bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apoptosis in Renal Proximal Tubules of Rats Treated with Low Doses of Aminoglycosides
Authors: El Mouedden Mohammed , Laurent Guy , Mingeot-Leclercq Marie-Paule , Taper Henryk S. , Cumps Jean , Tulkens Paul M. 
Published: July 2002

ABSTRACTKidney cortex apoptosis was studied with female Wistar rats treated for 10 days with gentamicin and netilmicin at daily doses of 10 or 20 mg/kg of body weight and amikacin or isepamicin at daily doses of 40 mg/kg. Apoptosis was detected and quantitated using cytological (methyl green-pyronine) and immunohistochemical (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining, in parallel with a measurement of drug-induced phospholipidosis (cortical phospholipids and phospholipiduria), cortical proliferative response (3H incorporation in DNA and histoautoradiography after in vivo pulse-labeling with [3H]thymidine), and kidney dysfunction (blood urea nitrogen and creatinine). Gentamicin induced in proximal tubules a marked apoptotic reaction which (i) was detectable after 4 days of treatment but was most conspicuous after 10 days, (ii) was dose dependent, (iii) occurred in the absence of necrosis, and (iv) was nonlinearly correlated with the proliferative response (tubular and peritubular cells). Comparative studies revealed a parallelism among the extents of phospholipidosis, apoptosis, and proliferative response for three aminoglycosides (gentamicin >> amikacin ≅ isepamicin). By contrast, netilmicin induced a marked phospholipidosis but a moderate apoptosis and proliferative response. We conclude that rats treated with gentamicin develop an apoptotic process as part of the various cortical alterations induced by this antibiotic at low doses. Netilmicin, and still more amikacin and isepamicin, appears safer in this respect. Whereas a relation between aminoglycoside-induced tubular apoptosis and cortical proliferative response seems to be established, no simple correlation with phospholipidosis can be drawn.
Pharmacologic Characteristics of Indinavir, Didanosine, and Stavudine in Human Immunodeficiency Virus-Infected Children Receiving Combination Therapy
Authors: Fletcher Courtney V. , Brundage Richard C. , Remmel Rory P. , Page Linda M. , Weller Dennis , Calles Nancy R. , Simon Cara , Kline Mark W. 
Published: July 2002

ABSTRACT

The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m
2
every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of ≥0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m
2
; nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean ± standard deviation) were the following: oral clearance, 1.4 ± 0.5 liters/h/kg; half-life, 1.1 ± 0.43 h; and trough concentration, 0.29 ± 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.
Pharmacokinetics of Single-Dose Oral Stavudine in Subjects with Renal Impairment and in Subjects Requiring Hemodialysis
Authors: Grasela Dennis M. , Stoltz Randall R. , Barry Michael , Bone Michael , Mangold Bernhard , O'Grady Padraig , Raymond Ralph , Haworth Stephen J. 
Published: July 2002

ABSTRACT

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL
CR
) normalized by body surface area (ml/min/1.73 m
2
): mild (CL
CR
, 60 to 80), moderate (30 to 50), and severe (≤20) renal impairment. Five healthy subjects (CL
CR
≥ 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC
0–∞
) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng · h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (
P
= 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing ≥60 kg: CL
CR
of >50 ml/min/1.73 m
2
, 40 mg every 12 h; CL
CR
of 21 to 50 ml/min/1.73 m
2
, 20 mg every 12 h; and CL
CR
of 10 to 20 ml/min/1.73 m
2
, 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUC
0–∞
, AUC
2–6
, time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.
If Taken 1 Hour before Indinavir (IDV), Didanosine Does Not Affect IDV Exposure, despite Persistent Buffering Effects
Authors: Shelton Mark J. , Mei Haijing , Hewitt Ross G. , Defrancesco Robin 
Published: July 2002

ABSTRACTConcurrent administration of indinavir and didanosine significantly reduces the level of exposure to indinavir, but it is unclear how soon after didanosine administration indinavir may be given safely. We compared indinavir pharmacokinetics and gastric pH in 12 human immunodeficiency virus-positive patients by use of 800 mg of indinavir alone versus 800 mg of indinavir administered 1 h after didanosine administration. Median gastric pH was significantly higher when indinavir was taken after didanosine administration; however, no significant difference in the maximum concentration in plasma or the area under the concentration-time curve from time zero to 8 h was observed. Indinavir may be taken with a light meal 1 h following the administration of 400 mg of didanosine.
Efficacy of 2-Amino-7-(1,3-Dihydroxy-2-Propoxymethyl)Purine for Treatment of Vaccinia Virus (Orthopoxvirus) Infections in Mice
Authors: Neyts Johan , De Clercq Erik 
Published: July 2002

ABSTRACT
We have previously shown that the N-7 substituted acyclic nucleoside analog 2-amino-7-[1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) is, both in vitro and in animal models, a potent inhibitor of the replication of several herpesviruses (Neyts et al., Antimicrob. Agents Chemother. 39:56–60, 1995). Here we report on the potent and selective antiviral activity of S2242 against vaccinia virus (VV), an orthopoxvirus. The 50% effective concentrations for inhibition of VV-induced cytopathic effect and viral DNA synthesis in cell culture were 2.4 and 0.2 μg/ml, respectively. We next studied the efficacy of S2242 in VV-infected mice. Immunocompetent NMRI mice that had been inoculated intravenously with VV developed tail lesions. Mice that had been treated for 5 consecutive days via the subcutaneous (s.c.) route with 100 mg of the diacetate ester prodrug of S2242 (compound H961) per kg of body weight did not develop any lesions and demonstrated no adverse effects. Severe combined immunodeficient (SCID) mice that had been inoculated intraperitoneally with VV became sick and died within 1 month after infection. Following treatment with H961 at 100 mg/kg for 10 consecutive days (either via oral gavage or s.c. injection) VV-inoculated SCID mice were completely protected, for at least 3 months, against virus-induced morbidity and mortality. At that time, no virus could be recovered from the organs of these mice (as assessed by titration for infectious virus, a DNA hybridization assay, and a PCR for VV-specific sequences). Compound S2242 and its oral prodrug H961 could be useful in treatment of orthopoxvirus infections.
Bronchopulmonary Disposition of the Ketolide Telithromycin (HMR 3647)
Authors: Muller-Serieys Claudette , Soler Paul , Cantalloube Cathy , Lemaitre Françoise , Gia Hai Pham , Brunner Françoise , Andremont Antoine 
Published: July 2002

ABSTRACT

Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with
Bacillus subtilis
ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.
Staphylococcus aureus
Mutants Isolated via Exposure to Nonfluorinated Quinolones: Detection of Known and Unique Mutations
Authors: Roychoudhury Siddhartha , Twinem Tracy L. , Makin Kelly M. , Nienaber Mark A. , Li Chuiying , Morris Timothy W. , Ledoussal Benoit , Catrenich Carl E. 
Published: July 2002

ABSTRACT

The in vitro development of resistance to the new nonfluorinated quinolones (NFQs; PGE 9262932, PGE 4175997, and PGE 9509924) was investigated in
Staphylococcus aureus
. At concentrations two times the MIC, step 1 mutants were isolated more frequently with ciprofloxacin and trovafloxacin (9.1 × 10
−8
and 5.7 × 10
−9
, respectively) than with the NFQs, gatifloxacin, or clinafloxacin (<5.7 × 10
−10
). Step 2 and step 3 mutants were selected via exposure of a step 1 mutant (selected with trovafloxacin) to four times the MICs of trovafloxacin and PGE 9262932. The step 1 mutant contained the known Ser80-Phe mutation in GrlA, and the step 2 and step 3 mutants contained the known Ser80-Phe and Ser84-Leu mutations in GrlA and GyrA, respectively. Compared to ciprofloxacin, the NFQs were 8-fold more potent against the parent and 16- to 128-fold more potent against the step 3 mutants. Mutants with high-level NFQ resistance (MIC, 32 μg/ml) were isolated by the spiral plater-based serial passage technique. DNA sequence analysis of three such mutants revealed the following mutations: (i) Ser84-Leu in GyrA and Glu84-Lys and His103-Tyr in GrlA; (ii) Ser-84Leu in GyrA, Ser52-Arg in GrlA, and Glu472-Val in GrlB; and (iii) Ser84-Leu in GyrA, Glu477-Val in GyrB, and Glu84-Lys and His103-Tyr in GrlA. Addition of the efflux pump inhibitor reserpine (10 μg/ml) resulted in 4- to 16-fold increases in the potencies of the NFQs against these mutants, whereas it resulted in 2-fold increases in the potencies of the NFQs against the parent.
Lack of Emergence of Cytomegalovirus UL97 Mutations Conferring Ganciclovir (GCV) Resistance following Preemptive GCV Therapy in Allogeneic Stem Cell Transplant Recipients
Authors: Gilbert C. , Roy J. , Belanger R. , Delage R. , Beliveau C. , Demers C. , Boivin G. 
Published: July 2002

ABSTRACT
Fifty allogeneic stem cell transplant recipients were enrolled in a prospective cytomegalovirus pp65 antigenemia-guided preemptive therapy trial. Among these, 10 of 34 patients who received ganciclovir exhibited sustained and/or recurrent antigenemia despite treatment. Thirteen leukocyte preparations from these 10 subjects were screened for the presence of the most frequent cytomegalovirus UL97 mutations conferring ganciclovir resistance. None of these mutations were detected after mean and median ganciclovir exposures of 31.6 and 28.0 days, respectively.
Comparative Antianaerobic Activity of BMS 284756
Authors: Hoellman Dianne B. , Kelly Linda M. , Jacobs Michael R. , Appelbaum Peter C. 
Published: July 2002

ABSTRACT

Agar dilution MIC methodology was used to compare the activity of BMS 284756 with those of ciprofloxacin, levofloxacin, moxifloxacin, trovafloxacin, amoxicillin-clavulanate, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 357 anaerobes. Overall, the respective MICs at which 50% of the isolates tested were inhibited (MIC
50
s) and MIC
90
s (in micrograms per milliliter) were as follows: BMS 284756, 0.5 and 2.0; ciprofloxacin, 2.0 and 16.0; levofloxacin, 1.0 and 8.0; moxifloxacin, 0.5 and 4.0; trovafloxacin, 0.5 and 2.0; amoxicillin-clavulanate, 0.5 and 2.0; piperacillin-tazobactam, 0.25 and 8.0; imipenem, 0.06 and 1.0; clindamycin, 0.25 and 8.0; and metronidazole, 1.0 and >16.0. BMS 284756 is a promising new quinolone with excellent antianaerobic activity.
Cyclopentane Neuraminidase Inhibitors with Potent In Vitro Anti-Influenza Virus Activities
Authors: Smee Donald F. , Huffman John H. , Morrison Ann C. , Barnard Dale L. , Sidwell Robert W. 
Published: July 2002

ABSTRACT

A novel series of cyclopentane derivatives have been found to exhibit potent and selective inhibitory effects on influenza virus neuraminidase. These compounds, designated RWJ-270201, BCX-1827, BCX-1898, and BCX-1923, were tested in parallel with zanamivir and oseltamivir carboxylate against a spectrum of influenza A (H1N1, H3N2, and H5N1) and influenza B viruses in MDCK cells. Inhibition of viral cytopathic effect ascertained visually and by neutral red dye uptake was used, with 50% effective (virus-inhibitory) concentrations (EC
50
) determined. Against the H1N1 viruses A/Bayern/07/95, A/Beijing/262/95, A/PR/8/34, and A/Texas/36/91, EC
50
s (determined by neutral red assay) of the novel compounds were ≤1.5 μM. Twelve strains of H3N2 and two strains of avian H5N1 viruses were inhibited at <0.3 μM. Influenza B/Beijing/184/93 and B/Harbin/07/94 viruses were inhibited at <0.2 μM, with three other B virus strains inhibited at 0.8 to 8 μM. The novel inhibitors were comparable in potency to (or slightly more potent than) zanamivir and oseltamivir carboxylate. No cytotoxicity was seen with the compounds at concentrations of ≤1 mM in cell proliferation assays. The antiviral activity of RWJ-270201, chosen for clinical development, was studied in greater detail. Its potency and that of oseltamivir carboxylate decreased with increasing multiplicity of virus infection. Time-of-addition studies indicated that treatment with either compound needed to begin 0 to 12 h after virus exposure for optimal activity. Exposure of cells to RWJ-270201 caused most of the virus to remain cell associated, with extracellular virus decreasing in a concentration-dependent manner. This is consistent with its effect as a neuraminidase inhibitor. RWJ-270201 shows promise in the treatment of human influenza virus infections.
Controlled Trial of 3-Day Quinine-Clindamycin Treatment versus 7-Day Quinine Treatment for Adult Travelers with Uncomplicated Falciparum Malaria Imported from the Tropics
Authors: Parola Phillippe , Ranque Stephane , Badiaga Sekene , Niang Mohamadou , Blin Olivier , Charbit Jean-Jacques , Delmont Jean , Brouqui Philippe 
Published: July 2002

ABSTRACT

We conducted a randomized, double-blind, placebo-controlled trial to compare a 3-day quinine-clindamycin regimen (group QC) with a 7-day quinine regimen (group Q) for the treatment of uncomplicated
Plasmodium falciparum
malaria in travelers returning from the tropics. A total of 55 and 53 patients in groups Q and QC were analyzed, respectively. Adverse effects were similar in both groups, although two patients in group Q had severe adverse reactions, leading to the cessation of treatment. The 28-day cure rate for the evaluated patients (per-protocol analysis) was 100% for group QC, whereas it was 96.3% for group Q (
P
= 0.5). The 28-day cure rate in the intention-to-treat analysis was 96.2% for group QC, whereas it was 94.6% for group Q (
P
= 1). There were no significant differences between the two regimens with regard to parasite and fever clearance times. Our study shows that the 3-day quinine-clindamycin regimen is well tolerated and compares favorably with a 7-day quinine treatment. This short-term regimen had previously been evaluated only in areas of endemicity. According to our results, the 3-day quinine-clindamycin regimen may be an alternative for the treatment of imported uncomplicated
P. falciparum
malaria in travelers returning from the tropics.
Activities and Conformational Fitting of 1,4-Naphthoquinone Derivatives and Other Cyclic 1,4-Diones Tested In Vitro againstPneumocystis carinii
Authors: Ball M. D. , Bartlett M. S. , Shaw M. , Smith J. W. , Nasr M. , Meshnick S. R. 
Published: July 2002

ABSTRACTAtovaquone is a chemotherapeutic agent used to treat pneumonia caused byPneumocystis cariniiin some immunocompromised patients. A set of cyclic 1,4-diones were tested in vitro for ability to inhibit growth ofP. carinii, including 22 variously substituted 1,4-naphthoquinones, one bis-1,4-naphthoquinone, and three other quinones. For comparison, the antipneumocystic primaquine and its 5-hydroxy-6-desmethyl metabolite were also tested. At 1.0 μg/ml, seven compounds inhibited growth by at least 39%, with atovaquone at 92%; of these seven, five are 2-hydroxy-1,4-naphthoquinones, while one is a 2-chloro- and another is a 2-methyl-1,4-naphthoquinone. At 0.1 μg/ml, however, the most active compound tested was the primaquine metabolite, which inhibited growth by more than 42% at this concentration. To ascertain a structure-activity relationship, all 1,4-naphthoquinones were compared conformationally by means of computer-based molecular modeling (Spartan) incorporating the Sybyl force field. Without exception, for all 21 monomers tested, the substituent at position 3 of the 1,4-naphthoquinone favored activity most strongly when it simultaneously occupied (i) space centered at about 3 Å from position 3, without projecting steric bulk from the area encompassed by atovaquone's cyclohexyl ring, and (ii) roughly planar space at about 7.3 Å from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents.
Antimicrobial Activities of BMS-284756 Compared with Those of Fluoroquinolones and β-Lactams against Gram-Positive Clinical Isolates
Authors: Bassetti Matteo , Dembry Louise M. , Farrel Patricia A. , Callan Deborah A. , Andriole Vincent T. 
Published: July 2002

ABSTRACT

The in vitro antibacterial activity of BMS-284756 was compared to those of ciprofloxacin, gatifloxacin, moxifloxacin, ceftriaxone, imipenem, piperacillin-tazobactam, and amoxicillin-clavulanic acid against 492 gram-positive clinical isolates. BMS-284756 was the most-active agent against
Streptococcus pneumoniae
,
Streptococcus viridans
, beta-hemolytic streptococci, methicillin-sensitive and -resistant
Staphylococcus aureus
, methicillin-sensitive and -resistant coagulase-negative staphylococci, and enterococci.
Use of Terbinafine in Mouse and Rat Models ofPneumocystis cariniiPneumonia
Authors: Walzer Peter D. , Ashbaugh Alan 
Published: July 2002

ABSTRACTTerbinafine, an allylamine used to treat onychomycosis, has been reported to be active against ratPneumocystis cariniiin vitro and in vivo. By contrast, our in vitro data showed that the 50% inhibitory concentration of terbinafine against ratP. cariniiis 3.7 μg/ml, a level that cannot be clinically achieved in serum. In the present study, terbinafine administered orally at doses of 20 to 400 mg/kg/day and 50 to 250 mg/kg/day was ineffective therapy for mouse and rat models of pneumocystosis, respectively. These results emphasize the complexities ofP. cariniidrug testing and the need for caution before considering studies in humans.
Integron-Locatedoxa-32Gene Cassette Encoding an Extended-Spectrum Variant of OXA-2 β-Lactamase fromPseudomonas aeruginosa
Authors: Poirel Laurent , Gerome Patrick , De Champs Christophe , Stephanazzi Jean , Naas Thierry , Nordmann Patrice 
Published: July 2002

ABSTRACTPseudomonas aeruginosaclinical isolate CY-1, which was resistant to ceftazidime, harbored a conjugative ca. 250-kb plasmid that contained a class 1 integron with two gene cassettes encoding OXA-32, an OXA-2- type β-lactamase, and the aminoglycoside acetyltransferase AAC(6′)Ib9. OXA-32 differed from OXA-2 by an Leu169Ile amino acid substitution (class D numbering). Site-directed mutagenesis established that Ile169 is responsible for resistance to ceftazidime but not to cefotaxime.
Comparison of Oral Artesunate and Dihydroartemisinin Antimalarial Bioavailabilities in Acute Falciparum Malaria
Authors: Newton Paul N. , van Vugt Michele , Teja-Isavadharm Paktiya , Siriyanonda Duangsuda , Rasameesoroj Maneerat , Teerapong Pramote , Ruangveerayuth Ronatrai , Slight Thra , Nosten Francois , Suputtamongkol Yupin , Looareesuwan Sornchai , White Nicholas J. 
Published: July 2002

ABSTRACT
Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ significantly from 1, suggesting that DHA can be formulated to be an acceptable oral alternative to artesunate.
Different Aminoglycoside-Resistant Phenotypes in a Rabbit
Staphylococcus aureus
Endocarditis Infection Model
Authors: Asseray N. , Caillon J. , Roux N. , Jacqueline C. , Bismuth R. , Kergueris M. F. , Potel G. , Bugnon D. 
Published: July 2002

ABSTRACT

The impact of different types of enzymatic resistance on the in vivo antibacterial activity of aminoglycosides (amikacin, gentamicin, and netilmicin) was studied in the rabbit endocarditis model with four strains of
Staphylococcus aureus
. Animals were treated in a manner simulating the administration of a single daily human dose. Amikacin had no effect on the three kanamycin-resistant strains despite apparent susceptibility in the disk diffusion test. Gentamicin appears to be the preferable aminoglycoside for treatment of staphylococcal infections.