Guidelines for aminoglycoside use and applicability to geriatric patients.

OBJECTIVES: The authors had for objective to evaluate the applicability of AFSSAPS guidelines for aminoglycoside use to geriatric patients. METHODS: Theoretical doses and dosing regimens allowing reaching target concentrations in this population were calculated by applying a pharmacokinetic model to 30 geriatric patients treated by amikacin. RESULTS: The dose allowing reaching a maximum concentration of 60 mg/L was 1.217 mg on average. The time required to reach a blood concentration lower than or equal to 2.5mg/L was 62.5±70.4 hours. Forty-six percent of patients had a trough concentration greater than 2.5 mg/L, 48 hours after administration. For these patients, the time between critical minimum inhibitory concentration (MIC) and toxicity threshold concentration was 21.9±14.9 hours. CONCLUSION: Reaching a target concentration can be problematic in geriatric patients. It is frequently necessary to use dosing intervals greater than 48 hours. The effectiveness and safety of these regimens remain uncertain.

Identification of acetylated, tetrahalogenated benzimidazole D-ribonucleosides with enhanced activity against human cytomegalovirus.

DNA packaging is the key step in viral maturation and involves binding and cleavage of viral DNA containing specific DNA-packaging motifs. This process is mediated by a group of specific enzymes called terminases. We previously demonstrated that the human cytomegalovirus (HCMV) terminase is composed of the large subunit pUL56 and the small subunit pUL89. While the large subunit mediates sequence-specific DNA binding and ATP hydrolysis, pUL89 is required only for duplex nicking. An excellent inhibitor targeting HCMV terminase is 2-bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB), but it was not developed as an antiviral drug due to its metabolic cleavage in experimental animals. We now have tested several new benzimidazole d-ribonucleosides in order to determine whether these compounds represent new, potent inhibitors. Analysis by bioluminometric ATPase activity assays identified two of the new compounds with a high inhibitory effect, 2-bromo-4,5,6-trichloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl) benzimidazole (BTCRB) and 2,4,5,6-tetrachloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl benzimidazole (Cl(4)RB). By using viral plaque formation, viral yield, and viral growth kinetics, we demonstrated that the two compounds BTCRB and Cl(4)RB had antiviral activities similar to that of BDCRB. Interestingly, BTCRB retained its inhibitory activity after preincubation with HFF cells. By use of electron microscopy, we observed an increase of B capsids and a lack of cytoplasmic capsids in the presence of the compounds that correlated with the virus yield. Furthermore, cleavage of concatenated DNA was inhibited by both compounds, and inhibition by BTCRB was shown to be dose dependent. These results demonstrate that the new compounds are highly active against HCMV and act by mechanisms similar but not identical to those of BDCRB.

Retinal vessel dilation following repletion of vitamin A deficiency.

We hypothesized that because depletion of vitamin A blocks the initiation of phototransduction, such inhibition of functional activation should lead to decrease retinal metabolism and perfusion. In a case study of a vitamin A-depleted patient, we found that retinal vessel diameters, a surrogate measure of retinal perfusion, increased in concert with the restitution of electroretinographic function following vitamin A supplementation. When normalized to conditions after treatment, the relative magnitude of study parameters at presentation were: scotopic electroretinography B-wave amplitude 1.2%, photopic electroretrinography B-wave amplitude 23%, retinal vein diameter 88%, retinal artery diameter 94%. These observations support that activation of the visual process results in increased retinal metabolism and perfusion.

Design, synthesis, and antiviral evaluation of some polyhalogenated indole C-nucleosides.

2,5, 6-Trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB), 2-bromo-5, 6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB) and 2-benzylthio-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BTDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. Polyhalogenated indole C-nucleosides were prepared as 1-deaza analogs of the benzimidazole nucleosides TCRB and BDCRB. A mild Knoevenagel coupling reaction between an indol-2-thione and a ribofuranose derivative was developed for the synthesis of 2-benzylthio-5, 6-dichloro-3-(beta-D-ribofuranosyl)indole (12). 3-(beta-D-ribofuranosyl)-2,5,6-trichloroindole (16) was prepared from 12 in 4 steps. A Lewis acid-mediated glycosylation method was then developed to prepare the targeted 2-haloindole C-nucleoside 16 stereoselectively in four steps from the corresponding 2-haloindole aglycons. Only 12 was active against HCMV but it also was somewhat cytotoxic.

Evaluation of 5-day therapy with telithromycin, a novel ketolide antibacterial, for the treatment of tonsillopharyngitis.

A pooled analysis of two double-blind, multicentre, Phase III studies compared oral telithromycin 800 mg once-daily for 5 days with penicillin V 500 mg three-times-daily or clarithromycin 250 mg twice-daily for 10 days in the treatment of Streptococcus pyogenes (group A beta-haemolytic streptococcus; GABHS) tonsillopharyngitis. Patients aged > or = 13 years with acute GABHS tonsillopharyngitis were randomised to receive telithromycin (n = 430), penicillin (n = 197) or clarithromycin (n = 231). Clinical isolates of S. pyogenes (n = 590) obtained from throat swab samples on study entry were tested for their in-vitro susceptibility to telithromycin, clarithromycin and azithromycin. Telithromycin demonstrated in-vitro activity against the clinical isolates of S. pyogenes (MIC50/90 0.03/0.06 mg/L) higher than clarithromycin or azithromycin (MIC50/90 0.06/0.06 mg/L and 0.12/0.25 mg/L, respectively), including erythromycin-resistant strains. At the post-therapy/test of cure (TOC) visit (days 16-23), satisfactory bacteriological outcome was demonstrated for 88.3% (234/265) and 88.6% (225/254) of telithromycin- and comparator-treated patients, respectively (per-protocol population). Overall, GABHS eradication rates were 88.7% (235/265) for telithromycin and 89.0% (226/254) for comparators. The clinical cure rates at the post-therapy/TOC visit were 93.6% (248/265) and 90.9% (220/242) for telithromycin and pooled comparators, respectively. Telithromycin was generally well-tolerated. Most adverse events considered to be possibly related to study medication were gastrointestinal and of mild intensity. Discontinuations as a result of adverse events were few in both treatment groups. In conclusion, telithromycin 800 mg once-daily for 5 days was as effective as penicillin V or clarithromycin for 10 days in the treatment of GABHS tonsillopharyngitis.

Safety issues in cell-based intervention trials.

We report on the deliberations of an interdisciplinary group of experts in science, law, and philosophy who convened to discuss novel ethical and policy challenges in stem cell research. In this report we discuss the ethical and policy implications of safety concerns in the transition from basic laboratory research to clinical applications of cell-based therapies derived from stem cells. Although many features of this transition from lab to clinic are common to other therapies, three aspects of stem cell biology pose unique challenges. First, tension regarding the use of human embryos may complicate the scientific development of safe and effective cell lines. Second, because human stem cells were not developed in the laboratory until 1998, few safety questions relating to human applications have been addressed in animal research. Third, preclinical and clinical testing of biologic agents, particularly those as inherently complex as mammalian cells, present formidable challenges, such as the need to develop suitable standardized assays and the difficulty of selecting appropriate patient populations for early phase trials. We recommend that scientists, policy makers, and the public discuss these issues responsibly, and further, that a national advisory committee to oversee human trials of cell therapies be established.

Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia.

BACKGROUND: This randomized, double-blind study compared the efficacy and tolerability of the new ketolide antimicrobial telithromycin with that of high-dose amoxicillin in the treatment of community-acquired pneumonia (CAP). PATIENTS AND METHODS: Adult patients (n = 404), with signs and symptoms of CAP and radiologic confirmation were randomized to receive telithromycin 800 mg once daily (n = 199) or amoxicillin 1,000 mg three times a day (n = 205) for 10 days. Clinical and bacteriologic outcomes were assessed at post-therapy test-of-cure (days 17-24) and late post therapy (days 31-36). RESULTS: The clinical cure rate for telithromycin-treated patients (per protocol) pst therapy (days 17-24) was 141/149 (94.6%) and compared well with that for amoxicillin (137/152 (90.1%)). Subset analysis of patients (per protocol) showed high clinical cure rates for patients aged >/= 65 years (telithromycin 21/24, 87.5%; amoxicillin 22/29, 75.9%); those with documented pneumococcal bacteremia (telithromycin 10/10, 100%; amoxicillin 7/9, 77.8%); and patients with a Fine score >/= III (telithromycin 31/34, 91.2%; amoxicillin 38/47, 80.9%). Bacterial eradication rates were comparable between treatments (telithromycin 42/48, 87.5%; amoxicillin 39/45, 86.7%), with 22/23 vs 18/21 Streptococcus pneumoniae strains 9/12 vs 11/13 Haemophilus influenzae strains and all Moraxella catarrhalis isolates (five and three patients, respectively) eradicated at the test-of-cure visit. Both treatments were generally well tolerated. CONCLUSION: Telithromycin 800 mg once daily is a convenient, optimal-spectrum, first-line treatment for CAP in adults, at least as effective and well tolerated as high-dose amoxicillin.

[Effect of the treatment with human recombinant erythropoietin on anemia in children with end-stage kidney failure. French multicenter study]. / Effet du traitement par érythropoïétine humaine recombinante sur l'anémie de l'enfant en insuffisance rénale terminale. Etude multicentrique française. Société de Néphrologie Pédiatrique.

BACKGROUND: The production of recombinant erythropoietin, has made large quantities of pure protein available for clinical studies. Published reports have concentrated on patients with end-stage renal disease, who develop transfusion-dependent anemia. MATERIAL AND METHODS: A total of 58 children aged less than 18 years (mean age: 11.48 +/- 4.62 years) with end-stage renal disease (hereditary in 9, congenital in 21 and acquired in 28) treated between July 1987 and February 1990, were included in the study. The mean duration of dialysis (hemodialysis in 56, peritoneal dialysis in 2) at the onset of the study was 35 +/- 28 months. 3 children had undergone bilateral nephrectomy, and 2 were infected with HIV. 54 children were given a phosphate-binder, 10 were given iron and 20 were given folic acid supplements. During the 6 months preceding the study, 51 patients received at least one blood transfusion (40 received 1 to 4 and 11 received 5 to 9 transfusions of packed red blood cells). Recombinant human erythropoietin (rHu EPO) (40 units/kg) was given intravenously three times per week for at least 6 weeks, with the exception of the first 9 patients who were given 80-100 units/kg. When the hematocrit increased less than 0.5% per week (or 3% for 6 weeks), the dose of rHu EPO was increased in stages, without exceeding 200 units/kg/injection. When the hematocrit reached 30 to 35%, the dose of rHu EPO was decreased by half, then gradually adjusted to maintain the hematocrit within this range. RESULTS: The mean value of reticulocytosis increased from 4.88 to 10.58% and the hematocrit increased from 19.34 to 29.95% during the study. The patients also reported that their appetites and general condition improved. The need for transfusion dramatically decreased after the first month of treatment. The main adverse effect of the rHu EPO administration was an increase in the number of patients with hypertension (31/45 versus 19/45), indicating the need for good control of blood pressure before treatment. CONCLUSION: Erythropoietin treatment increases packed blood volume in a dose-dependent fashion. Most patients need no further transfusion and the quality of life clearly improves.

[Transcutaneous electric stimulation of the brain: a comparative study of the effects of its combination with peridural anesthesia using bupivacaine-fentanyl during obstetrical analgesia]. / Electrostimulation cérébrale transcutanée: étude comparative des effets de son association à l'anesthésie péridurale par bupivacaïne-fentanyl au cours de l'analgésie obstétricale.

In order to test the effectiveness of Anesthelec (transcutaneous cranial electrical stimulation with Limoge currents) during labour and delivery, a randomized study was carried out in 120 primiparous women with extradural anaesthesia during active labor. Combination of transcutaneous cranial electrical stimulation with epidural bupivacaine administration has been showed to provide a 20% pain relief prolongation of the first bupivacaine injection. Statistical studies of drug requirement during labor, of cervical dilatation duration, of mode and duration of delivery and of analgesia quality showed no beneficial additive effect of electrical stimulation for obstetrical analgesia when extradural anaesthesia is performed.