacological data on AZT . HIV experts all agree that only the triphosphorylated form of AZT (AZTTP) and not the unphosphorylated form administered to patients, nor its mono- or diphosphate, is the active agent . Furthermore, the mechanism of action is the ability of AZTTP to halt the formation of HIV-DNA (chain termination) . However, although this claim was posited from the outset, AZT underwent clinical trials and was introduced as a specific anti-HIV drug many years before there were any data proving that the cells of patients are able to triphosphorylate the parent compound to a level considered sufficient for its putative pharmacological action . Notwithstanding, from the evidence published since 1991 it has become apparent that no such phosphorylation takes place and thus AZT cannot possess an anti-HIV effect . However, the scientific literature does elucidate: (i) a number of biochemical mechanisms which predicate the likelihood of widespread, serious toxicity from use of this drug; (ii) in vitro data proving that AZT has significant antibacterial and antiviral properties which confound interpretation of its effects when administered to patients . Based on all these data it is difficult if not impossible to explain why AZT was introduced and still remains the most widely recommended and used anti-HIV drug. J Endod, 2001 Oct, 27(10), 610 - 2 Radiographic evaluation of periradicular repair after endodontic treatment of dog's teeth with induced periradicular periodontitis; Grecca FS et al.; Eighty-four root canals of premolars from six dogs were left open for 7 days, and then sealed and followed for 45 days until periradicular periodontitis developed . The root canals were then treated endodontically using 5.25% sodium hypochlorite as the irrigating solution . After instrumentation, all root canals were filled with a calcium hydroxide-based antibacterial dressing (Calen PMCC or Calasept) that was left in place for 30 days . After this period the root canals were filled with gutta-percha cones and a root canal sealer (Sealapex or AH Plus)--group I: Calen PMCC + Sealapex; group II: Calasept + Sealapex; group III: Calen PMCC + AH Plus; and group IV: Calasept + AH Plus . Periapical radiographs of the teeth were made after root canal filling and after 90, 180, 270, and 360 days . Radiographic images were digitalized by scanning, and the Mocha program was used to measure the periapical lesions . Analysis showed that the lesions of groups I to III were statistically similar reduction in size, whereas group IV had a smaller reduction in lesion size (p < 0.05). Peptides, 2001 Oct, 22(10), 1675 - 81 N-terminal modifications of Polymyxin B nonapeptide and their effect on antibacterial activity; Tsubery H et al.; Polymyxin B (PMB) is a potent antibacterial lipopeptide composed of a positively charged cyclic peptide ring and a fatty acid containing tail . Polymyxin B nonapeptide (PMBN), the deacylated amino derivative of polymyxin B, is much less bactericidal but able to permeabilize the outer membrane of Gram-negative bacteria and to neutralize the toxic effects of lipopolysaccharide (LPS) . In this study, we synthesized and evaluated the antibacterial and LPS neutralizing activities of four PMBN analogs modified at their N-terminal . Our results suggest that oligoalanyl substitutions of PMBN do not effect most of PMBN activities . However, a hydrophobic aromatic substitution generated a PMB-like molecule with high antibacterial activity and significant reduced toxicity. Perit Dial Int, 2001 Jul-Aug, 21(4), 372 - 7 Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD; Kent JR et al.; BACKGROUND: Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity . Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin . This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis . OBJECTIVE: This study aimed to define the potential role of azithromycin in treating CAPD peritonitis . DESIGN: The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin . Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography . SETTING: The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom . PATIENTS: Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day) . RESULTS: Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75) . The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour . This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers . After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr . CONCLUSION: Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present . However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported . Future research should address this possibility. Chemotherapy, 2001, 47 Suppl 4, 47 - 52; discussion 53-4 Optimal treatment strategies for acute exacerbations of chronic bronchitis: high-risk patients; Norrby SR; Diagnosis of high-risk patients with acute exacerbations of chronic bronchitis (AECB) should include an evaluation of the patient's respiratory function, chest X-ray to exclude pneumonia, and sputum culture . Increasing resistance to amoxicillin, cephalosporins, macrolides, trimethoprim-sulfamethoxazole, and doxycycline means that fluoroquinolones are often the only oral empiric treatment available . Levofloxacin, a new respiratory fluoroquinolone with a wide spectrum of antibacterial activity and no cross-resistance with other classes of antibiotics, can be administered as an intravenous formulation as well as orally . Sequential therapy is easily administered due to its high oral bioavailability, and the dosing schedule can be a convenient once-daily dose . Clinical trials have established that levofloxacin is effective in AECB and is well tolerated . Biochemistry, 2001 Oct 9, 40(40), 11995 - 2003 Solution structures of the antifungal heliomicin and a selected variant with both antibacterial and antifungal activities; Lamberty M et al.; In response to an experimental infection, the lepidopteran Heliothis virescens produces an antifungal protein named heliomicin . Heliomicin displays sequence similarities with antifungal plant defensins and antibacterial or antifungal insect defensins . To gain information about the structural elements required for either antifungal or antibacterial activity, heliomicin and selected point-mutated variants were expressed in yeast as fusion proteins . The effects of mutations, defined by comparing the primary structure of heliomicin with the sequences of members of the insect defensin family, were analyzed using antibacterial and antifungal assays . One of the variants shows significant activity against Gram-positive bacteria while remaining efficient against fungi . The three-dimensional structures of this variant and of the wild-type protein were determined by two-dimensional (1)H NMR to establish a correlation between structure and antibacterial or antifungal activity . Wild-type and mutated heliomicins adopt a similar scaffold, including the so-called cysteine-stabilized alphabeta motif . A comparison of their structures with other defensin-type molecules indicates that common hydrophobic characteristics can be assigned to all the antifungal proteins . A comparative analysis of various structural features of heliomicin mutant and of antibacterial defensins enables common properties to be assessed, which will help to design new mutants with increased antibacterial activity. Drugs, 2001, 61(11), 1581 - 91 Optimising outcomes in acute pancreatitis; Norton ID et al.; Acute pancreatitis is a common cause for presentation to emergency departments . Common causes in Western societies include biliary pancreatitis and alcohol (the latter in the setting of chronic pancreatitis) . Acute pancreatitis also follows endoscopic retrograde pancreatography in 5 to 10% of patients, a group that could potentially benefit from prophylactic treatment . Although episodes of pancreatitis usually run a relatively benign course, up to 20% of patients have more severe disease, and this group has significant morbidity and mortality . Therefore, attempts have been made to identify, at or soon after presentation, those patients likely to have a poor outcome and to channel resources to this group . The mainstay of treatment is aggressive support and monitoring of those patients likely to have a poor outcome . Pharmacotherapy for acute pancreatitis (both prophylactic and in the acute setting) has been generally disappointing . Efforts initially focused on protease inhibitors, of which gabexate shows some promise as a prophylactic agent . Agents that suppress pancreatic secretion have produced disappointing results in human studies . Infection of pancreatic necrosis is associated with high mortality and requires surgical intervention . In view of the seriousness of infected necrosis, the use of prophylactic antibacterials such as carbapenems and quinolones has been advocated in the setting of pancreatic necrosis . Similarly, data are accumulating to support the use of prophylactic antifungal therapy . Recently, it has become apparent that the intense inflammatory response associated with acute pancreatitis is responsible for much of the local and systemic damage . With this realisation, future efforts in pharmacotherapy are likely to focus on suppression or antagonism of pro-inflammatory cytokines and other inflammatory mediators . Similarly, animal studies have demonstrated the importance of oxidative stress in acute pancreatitis, although to date there is a paucity of information regarding the efficacy of antioxidants . Although the clinical course for most patients with acute pancreatitis is mild, severe acute pancreatitis continues to be a clinical challenge, requiring a multidisciplinary approach of physician, intensivist and surgeon. Chemistry, 2001 Sep 3, 7(17), 3824 - 43 Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorial synthesis; Nicolaou KC et al.; Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents . Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g . combinatorial synthesis in the presence of vancomycin's target Ac2-L-Lys-D-Ala-D-Ala) to generate libraries of vancomycin dimers . Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistant and, most significantly, vancomycin-resistant bacteria. Biomaterials, 2001 Nov, 22(22), 2999 - 3004 Design and evaluation of drug-loaded wound dressing having thermoresponsive, adhesive, absorptive and easy peeling properties; Lin SY et al.; In order to develop a novel unique wound dressing, a combination of self-adhesive Eudragit E film with antibacterial drug-loaded poly (N-isopropyl-acrylamide) (PNIPAAm) microgel beads was designed . The result indicates that the tack property of Eudragit E film increased with an increase of the PNIPAAm microgel beads added, but there was no significant difference between the dried PNIPAAm microgel beads with or without adsorbing drug . In addition, the peel strength of Eudragit E film initially decreased with the addition of PNIPAAm microgel beads, but increased to a maximum value when PNIPAAm microgel beads were added from 4% to 7.6% . then decreased again after 7.6% . The optimal concentration of PNIPAAm microgel beads was 7.6% (w/v) which had better tack and peel adhesive properties . The water uptake ratio of Eudragit E film containing PNIPAAm microgel beads was found to be temperature-dependent, suggesting that the Eudragit E film containing PNIPAAm microgel beads enabled to absorb the wound fluid . Eudragit E film containing PNIPAAm microgel beads with or without adsorbing drug had significantly reduced peel strength after 12 h-immersion in solution . All these results suggest that a novel drug-loaded wound dressing has been developed by binding a self-adhesive Eudragit E film with an antibacterial drug-loaded PNIPAAm microgel beads to achieve thermo-responsive, adhesive, absorptive and easy peeling functions. Org Lett, 2001 Oct 4, 3(20), 3189 - 91 Total synthesis of (+/-)-hapalindole Q; Kinsman AC et al.; {reaction: see text} The total synthesis of the antibacterial and antimycotic alkaloid hapalindole Q has been achieved in eight steps and 12.4% overall yield . The key step involves a regio- and diastereoselective Diels-Alder reaction to afford a bicyclo{2.2.2}oct-2-ene . This cycloadduct was subsequently dihydroxylated, cleaved, and converted to the natural product. Arch Toxicol, 2001 Aug, 75(6), 369 - 74 Biochemical changes in Achilles tendon from juvenile dogs after treatment with ciprofloxacin or feeding a magnesium-deficient diet; Shakibaei M et al.; Quinolones are antibacterial agents that have the potential to induce Achilles tendon disorders - such as tendinitis or even ruptures - in patients treated with these drugs . We studied the effects of ciprofloxacin on several proteins of Achilles tendons from immature dogs, 10- to 11-weeks-old . The dogs were treated orally for 5 days with 30 or 200 mg ciprofloxacin/kg body weight or with the vehicle alone . Since quinolone-like alterations in joint cartilage were observed in magnesium-deficient animals, another group was fed a magnesium-deficient diet for 6 weeks . At necropsy, tendons (n=3 from each group) were frozen and stored until analysis when they were homogenized in a lysis buffer to release a soluble fraction of the tendon proteins . Densitometric analysis of the immunoblots with anticollagen type I, anti-elastin, anti-fibronectin, and antiintegrin antibodies showed a significant reduction of all proteins . For example, collagen type I concentrations (mean +/-SD, arbitrary densitometric units) were 3190+/-217 (controls), 1890+/-468 (30mg/kg), 1695+/-135 (200mg/kg) and 2053+/-491 in the magnesium-deficient dogs . The differences between concentrations in controls and all treated groups were statistically significant (P<0.01, t-test) . Similarly, compared with control samples, relative concentrations of other proteins in tendons from ciprofloxacin-treated dogs (30 mg/kg) decreased by 73% (elastin), 88% (fibronectin), and 96% (beta1 integrin) (data from low-dose group only) . A very similar pattern of protein alterations was detected in samples from magnesium-deficient dogs . In conclusion, rather low doses of a fluoroquinolone or a diet-induced magnesium deficiency caused similar biochemical alterations in the soluble fraction of proteins from canine tendons . These findings support our hypothesis that quinolone-induced toxic effects on connective tissue structures are due to the magnesium-antagonistic effects of these antibacterial agents . They also indicate that patients with a latent magnesium deficiency could be at an increased risk of quinolone-induced tendon disorders. Boll Chim Farm, 2001 Jul-Aug, 140(4), 215 - 20 Simple and convenient preparation of 1-(arylamino)methylbenzotriazoles and -(arylamino)methylbenzimidazoles; Milata V et al.; The preparation of 1-(arylamino)methylbenzotriazoles 1a-17a and benzimidazoles 1b-17b is described and their antibacterial activity evaluated . 1-Hydroxymethylbenzazo-les react with the appropriate aniline to yield the target compounds . These were characterized using 1H NMR, IR, UV spectra . The compounds displayed no significant antibacterial activity. Infect Dis Clin North Am, 2001 Sep, 15(3), 983 - 1002, xi Use of antibacterial agents in renal failure; Livornese LL Jr et al.; This article reviews the pharmacokinetics of antibacterial agents in patients with normal and decreased renal function . The concepts of volume and distribution, rate of elimination, loading and maintenance doses, and therapeutic drug monitoring are delineated . Special reference is made to the intermittent dosing of cefazolin with hemodialysis . Newer, as well as traditional methods of extracorporeal circulation and the resultant changes in antibacterial agent pharmacodynamics are discussed. Vestn Oftalmol, 2001 Jul-Aug, 117(4), 29 - 32 {Effects of gaseous flow containing nitric oxide on the eyeball structures (an experimental study)}; Gundarova RA et al.; Nitric oxide is one of the main factors of intra- and intercellular regulation in the organism . Its vasodilating, antiaggregant, antithrombogenic, antibacterial, anticarcinogenic, and immunogenic effects are well known . It stimulates the reparative processes in soft tissue injuries . We failed to find reports about the role of NO in the wound process in the eyes . The source of NO in our experiments was medical air-plasma device Plason . Exposure of the eye to NO-containing gaseous flow did not cause changes in the lacrimal pH; NO penetrated through the cornea and sclera, exerted no appreciable cytotoxic effect on the surface epithelium of the eye, did not change the intraocular pressure, and caused no morphological changes in ocular tissues . On the other hand, NO-containing gaseous flow had an appreciable lasting effect on the diameter of the conjunctival vessels, this effect being dose-dependent . The doses of NO-containing gaseous flow which can be used in the treatment of eye wounds were determined. J Antimicrob Chemother, 2001 Sep, 48 Suppl T1, 25 - 31 Activity of telithromycin, a new ketolide antibacterial, against atypical and intracellular respiratory tract pathogens; Hammerschlag MR et al.; Atypical respiratory pathogens such as Mycoplasma pneumoniae and intracellular pathogens such as Legionella spp . and Chlamydia spp . form a significant proportion of the aetiological agents underlying community-acquired pneumonia (CAP) . The clinical signs or radiological features of atypical pneumonia are generally insufficient to predict accurately the pathogen involved; in addition, high costs and a considerable length of time are involved in the identification of atypical pathogens . Treatment is, therefore, most often empirical, and it is important that the activity of antibacterial agents available to treat CAP is sufficiently broad to eradicate infection with both common and atypical bacterial pathogens . Telithromycin (HMR 3647) is the first of a new family of antibacterials, the ketolides, and has been designed specifically for the treatment of community-acquired respiratory tract infections (RTIs) . The excellent activity of telithromycin against the respiratory tract bacterial pathogens most commonly associated with community-acquired RTIs, including resistant strains, is well established . This review examines the considerable body of evidence showing that telithromycin also has a high level of activity against atypical and intracellular respiratory tract bacterial pathogens. Int J Pharm, 2001 Oct 4, 227(1-2), 149 - 56 Investigation of Smith's quinolone killing mechanisms during the PAE of ciprofloxacin on Escherichia coli; Wickens HJ et al.; Quinolone antibacterials interact with the DNA-DNA gyrase complex, but subsequent events that lead to cell death are unresolved . Three distinct mechanisms of quinolone lethality have been identified by Smith and co-workers: Mechanism A, which requires RNA and protein synthesis and cell division for expression; Mechanism B, which remains active when thes