bluuebunny/crossref_metadata_2025 huggingface dataset:
Food group categories used in dietary analysis can misrepresent the amount and type of fat present in foods
Authors: MANN Neil , ASHTON Yvonne , O’CONNELL Stella , SINCLAIR Andrew , KELLY Fiona
Published: May 2006

Objective:  To determine whether analysis of food intake data using different food group classification systems changes the apparent contribution of defined food groups to total daily fat intake.

Design:  Three food classification systems were used to assess dietary intake of male omnivore subjects from a food frequency questionnaire.

Setting:  RMIT University, Melbourne, Australia.

Subjects:  A total of 78 healthy men aged 20–55 years, divided by meat consumption into moderate meat‐eaters (n = 60) and high meat‐eaters (n = 18).

Methods:  Dietary intake data were collected as semi‐quantitative food frequency questionnaires and analysed using the NUTTAB 95 database. The contribution of food groups to nutrient intakes was determined using three food classification systems.

Results:  When red meat was grouped with meat, poultry and game products and dishes, ‘meat’ contributed 19.8% of total fat to a diet typical of an adult Australian man. When lean meat cuts were distinguished from meat products or dishes and fast foods, ‘red meat cuts’ provided only 4.3% of the total fat in this diet, whereas ‘fast foods’ provided 18.7%.

Conclusions:  Food classification systems have a profound impact on the apparent nutrient content of defined food groups, particularly the fat content attributed to meats. Less precise systems may result in provision of misleading dietary advice. Meats such as lean beef and lamb can be a valuable part of a healthy diet by providing important nutrients, especially iron, zinc and vitamin B12, but relatively little fat.
Alcohol and lactation: A systematic review
Authors: GIGLIA Roslyn , BINNS Colin
Published: May 2006

The aim of the present paper is to critically review the current literature on the effect of alcohol intake during lactation on the hormonal control of lactogenesis; breast milk and infant blood alcohol concentration; and on the breastfeeding infant. The databases PubMed, CINAHL, Proquest Health and Medical Complete, ScienceDirect and ISI Web of Knowledge were searched for articles published between 1990 and 2005. We found limited research investigating the effect of alcohol intake on the infants of lactating women, with most being conducted using animal models. Results consistently show a decrease in lactational performance in both animal and human studies of alcohol intake and breastfeeding. Alcohol intake by lactating mothers in amounts recommended as ‘safe’ for non‐lactating women may have a negative effect on infant development and behaviour. Clear guidelines for alcohol consumption are required for lactating women and health professionals to guide breastfeeding mothers to make educated choices regarding alcohol intake during this critical period of infant development.
Delirium, nursing practice and the future
Authors: Irving Kate , Foreman Marquis
Published: May 2006

The preceding papers have outlined the issues of under‐recognition of delirium, aspects of assessment to improve this situation and presented an alternative discursive construction of delirious patients. With respect to the understandings from the first two papers, the authors intend to suggest a direction for future practice and research in the area of delirium. The discussion will start with an overview of current international practice. Approaches focussing on the specific care of team members or on multidisciplinary care have been reported as well as approaches that focus on a clinical expert such as a nurse specialist or those that focus care of patients with delirium in a specific identified clinical setting. The literature represents variable evidence of the success, or otherwise, of different initiatives. The authors intend to provoke debate on the care of delirious patients and indicate the priorities for the future management of delirium.
Delirium and older people: repositioning nursing care
Authors: Neville Stephen
Published: May 2006

Aims. To critically examine the nursing care offered to older people who have been delirious.

Background. Delirium occurs as a result of physiological imbalances resulting in an alteration in consciousness and cognitive impairment. Delirium is a prevalent and serious cognitive disorder experienced by older people. While there is a vast number of studies published utilizing quantitative methods, there remains a dearth of research relating to delirium in older people from a qualitative perspective.

Design. A qualitative research design that utilized a critical gerontological framework underpinned this study. This framework drew on aspects of postmodernism and Foucault's understanding of discourse.

Methods. Data sources included published documents on delirium, semi‐structured taped interviews with people over the age of 65 years who had been delirious (as well as their clinical notes), family members, Registered Nurses and a hospital doctor. A postmodern discourse analytic approach was used to interrogate the 20 sets of data collected.

Findings. Textual analysis revealed the presence of two major discourses impacting on being an older person with delirium. These were identified as a nursing discourse of delirium and a personal discourse of delirium. A nursing discourse of delirium was largely focussed on the biomedical processes that resulted in a delirious episode. Conversely, a personal discourse of delirium highlights that there are other ways of ‘knowing’ about delirium through considering the narratives of older adults, and their families, when offering a nursing service to this group of people.

Relevance to clinical practice. Nursing needs to critically examine all aspects of nursing care as it applies to older people who have delirium to ensure the rhetorical claims of the profession become the reality for consumers of health services. The use of critical gerontology provides nurses with the tools to challenge the status quo and uncover the multiple, varied, contradictory and complex representations of delirium in older people. Inherent within a personal discourse of delirium is the importance of incorporating into nursing care communicative and other relational activities, such as forming and maintaining a therapeutic relationship.
Bacterial cholangitis/cholangiohepatitis with or without concurrent cholecystitis in four dogs
Authors: O’Neill E. J. , Day M. J. , Hall E. J. , Holden D. J. , Murphy K. F. , Barr F. J. , Pearson G. R.
Published: May 2006

Objectives:To evaluate the clinical, clinical pathology, diagnostic imaging, microbiological and pathological features of cholangitis/cholangiohepatitis in the dog.

Methods:The study design was a retrospective review of cases of bacterial cholangitis/cholangiohepatitis presented to the University of Bristol during the period 1995 to 2000. The diagnosis was made based on hepatic histopathological findings and positive bile culture results.

Results:Four dogs met the inclusion criteria. Common presenting signs included anorexia (n=4), jaundice (n=4), vomiting (n=4) and pyrexia (n=2). All four dogs had a leucocytosis or neutrophilia reported at some time in their history along with serum bilirubin elevation. In addition, serum alkaline phosphatase and alanine transaminase activity was increased in all of the dogs in which it was measured both before and at the time of referral. In general, the diagnostic imaging findings were non‐specific. Organisms cultured from bile aspirates wereEscherichia coli(n=3),Clostridiumspecies (n=2) and a faecalStreptococcusspecies (n=1). Two cases resolved with medical treatment alone; two with concurrent cholecystitis required cholecystectomy. Following surgery, both of these cases showed a resolution of clinical signs.

ClinicalSignificance:This report highlights the fact that bacterial cholangitis/cholangiohepatitis with or without concurrent cholecystitis should be considered as a potential differential in dogs presenting with signs referable to biliary tract disease.
Combined clotrimazole irrigation and depot therapy for canine nasal aspergillosis
Authors: Sissener T. R. , Bacon N. J. , Friend E. , Anderson D. M. , White R. A. S.
Published: May 2006

Objectives:To evaluate the effect of short duration 1 per cent clotrimazole flush when combined with 1 per cent clotrimazole cream instilled into the frontal sinuses for the treatment of nasal aspergillosis in 14 dogs.

Methods:Fourteen dogs with clinical, radiological, serological and rhinoscopic findings consistent with nasal aspergillosis were treated by frontal sinus trephination and a short, five‐minute flushing of 1 per cent topical clotrimazole solution followed by a 1 per cent clotrimazole cream instilled as a depot agent.

Results:Twelve of the 14 dogs (86 per cent) responded well to treatment and either had no clinical signs after treatment or had signs consistent with mild rhinitis during a minimum follow‐up period of six months. Only one dog required multiple treatments. Treatment was well tolerated by all patients, with minimal complications.

ClinicalSignificance:This treatment compares favourably to previously published data using one‐hour topical clotrimazole or enilconazole flushing treatment protocols. The treatment technique significantly reduced treatment time under anaesthesia.
Suspected drug‐induced destructive cholangitis in a young dog
Authors: Gabriel A. , Van Den Ingh T. S. G. A. M. , Clercx C. , Peeters D.
Published: May 2006

A nine‐month‐old miniature dobermann was referred for the evaluation of chronic icterus. History and clinical and histopathological findings were supportive of a diagnosis of drug‐induced destructive cholangitis. The main histopathological findings were canalicular, centrilobular cholestasis and ductopenia with moderate inflammatory infiltrate. The dog had received three types of treatment for demodicosis before the onset of jaundice. Amoxicillin‐clavulanate, amitraz, milbemycin oxime or an interaction between two of the three drugs may have been responsible for the destructive cholangitis.
Antimicrosporidial Activities of Fumagillin, TNP-470, Ovalicin, and Ovalicin Derivatives In Vitro and In Vivo
Authors: Didier Peter J. , Phillips Jennifer N. , Kuebler Dorothy J. , Nasr Mohamed , Brindley Paul J. , Stovall Mary E. , Bowers Lisa C. , Didier E. S.
Published: May 2006

Therapies for microsporidiosis in humans are limited, and fumagillin, which appears to be the most broadly effective antimicrosporidial drug, is considered to be moderately toxic. The purpose of this study was to apply an in vitro drug screening assay forEncephalitozoon intestinalisandVittaforma corneaeand an in vivo athymic mouse model ofV. corneaeinfection to assess the efficacy of TNP-470 (a semisynthetic analogue of fumagillin), ovalicin, and eight ovalicin derivatives. TNP-470, ovalicin, and three of the ovalicin derivatives inhibited bothE. intestinalisandV. corneaereplication by more than 70% in vitro. Another three of the ovalicin derivatives inhibited one of the two microsporidian species by more than 70%. None of the treated athymic mice survived theV. corneaeinfection, but they did survive statistically significantly longer than the untreated controls after daily treatment with fumagillin administered at 5, 10, and 20 mg/kg of body weight subcutaneously (s.c.), TNP-470 administered at 20 mg/kg intraperitoneally (i.p.), or ovalicin administered at 5 mg/kg s.c. Of two ovalicin derivatives that were assessed in vivo, NSC 9665 given at 10 mg/kg i.p. daily also statistically significantly prolonged survival of the mice. No lesions associated with drug toxicity were observed in the kidneys or livers of uninfected mice treated with these drugs at the highest dose of 20 mg/kg daily. These results thus support continued studies to identify more effective fumagillin-related drugs for treating microsporidiosis.
Antimalarial Effects of Human Immunodeficiency Virus Type 1 Protease Inhibitors Differ from Those of the Aspartic Protease Inhibitor Pepstatin
Authors: Parikh Sunil , Liu Jun , Sijwali Puran , Gut Jiri , Goldberg Daniel E. , Rosenthal Philip J.
Published: May 2006

Human immunodeficiency virus type 1 protease inhibitors (HIVPIs) and pepstatin are aspartic protease inhibitors with antimalarial activity. In contrast to pepstatin, HIVPIs were not synergistic with a cysteine protease inhibitor or more active against parasites with the cysteine protease falcipain-2 knocked out than against wild-type parasites. As with pepstatin, HIVPIs were equally active against wild-type parasites and against parasites with the food vacuole plasmepsin aspartic proteases knocked out. The antimalarial mechanism of HIVPIs differs from that of pepstatin.
Efficacy of Voriconazole in a Guinea Pig Model of Invasive Trichosporonosis
Authors: Serena Carolina , Gilgado Félix , Mariné Marçal , Pastor F. Javier , Guarro Josep
Published: May 2006

We have evaluated the efficacy of voriconazole (VRC) in a systemic infection by
Trichosporon asahii
in immunosuppressed guinea pigs. VRC was more effective than amphotericin B in prolonging survival and reducing tissue burden. The best results were obtained with VRC at 10 mg/kg of body weight/day.
Differential Effects of Levofloxacin and Ciprofloxacin on the Risk for Isolation of Quinolone-Resistant
Pseudomonas aeruginosa
Authors: Kaye Keith S. , Kanafani Zeina A. , Dodds Ashley E. , Engemann John J. , Weber Stephen G. , Carmeli Yehuda
Published: May 2006

Due to the greater in vitro activity of ciprofloxacin than that of levofloxacin against
Pseudomonas aeruginosa
, the likelihood of isolating a clinical strain of quinolone-resistant (QR)
P. aeruginosa
might be greater after exposure to levofloxacin than ciprofloxacin. We examined the risk of isolating QR
P. aeruginosa
in association with prior levofloxacin or ciprofloxacin exposure. A case-case-control study was conducted. Two groups of cases, one with nosocomial QR
P. aeruginosa
infections and one with nosocomial quinolone-susceptible (QS)
P. aeruginosa
infections, were compared to a control group of hospitalized patients without
P. aeruginosa
infections. Bivariable and multivariable analyses were used to determine risk factors for isolation of QR
P. aeruginosa
and QS
P. aeruginosa
. One hundred seventeen QR
P. aeruginosa
and 255 QS
P. aeruginosa
cases were identified, and 739 controls were selected. Exposures to ciprofloxacin were similar among all three groups (8% for controls, 9.4% for QR
P. aeruginosa
cases, and 7.5% for QS
P. aeruginosa
cases;
P
≥ 0.6). Levofloxacin use was more frequent in the QR
P. aeruginosa
cases than in the controls (35.9% and 22.1%, respectively; odds ratio [OR] = 2.0; 95% confidence interval [CI] = 1.3 to 3.0) and less frequent in QS
P. aeruginosa
cases (14.1% of QS
P. aeruginosa
cases; OR = 0.6; 95% CI = 0.4 to 0.9). In multivariable analysis, levofloxacin, but not ciprofloxacin, was a significant risk factor for isolation of QR
P. aeruginosa
(OR for levofloxacin = 1.7 [95% CI = 1.0 to 2.9]; OR for ciprofloxacin = 1.2 [95% CI = 0.6 to 2.5]). Levofloxacin was associated with a reduced risk of isolation of QS
P. aeruginosa
(OR = 0.6; 95% CI = 0.4 to 0.9), whereas ciprofloxacin had no significant effect (OR = 1.0; 95% CI = 0.6 to 1.8). In conclusion, the use of levofloxacin, but not ciprofloxacin, was associated with isolation of QR
P. aeruginosa
.
Targeting of Hematin by the Antimalarial Pyronaridine
Authors: Auparakkitanon Saranya , Chapoomram Soebsakul , Kuaha Kannika , Chirachariyavej Thamrong , Wilairat Prapon
Published: May 2006

Pyronaridine, 2-methoxy-7-chloro-10[3′,5′-bis(pyrrolidinyl-1-methyl-)4′hydroxyphenyl]aminobenzyl-(b)-1,5-naphthyridine, a new Mannich base schizontocide originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. We now show that pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro β-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione-dependent degradation of hematin. Our observations that pyronaridine exerted this mechanism of action in situ, based on growth studies of
Plasmodium falciparum
K1 in culture showing antagonism of pyronaridine in combination with antimalarials (chloroquine, mefloquine, and quinine) that inhibit β-hematin formation, were equivocal.
Accumulation and Intracellular Distribution of Antitrypanosomal Diamidine Compounds DB75 and DB820 in African Trypanosomes
Authors: Mathis Amanda M. , Holman Jacqueline L. , Sturk Lisa M. , Ismail Mohamed A. , Boykin David W. , Tidwell Richard R. , Hall James Edwin
Published: May 2006

The aromatic diamidine pentamidine has long been used to treat early-stage human African trypanosomiasis (HAT). Two analogs of pentamidine, DB75 and DB820, have been shown to be more potent and less toxic than pentamidine in murine models of trypanosomiasis. The diphenyl furan diamidine, DB75, is the active metabolite of the prodrug DB289, which is currently in phase III clinical trials as a new orally active candidate drug to treat first-stage HAT. The new aza analog, DB820, is the active diamidine of the prodrug DB844, currently undergoing preclinical evaluation as a new candidate to treat HAT of the central nervous system. The exact mechanisms of antitrypanosomal activity of aromatic dications remain poorly understood, with multiple mechanisms hypothesized. Pentamidine is known to be actively transported into trypanosomes and binds to DNA within the nucleus and kinetoplast. A long-hypothesized mechanism of action has been that DNA binding ultimately leads to interference with DNA-associated enzymes. Both DB75 and DB820 are intensely fluorescent, which provides an important tool for determining the kinetics of accumulation and intracellular distribution in trypanosomes. We show in the current study that DB75 and DB820 rapidly accumulate and strongly concentrate within trypanosomes, with intracellular concentrations over 15,000-fold higher than mouse plasma concentrations. Both compounds initially accumulate in the DNA-containing nucleus and kinetoplast, but at later time points, they concentrate in non-DNA-containing cytoplasmic organelles. Analyses of the kinetics of uptake and intracellular distribution are necessary to begin to define antitrypanosomal mechanisms of action of DB75, DB820, and other aromatic diamidines.
Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity againstMycobacterium tuberculosis
Authors: Schwartz Y. S. , Dushkin M. I. , Vavilin V. A. , Melnikova E. V. , Khoschenko O. M. , Kozlov V. A. , Agafonov A. P. , Alekseev A. Y. , Rassadkin Y. , Shestapalov A. M. , Azaev M. S. , Saraev D. V. , Filimonov P. N. , Kurunov Y. , Svistelnik A. V. , Krasnov V. A. , Pathak A. , Derrick S. C. , Reynolds R. C. , Morris S. , Blinov V. M.
Published: May 2006

Mycobacterium tuberculosisis an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 μg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.
Detection of Live and Antibiotic-Killed Bacteria by Quantitative Real-Time PCR of Specific Fragments of rRNA
Authors: Aellen Steve , Que Yok-Ai , Guignard Bertrand , Haenni Marisa , Moreillon Philippe
Published: May 2006

Assessing bacterial viability by molecular markers might help accelerate the measurement of antibiotic-induced killing. This study investigated whether rRNA could be suitable for this purpose. Cultures of penicillin-susceptible and penicillin-tolerant (Tol1 mutant)
Streptococcus gordonii
were exposed to mechanistically different penicillin and levofloxacin. Bacterial survival was assessed by viable counts and compared to quantitative real-time PCR amplification of either the 16S rRNA genes or the 16S rRNA, following reverse transcription. Penicillin-susceptible
S. gordonii
lost ≥4 log
10
CFU/ml of viability over 48 h of penicillin treatment. In comparison, the Tol1 mutant lost ≤1 log
10
CFU/ml. Amplification of a 427-bp fragment of 16S rRNA genes yielded amplicons that increased proportionally to viable counts during bacterial growth but did not decrease during drug-induced killing. In contrast, the same 427-bp fragment amplified from 16S rRNA paralleled both bacterial growth and drug-induced killing. It also differentiated between penicillin-induced killing of the parent and the Tol1 mutant (≥4 log
10
CFU/ml and ≤1 log
10
CFU/ml, respectively) and detected killing by mechanistically unrelated levofloxacin. Since large fragments of polynucleotides might be degraded faster than smaller fragments, the experiments were repeated by amplifying a 119-bp region internal to the original 427-bp fragment. The amount of 119-bp amplicons increased proportionally to viability during growth but remained stable during drug treatment. Thus, 16S rRNA was a marker of antibiotic-induced killing, but the size of the amplified fragment was critical for differentiation between live and dead bacteria.
Idebenone Acts against Growth of
Helicobacter pylori
by Inhibiting Its Respiration
Authors: Inatsu Sakiko , Ohsaki Ayumi , Nagata Kumiko
Published: May 2006

Growth of
Helicobacter pylori
was inhibited by the quinones, idebenone, duroquinone, menadione, juglone, and coenzyme Q
1
at low concentrations of 0.8 to 3.2 μg/ml. Idebenone specifically inhibited
H. pylori
growth by inhibiting respiration and decreasing the cellular ATP level. The respiratory inhibition was accompanied by reduction of idebenone by the
H. pylori
cells.
Effect of Culture Medium on the Disk Diffusion Method for Determining Antifungal Susceptibilities of Dermatophytes
Authors: Fernández-Torres Belkys , Carrillo-Muñoz Alfonso , Inza Isabel , Guarro Josep
Published: May 2006

We have evaluated a disk diffusion method to determine the activities of five drugs against 50 strains of dermatophytes and to assess the influence of the culture medium (antibiotic medium 3, high-resolution medium, and RPMI) on the inhibition zone diameters (IZD). There were no differences among the medium/drug combinations, except for itraconazole-RPMI, which showed the narrowest IZD.
Levofloxacin Pharmacokinetics and Pharmacodynamics in Patients with Severe Burn Injury
Authors: Kiser Tyree H. , Hoody Dorie W. , Obritsch Marilee D. , Wegzyn Colleen O. , Bauling Paulus C. , Fish Douglas N.
Published: May 2006

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ± standard deviations; age, 41 ± 17 years; weight, 81 ± 12 kg; creatinine clearance, 114 ± 40 ml/min) received intravenous levofloxacin at 750 mg (
n
= 10 patients) or 500 mg (
n
= one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ± 3.2 liters/h, 7.8 ± 1.6 h, and 93 ± 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of ≤0.5 μg/ml and MICs of ≤1 μg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 μg/ml or any organism with a MIC of ≥2 μg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 μg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.
Efficacy of Macrolides and Telithromycin against Leptospirosis in a Hamster Model
Authors: Moon James E. , Ellis Michael C. , Griffith Matthew E. , Hawley Joshua S. , Rivard Robert G. , McCall Suzanne , Hospenthal Duane R. , Murray Clinton K.
Published: May 2006

Human studies support the use of β-lactams and tetracyclines in the treatment of leptospirosis. Additional agents from these and other classes of antimicrobials also have in vitro activity againstLeptospiraspecies, though corroborating in vivo data are limited or lacking. We evaluated the therapeutic efficacy of azithromycin, clarithromycin, and telithromycin in a lethal hamster model of leptospirosis usingLeptospira interrogansserogroup Canicola serovar Portlandvere. A range of dosages for each antimicrobial was given to the infected animals on days 2 through 7 (5 days) of the 21-day survival model. All untreated control animals survived less than 10 days from infection. Ninety to 100% of doxycycline controls, treated for 5 days with 5 mg/kg of body weight of drug, survived to 21 days. Treatment with azithromycin (daily dose: 6.25, 12.5, 25, 50, 100, or 200 mg/kg) resulted in 100% survival at all evaluated doses. Animals receiving 20 mg/kg or more of clarithromycin (daily dose: 1, 5, 10, 15, 20, 40, 60, or 100 mg/kg) had improved survival. Ninety-eight percent of animals treated with telithromycin (daily dose: 1, 5, 10, 15, 20, or 40 mg/kg) survived. We conclude that all agents tested have demonstrated in vivo efficacy in treating acute leptospirosis. These results provide support for further evaluation of macrolide and ketolide antimicrobial agents in human trials.
Transmission-Blocking Activities of Quinine, Primaquine, and Artesunate
Authors: Chotivanich Kesinee , Sattabongkot Jetsumon , Udomsangpetch Rachanee , Looareesuwan Sornchai , Day Nicholas P. J. , Coleman Russell E. , White Nicholas J.
Published: May 2006

The infectivity of
Plasmodium falciparum
gametocytes after exposure in vitro to quinine, artesunate, and primaquine was assessed in
Anopheles dirus
, a major vector of malaria in Southeast Asia. Mature gametocytes (stage 5) of a Thai isolate of
P. falciparum
were exposed to the drugs for 24 h in vitro before membrane feeding to
A. dirus
. After 10 days, the mosquito midguts were dissected and the oocysts were counted. In this system, artesunate showed the most potent transmission-blocking activity; the mean (standard deviation [SD]) 50% and 90% effective concentrations (EC
50
, and EC
90
, respectively, in nanograms per milliliter) were 0.1 (0.02) and 0.4 (0.15), respectively. Transmission-blocking activity of quinine and primaquine was observed at relatively high concentrations (SDs): EC
50
of quinine, 642 (111) ng/ml; EC
50
of primaquine, 181 (23) ng/ml; EC
90
of quinine, 816 (96) ng/ml; EC
90
of primaquine, 543 (43) ng/ml. Artesunate both prevents the maturation of immature
P. falciparum
gametocytes and reduces the transmission potential of mature gametocytes. Both of these effects may contribute to reducing malaria transmission.
Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics ofS-(+)- andR-(−)-Ibuprofen
Authors: Hynninen Ville-Veikko , Olkkola Klaus T. , Leino Kari , Lundgren Stefan , Neuvonen Pertti J. , Rane Anders , Valtonen Mika , Vyyryläinen Hanna , Laine Kari
Published: May 2006

Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics ofS-(+)- andR-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations ofS-(+)- andR-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) ofS-(+)-ibuprofen was 205% (P< 0.001) of the respective control value and the mean peak plasma concentration (Cmax) was 122% (P< 0.01) of the respective control value. The mean elimination half-life (t1/2) was prolonged from 2.4 to 3.2 h (P< 0.01) by voriconazole. In the fluconazole phase, the mean AUC ofS-(+)-ibuprofen was 183% of the control value (P< 0.001) and its meanCmaxwas 116% of the control value (P< 0.05). The meant1/2ofS-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P< 0.05) by fluconazole. The geometric meanS-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics ofR-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure toS-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism ofS-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.
Single-Dose Safety and Pharmacokinetics of Brecanavir, a Novel Human Immunodeficiency Virus Protease Inhibitor
Authors: Ford Susan L. , Reddy Y. Sunila , Anderson Maggie T. , Murray Sharon C. , Fernandez Pedro , Stein Daniel S. , Johnson Mark A.
Published: May 2006

Brecanavir (BCV, 640385) is a novel, potent protease inhibitor (PI) with low nanomolar 50% inhibitory concentrations against PI-resistant human immunodeficiency virus (HIV) in vitro. This phase I, double-blind, randomized, placebo-controlled, two-part single-dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of BCV administered at 10 mg/ml in a tocopherol-polyethylene glycol succinate-polyethylene glycol 400-ethanol 50:40:10 solution. In part 1 of the study, single oral doses of BCV ranged from 25 mg to 800 mg. In part 2, single oral doses of BCV ranged from 10 mg to 300 mg and were coadministered with 100-mg oral ritonavir (RTV) soft gel capsules. Single doses of BCV and BCV/RTV were generally well tolerated. There were no severe adverse events (SAEs), and no subject was withdrawn due to BCV. The most commonly reported drug-related AEs during both parts of the study combined were gastrointestinal disturbances (similar to placebo) and headache. BCV was readily absorbed following oral administration with mean times to maximum concentration from >1 h to 2.5 h in part 1 and from 1.5 h to 3 h in part 2. Administration of BCV without RTV resulted in BCV exposures predicted to be insufficient to inhibit PI-resistant virus based on in vitro data. Coadministration of 300 mg BCV with 100 mg RTV, however, significantly increased the plasma BCV area under the concentration-time curve and maximum concentration 26-fold and 11-fold, respectively, achieving BCV concentrations predicted to inhibit PI-resistant HIV.
Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline
Authors: Olson Matthew W. , Ruzin Alexey , Feyfant Eric , Rush Thomas S. , O'Connell John , Bradford Patricia A.
Published: May 2006

Tigecycline is a novel glycylcycline antibiotic that possesses broad-spectrum activity against many clinically relevant species of bacterial pathogens. The mechanism of action of tigecycline was delineated using functional, biophysical, and molecular modeling experiments in this study. Functional assays showed that tigecycline specifically inhibits bacterial protein synthesis with potency 3- and 20-fold greater than that of minocycline and tetracycline, respectively. Biophysical analyses demonstrated that isolated ribosomes bind tigecycline, minocycline, and tetracycline with dissociation constant values of 10
−8
, 10
−7
, and >10
−6
M, respectively. A molecular model of tigecycline bound to the ribosome was generated with the aid of a 3.40-angstrom resolution X-ray diffraction structure of the 30S ribosomal subunit from
Thermus thermophilus
. This model places tigecycline in the A site of the 30S subunit and involves substantial interactions with residues of H34 of the ribosomal subunit. These interactions were not observed in a model of tetracycline binding. Modeling data were consistent with the biochemical and biophysical data generated in this and other recent studies and suggested that tigecycline binds to bacterial ribosomes in a novel way that allows it to overcome tetracycline resistance due to ribosomal protection.
Persistence of
Mycoplasma hyopneumoniae
in Experimentally Infected Pigs after Marbofloxacin Treatment and Detection of Mutations in the
parC
Gene
Authors: Le Carrou J. , Laurentie M. , Kobisch M. , Gautier-Bouchardon A. V.
Published: May 2006

The ability of
Mycoplasma hyopneumoniae
to persist despite fluoroquinolone treatments was investigated with pigs. Groups of specific-pathogen-free pigs were experimentally infected with
M. hyopneumoniae
strain 116 and treated with marbofloxacin at the therapeutic dose (TD) or half of the therapeutic dose (TD/2) for 3 days. Results showed that, despite tissue penetration of marbofloxacin, particularly in the trachea and the tracheal secretions, the treatments did not have any influence on
M. hyopneumoniae
recovery from tracheal swabs. Mycoplasmas were also isolated from inner organs and tissues such as liver, spleen, kidneys, and bronchial lymph nodes. Recontamination of pigs via environment could not explain mycoplasma persistence after medication, as decontamination of pigs and allocation to a new disinfected environment did not have any significant effect on the phenomenon. A significant decrease in the susceptibility level to marbofloxacin of 12 mycoplasma clones reisolated after the treatments (TD/2 and TD) was observed. Two point mutations were found in the ParC quinolone resistance-determining region (QRDR) of DNA topoisomerase IV (Ser80→Phe and Asp84→Asn), and one point mutation was observed just behind the QRDR of ParC (Ala116→Glu). This is the first time that mutations in a gene coding for topoisomerase IV have been described for
M. hyopneumoniae
after in vivo marbofloxacin treatments in experimentally infected pigs. However, development of resistance is not sufficient to explain
M. hyopneumoniae
persistence in vivo since (i) marbofloxacin concentrations were above the marbofloxacin MIC of the wild-type strain and (ii) mycoplasmas reisolated after a single injection of marbofloxacin did not display an increased marbofloxacin MIC.
VanG-Type Vancomycin-Resistant
Enterococcus faecalis
Strains Isolated in Canada
Authors: Boyd David A. , Du Tim , Hizon Romeo , Kaplen Brynn , Murphy Travis , Tyler Shaun , Brown Shirley , Jamieson Frances , Weiss Karl , Mulvey Michael R. ,   the Canadian Nosocomial Infection Surveillance Program
Published: May 2006

Enterococcus faecalis
G1-0247 (vancomycin MIC, 16 μg/ml) was found to harbor a
vanG
operon 99% identical to the
vanG
operon in
E. faecalis
BM4518.
E. faecalis
N03-0233 (vancomycin MIC, 16 μg/ml) was found to harbor a novel
vanG
operon,
vanG2
, on an element in a different chromosomal location than the
vanG
-harboring elements in G1-0247 and BM4518.
Inhibition of Human Coronavirus NL63 Infection at Early Stages of the Replication Cycle
Authors: Pyrc Krzysztof , Bosch Berend Jan , Berkhout Ben , Jebbink Maarten F. , Dijkman Ronald , Rottier Peter , van der Hoek Lia
Published: May 2006

Human coronavirus NL63 (HCoV-NL63), a recently discovered member of the
Coronaviridae
family, has spread worldwide and is associated with acute respiratory illness in young children and elderly and immunocompromised persons. Further analysis of HCoV-NL63 pathogenicity seems warranted, in particular because the virus uses the same cellular receptor as severe acute respiratory syndrome-associated coronavirus. As there is currently no HCoV-NL63-specific and effective vaccine or drug therapy available, we evaluated several existing antiviral drugs and new synthetic compounds as inhibitors of HCoV-NL63, targeting multiple stages of the replication cycle. Of the 28 compounds that we tested, 6 potently inhibited HCoV-NL63 at early steps of the replication cycle. Intravenous immunoglobulins, heptad repeat 2 peptide, small interfering RNA1 (siRNA1), siRNA2, β-
d
-N
4
-hydroxycytidine, and 6-azauridine showed 50% inhibitory concentrations of 125 μg/ml, 2 μM, 5 nM, 3 nM, 400 nM, and 32 nM, respectively, and low 50% cytotoxicity concentrations (>10 mg/ml, >40 μM, >200 nM, >200 nM, >100 μM, and 80 μM, respectively). These agents may be investigated further for the treatment of coronavirus infections.
Biological, Biochemical, and Molecular Characterization of a New Clinical
Trichophyton rubrum
Isolate Resistant to Terbinafine
Authors: Osborne Colin S. , Leitner Ingrid , Hofbauer Bettina , Fielding Ceri A. , Favre Bertrand , Ryder Neil S.
Published: May 2006

We have characterized a new clinical strain of
Trichophyton rubrum
highly resistant to terbinafine but exhibiting normal susceptibility to drugs with other mechanisms of action. Resistance to terbinafine in this strain is caused by a missense mutation in the squalene epoxidase gene leading to the amino acid substitution F397L.
Synthesis of Oligoribonucleotides Containing Pyrimidine 2'-O-[(Hydroxyalkoxy)methyl]ribonucleosides
Authors: Bobkov Georgii V. , Brilliantov Kirill V. , Mikhailov Sergey N. , Rozenski Jef , Van Aerschot Arthur , Herdewijn Piet
Published: May 2006

A simple and efficient method for the preparation of pyrimidine 2'-O-[(2-hydroxyethoxy)methyl]ribonucleosides and 2'-O-[(3-hydroxypropoxy)methyl]ribonucleosides has been developed. These modified nucleosides were incorporated into oligoribonucleotides, which were shown to form stable RNA/RNA duplexes.
Organosulfur oxoacids. Part 1. Synthesis, structure, and reactivity of dimethylaminoiminomethanesulfinic acid (DMAIMSA)
Authors: Ojo Jonathan F , Petersen Jeffrey L , Otoikhian Adenike , Simoyi Reuben H
Published: May 2006

One of the major metabolites of dimethylthiourea, dimethylaminoiminomethanesulfinic acid (DMAIMSA), was synthesized by controlled oxidation of dimethylthiourea using hydrogen peroxide. The crystal structure was determined by X-ray crystallography. It is a zwitterionic species in its solid form, with a positive charge delocalized around an sp2-hybridized carbon center and two nitrogen atoms. It crystallizes in the triclinic P[Formula: see text] space group. The CS bond, at 1.880(2) Å, is much longer than a typical CS single bond length of 1.79 Å. It is also longer than the one observed in thiourea trioxide, a comparable sulfonic acid. This CS bond is stable in acidic conditions and is easily cleaved in basic conditions or in the presence of suitable nucleophiles that can attack the positively disposed carbon center. DMAIMSA is highly reactive and easily decomposes in basic conditions to yield dithionite in the presence of oxygen, whereas in strictly anaerobic conditions it gives a mixture of sulfite and sulfide. The precursor to dithionite, SO2·, is formed from the one-electron oxidation of the sulfoxylate anion, SO22, which results from an initial heterolytic cleavage of the CS bond in DMAIMSA. The sulfur center is oxidized, even by mild oxidants such as aqueous iodine, to sulfate. Key words: thiourea metabolites, synthesis, structure, reactivity.
Facile synthesis of α-D-Araf-(1→5)-D-Galf, the linker unit of the arabinan to the galactan in Mycobacterium tuberculosis
Authors: Gandolfi-Donadío Lucía , Gallo-Rodriguez Carola , de Lederkremer Rosa M
Published: May 2006

The arabinogalactan is a crucial constituent of the cell wall of mycobacteria. Both monosaccharides (arabinose and galactose) are found in the furanose configuration, absent in mammals. An efficient synthesis of α-D-Araf-(1→5)-D-Galf, the linker unit of the arabinan to the galactan, is described. The strategy relies on the use of a conveniently substituted D-galactono-1,4-lactone as a precursor of the reducing furanose ring. The glycosylation step was performed by the tin(IV) chloride promoted method using 1,2,3,5-tetra-O-benzoyl-α,β-D-arabinofuranose. The arabinose donor was obtained in a crystalline state in one step by benzoylation of arabinose in hot pyridine. Selective glycosylation of the exocyclic OH-5 was obtained in 75% yield to give 2,3,5-tri-O-benzoyl-α-D-arabinofuranosyl-(1→5)-2,6-di-O-pivaloyl-D-galactono-1,4-lactone. Reduction with disiamylborane gave the disaccharide synthon, useful for further glycosylations. Dec-9-enyl α-D-Araf-(1→5)-β-D-Galf, a convenient substrate for arabinofuranosyl transferases studies, was obtained by the trichloroacetimidate method of glycosylation.Key words: arabinofuranose, galactofuranose, Mycobacterium arabinogalactan, trichloroacetimidate, tin(IV) chloride.
Pyrolysis of 2-methoxy-5,5-dimethyl-2-methylthio- 2,5-dihydro[1,3,4]oxadiazole studied with photoelectron spectroscopy and DFT calculations  He(I) photoelectron spectrum of methoxy(methylthio)carbene
Authors: Werstiuk N H , Klys A , Warkentin J
Published: May 2006

Gas-phase pyrolysis of 2-methoxy-2-methylsulfanyl-5,5-dimethyl-2,5-dihydro[1,3,4]oxadiazole (1) (also known as 2-methoxy-5,5-dimethyl-2-methylthio-2,5-dihydro[1,3,4]oxadiazole and 2-methoxy-2-methylthio-5,5-dimethyl-Δ3-l,3,4-oxadiazoline) in the source of an UV photoelectron spectrometer, by means of a CW CO2 laser as directed heat source, gave a photoelectron (PE) spectrum that included ionization bands belonging to acetone and methoxy(methylthio)carbene (3). Photoelectron spectra of authentic samples of (E)-1,2-dimethoxy-1,2-dimethyl thioethene (4), (Z)-1,2-dimethoxy-1,2-dimethylthioethene (5), S-methyl thioethanoate (6), and O-methyl ethanethioate (7), which can be derived by dimerization and rearrangement of the carbene, established that these compounds are not present in the pyrolysate. DFT calculations at the B3PW91/6-31+G(d,p) level and simulation of PE spectra at the B3LYP/6-31+G(d,p) level were instrumental in the interpretation of the experimental results. From the available experimental and calculated data, 3 is formed in a Sickle conformation upon pyrolysis of 1. Transition states for the rearrangement of 3 were examined with QTAIM. Key words: 2-methoxy-5,5-dimethyl-2-methylthio-2,5-dihydro[1,3,4]oxadiazole, pyrolysis, He(I) photoelectron spectroscopy, methoxy(methylthio)carbene, DFT calculations, QTAIM.
Synthesis of zwitterionic selenonium and sulfonium sulfates from D-mannose as potential glycosidase inhibitors
Authors: Liu Hui , Pinto B Mario
Published: May 2006

Four chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol were synthesized for structureactivity studies with different glycosidase enzymes. The syntheses involved the reaction of isopropylidene-protected 1,4-thio- and 1,4-seleno-D-talitols and 1,5-thio- and 1,5-seleno-L-gulitols, derived from D-mannose, with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, also derived from D-mannose. Deprotection of the products afforded the novel selenonium and sulfonium sulfates composed of heterocyclic five- and six-membered ring core structures with pendant polyhydroxylated, acyclic chains of six carbon atoms.Key words: glycosidase inhibitors, zwitterionic selenonium and sulfonium sulfates, cyclic sulfate
Synthesis of mono- and di-sialophospholipids via the H-phosphonate approach
Authors: Yan Hongbin , Jennings Harold J
Published: May 2006

To overcome their inherent instability, stable modified mono- and di-sialophospholipids of the group C meningococcal polysaccharide were synthesized. Stability was achieved by introducing a spacer between the sialic acid residue and the phospholipid component, and by replacing the native ester linkages to the lipid by ether linkages. Mono- and di-hydroxylethylenesialosides were coupled to phosphoglyceroldietherlipid using H-phosphonate chemistry to give the anomerically pure sialophospholipids in good yields.Key words: polysialic acid, glycolipid, H-phosphonate, meningococcus.
Kinetics of the reaction catalyzed by inositol dehydrogenase fromBacillussubtilisand inhibition by fluorinated substrate analogs
Authors: Daniellou Richard , Zheng Hongyan , Palmer David RJ
Published: May 2006

Inositol dehydrogenase (EC 1.1.1.18) from Bacillus subtilis catalyzes the oxidation of myo-inositol to scyllo-inosose by transfer of the equatorial hydride of the substrate to NAD+. This is a key enzyme in the metabolism of myo-inositol, a primary carbon source for soil bacteria. In light of our recent discovery that the enzyme has a broad substrate spectrum while maintaining high stereoselectivity, we seek a more thorough understanding of the enzyme and its active site. We have examined the kinetics of the recombinant enzyme, and synthesized fluorinated substrate analogues as competitive inhibitors. We have evaluated all rate constants in the ordered, sequential Bi Bi mechanism. No steady-state kinetic isotope effect is observed using myo-[2-2H]-inositol, indicating that the chemical step of the reaction is not rate-limiting. We have synthesized the substrate analogs 2-deoxy-2-fluoro-myo-inositol, its equatorial analog 1-deoxy-1-fluoro-scyllo-inositol, the gem-difluorinated analog 1-deoxy-1,1-difluoro-scyllo-inositol, and the sugar analog α-D-glucosyl fluoride. Of these, 1-deoxy-1-fluoro-scyllo-inositol showed no inhibition, while all others tested had Kivalues comparable to the Kmvalues of the analogous substrates myo-inositol and α-D-glucose.Key words: inositol dehydrogenase, enzyme mechanism, kinetics, competitive inhibitor, substrate analogue.
Selective chemistry of tripentaerythritol  Synthesis of acetals and their derivatives
Authors: Al-Mughaid Hussein , Grindley T Bruce
Published: May 2006

Tripentaerythritol was converted efficiently into 2′,2′′:6′,6′′:10′,10′′-tri-O-cyclohexylidene-2,2,6,6,10,10-hexakis(hydroxymethyl)-4,8-dioxa-1,11-undecandiol (4) by the toluenesulfonic acid catalysed reaction with cyclohexanone in a mixture of N,N-dimethylformamide and benzene. Reaction of tripentaerythritol with benzaldehyde under similar conditions gave an easily separated mixture of the four possible stereoisomers. Structures of these stereoisomers were assigned based on 1H and 13C NMR chemical shifts using trends previously observed for the dibenzylidene acetals of dipentaerythritol, whose structures had been established unambiguously by X-ray crystallography. It was found that reduction of the mixture of benzylidene acetals to 2,6,10-tris(benzyloxymethyl)-4,8-dioxa-1,11-undecanediol could be accomplished using triethylsilane with ethylaluminium dichloride as the Lewis acid after a number of commonly used conditions for this transformation failed.Key words: pentaerythritol, tripentaerythritol, dipentaerythritol, acetals, benzylidene acetals, reduction.