Comparable aciclovir exposures produced by oral valaciclovir and intravenous aciclovir in immunocompromised cancer patients

The objective of this study was to evaluate the comparability of systemic aciclovir exposure at steady state in immunocompromised patients following oral valaciclovir 1000 mg tds and intravenous (iv) aciclovir 5 mg/kg tds. A two-centre, randomized, open label, two-way crossover study was undertaken. Patients aged 18-65 years who had undergone high-dose chemotherapy for cancer and were neutropenic (neutrophil count <0.5 x 109/mL) with normal renal function were recruited. The pharmacokinetic parameters of aciclovir after oral valaciclovir 1000 mg or iv aciclovir 5 mg/kg given as 1 h infusion, each administered every 8 h for seven doses, were compared. Fifteen patients were enrolled and 13 completed both treatments. The mean (s.d.) values for aciclovir after oral valaciclovir and iv aciclovir were: AUC0-8 76.3 (29.7) and 64.2 (20.0) microM x h; peak plasma concentration (Cmax) 26.6 (10.5) and 34.0 (11.9) microM; time to maximal plasma concentration (tmax) 2.01 (0.65) and 0.95 (0.19); and plasma elimination half-life (t1/2) 2.83 (0.91) and 2.44 (0.62) h, respectively. The mean absolute bioavailability of aciclovir from oral valaciclovir was 60 +/- 21%. Equivalent systemic exposure to aciclovir after oral valaciclovir 1000 mg and iv aciclovir 5 mg/kg was observed with AUC0-8 (oral/iv ratio = 1.16; 90% CI 0.98-1.39), whilst significantly reduced peak aciclovir concentrations were obtained with oral valaciclovir (ratio = 0.75; 90% CI 0.60-0.94). Oral valaciclovir offers a convenient, and possibly safer, alternative to iv aciclovir, delivering comparable systemic exposures with reduced peak levels. This may contribute to shorter hospitalization, reduced costs for healthcare providers and improved quality of life for patients.     

The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during aciclovir and valaciclovir treatment

OBJECTIVES: Neuropsychiatric symptoms related to aciclovir or valaciclovir treatment have been a problem since aciclovir was introduced in the early 1980s. We have previously found that subjects with aciclovir-related neuropsychiatric symptoms have increased serum concentrations of aciclovir's main metabolite, 9-carboxymethoxymethylguanine (CMMG). The aim of this study was to investigate whether CMMG was present in the CSF of aciclovir- or valaciclovir-treated subjects with or without neuropsychiatric side effects that appeared during therapy. METHODS: We investigated retrospectively CSF collected from 21 aciclovir- or valaciclovir-treated subjects. Of these, 9 were subjects with neuropsychiatric signs and symptoms and 12 were asymptomatic subjects, including 10 subjects from a valaciclovir multiple sclerosis trial and 2 subjects with recurrent herpes encephalitis. RESULTS: CMMG could only be detected in the CSF of subjects with neuropsychiatric symptoms and signs (median CMMG concentration 1.0 micromol/L, range 0.6-7.0). The concentration of CMMG was below the limit of quantification (<0.5 micromol/L) in asymptomatic subjects (P < 0.001). All patients with neuropsychiatric signs and symptoms, except one, had acute renal function impairment or chronic renal failure. CONCLUSIONS: These results are consistent with the hypothesis that CMMG is involved in the development of neuropsychiatric side effects in aciclovir- or valaciclovir-treated patients. Measurement of CMMG in CSF and/or serum is a promising tool in the diagnostic procedure for aciclovir- or valaciclovir-treated patients with neuropsychiatric symptoms and may help to differentiate between side effects and herpes encephalitis.     

Pharmacokinetics of acyclovir after intravenous infusion of acyclovir and after oral administration of acyclovir and its prodrug valacyclovir in healthy adult horses

The purpose of this study was twofold. The first aim was to evaluate the oral bioavailability and pharmacokinetics (PKs) of acyclovir in horses after intravenous (i.v.) administration and after oral administration of acyclovir and its prodrug, valacyclovir. Second, we aimed to combine these PK data with pharmacodynamic (PD) information, i.e., 50% effective concentrations (EC(50) values) from in vitro studies, to design an optimal dosage schedule. Three treatments were administered to healthy adult horses: 10 mg of acyclovir/kg of body weight delivered as an i.v. infusion over 1 h, 20 mg of acyclovir/kg administered as tablets by nasogastric intubation, and 20 mg of valacyclovir/kg administered as tablets by nasogastric intubation. Total plasma concentrations were measured by a high-performance liquid chromatography method combined with fluorescence detection, while unbound plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. The peak concentration of i.v. acyclovir was approximately 10 mug/ml for both the total and the unbound plasma concentrations. The mean half-life of elimination was between 5.05 h (total concentration) and 11.9 h (unbound concentration). Oral administration of acyclovir resulted in low maximum concentration in plasma (C(max)) and poor bioavailability. A 10-times-higher C(max) and an 8-times-higher bioavailability were achieved with oral administration of valacyclovir. The i.v. administration of 10 mg/kg acyclovir and the oral administration of 20 mg/kg valacyclovir achieved concentrations within the sensitivity range of equine herpesvirus type 1 (EHV-1). The higher bioavailability of valacyclovir makes it an attractive candidate for the prophylactic and/or therapeutic treatment of horses infected with EHV-1. The results from the PK/PD modeling showed that a dosage of 40 mg/kg valacyclovir, administered three times daily, would be sufficient to reach plasma concentrations above the EC(50) values.     

恶性肿瘤病人化疗后白细胞减少致感染的预防与护理

化疗是治疗恶性肿瘤的重要三大手段之一,但在杀灭肿瘤细胞的同时不可避免地对正常组织和器官造成损害。化疗中最常见的不良反应是骨髓抑制、外周血中白细胞数的减少导致机体免疫功能下降,引发病人发生各种感染,严重时可致死亡[1]。本研究对肿瘤病人化疗后白细胞减少所致感染的原因与护理对     

Safe administration of oral chemotherapy

High standards of care are desirable for patients in any setting who receive chemotherapy by any route. Patients who self-administer oral chemotherapy are subject to risks of adverse effects similar to those who receive i.v. chemotherapy. Safeguards to prevent medication error in these patients may not be achieved to the same degree as for patients receiving i.v. drugs in an institutional setting. This article describes the differences between typical administration standards for i.v. chemotherapy versus oral chemotherapy. The process of oral chemotherapy provision is examined, with examples of drug characteristics and patient features important in each step. Recommendations are made for improving the care of patients receiving oral chemotherapy medications, particularly in the home setting.     

Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus

Six patients with human immunodeficiency virus were given foscarnet in oral solution, 4000 mg every 6 hours for 3 days, followed by a washout period for 2 days and continuous intravenous infusion of 16,000 mg/24 hr over 72 hours. After oral foscarnet, plasma concentrations were less than 33 mumol/L in four patients; two had occasional concentrations of 35 to 50 mumol/L. The extent of absorption varied between 12% and 22%. During intravenous infusion, plasma concentrations ranged between 75 and 265 mumol/L. The disposition of foscarnet was triphasic, with mean half-lives of 0.45, 3.3, and 18 hours. Excretion data suggested elimination was by tubular secretion and glomerular filtration. Renal clearance was 176 ml/min 1.73 m2. The apparent nonrenal clearance, 40 ml/min 1.73 m2, probably reflects sequestration of foscarnet into bone. Ten percent to 28% of the cumulative dose may have been deposited in bone 2 days after infusion. A slight increase in serum calcium levels and changes in serum phosphate values may reflect the uptake of foscarnet in bone. Five patients had diarrhea (oral) and two had thrombophlebitis (intravenous).     

Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans

Therapeutically, magnesium salts represent an important class of compounds and exhibit various pharmacologic actions. Examples of magnesium salts are ionic magnesium and magnesium citrate in nephrolithiasis, magnesium salicylate in rheumatoid arthritis, magnesium hydroxide as an antacid as well as a cathartic, and magnesium mandelate as urinary antiseptic. Various anions attached to the cation magnesium, such as oxide, chloride, gluconate, and lactate, affect the delivery of the amounts of elemental magnesium to the target site and thereby produce different pharmacodynamic effects. This review examines the bioavailability and pharmacokinetics of various magnesium salts and correlates pharmacodynamic action with the structure-activity relationship.     

肿瘤化疗患者白细胞减少并发感染的危险因素及预防对策

目的探讨肿瘤化疗患者白细胞减少并发感染的危险因素及预防对策。方法选取562例白细胞减少肿瘤患者,其中并发感染的患者共71例。采集感染患者的血液、痰液、穿刺液、尿液等标本进行细菌培养、鉴定及药敏实验,并对并发感染的危险因素进行分析。结果 562例肿瘤化疗白细胞减少患者中,并发感染71例,感染率为12.63%。71例感染患者共检出114株病原菌,其中革兰阳性菌占32.46%,革兰阴性菌占59.65%,真菌占7.89%。Logistic回归分析显示,合并糖尿病、血清蛋白35 g/L、皮肤或黏膜溃疡、侵入性操作、肿瘤分期≥Ⅲ期、住院时间≥4周、广谱抗生素应用20 d是肿瘤患者化疗白细胞减少并发感染的独立危险因素。结论合并糖尿病、血清蛋白35 g/L、皮肤或黏膜溃疡、侵入性操作、肿瘤分期≥Ⅲ期、住院时间≥4周、广谱抗生素应用20 d是肿瘤患者化疗白细胞减少并发感染的独立危险因素。     

Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans.

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma = 0.19 microM), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 45% in urine and 475 in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9- [(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.     

Bioavailability and pharmacokinetics of cyclosporine A-loaded pH-sensitive nanoparticles for oral administration.

The pH-sensitive cyclosporine A (CyA) nanoparticles were prepared by the solvent displacement method with enteric dissolved polymer of hydroxypropyl methylcellulose phthalate (HPMCP; including HP50 and HP55). The CyA nanoparticles were analyzed by HPLC for yield and encapsulation efficiency, dynamic light scattering for particle size and transmission electron microscopy (TEM) for morphology. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids were evaluated in rats, compared with the current available CyA microemulsion (Neoral). The bioavailability of CyA-HP55 nanoparticle colloids with various suspending agents was also investigated. The results obtained demonstrated that the pH-sensitive CyA nanoparticles with a particle size of 50-60 nm and encapsulation efficiency over 95% could be reproducibly prepared. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids calculated by the AUC(0-72) were 82.3% and 119.6%, similar to the reference of Neoral, while the bioavailability of CyA-HP55 nanoparticle colloids was found to be higher than that of CyA-HP50 nanoparticle colloids. The increase of mean residence time (MRT) and the decrease of elimination constant of the central compartment (K10) for both CyA-HP50 and CyA-HP55 nanoparticle colloids compared with the reference indicated significant sustained release of CyA from the nanoparticles. The effects of the suspending agents on the bioavailability of CyA-HP55 nanoparticles were observed, and the bioavailability decreased as the concentration of suspending agents or the viscosity of the nanoparticle colloids increased.     

慢性心房颤动患者口服华法林的观察与护理

心房颤动(AF)是一种十分常见的心律失常,60岁以上的人群中,AF发生率为1%,并随年龄的增长而增高.AF最大的危害是脑卒中,慢性AF患者脑卒中的发生率高达10%,因此预防脑卒中的发生十分重要.     

碱性成纤维细胞生长因子治疗恶性血液病化疗后口腔黏膜炎的效果观察

口腔黏膜炎(OM)是恶性血液病病人化疗后常见的并发症,具有潜在危险性,且缺乏有效防治手段,不仅给病人带来疼痛,影响病人的生存质量,也是致死性感染的重要原因之一[1]。本组观察2004年6月—2005年6月在我科住院的74例次恶性血液病病人化疗所致的溃疡性OM的临床表现,比较了碱性成纤维细胞生长因子(bFGF)治疗和常规漱口液、软膏治疗对OM的疗效。1资料与方法1.1临床资料74例恶性血液病溃疡性OM病人中,男42例,女32例;年龄16岁~78岁,平均54岁;其中急性白血病42例、淋巴瘤20例、多发性骨髓瘤12例;接受常规剂量化疗65例,接受大剂量化疗9例。用…     

Bioavailability of oral trimetrexate in patients with acquired immunodeficiency syndrome.

The combination of the lipophilic antifolate trimetrexate and the rescue agent leucovorin has shown promise in the treatment of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. The pharmacokinetic behavior of trimetrexate administered either by intravenous bolus or orally was studied in six patients with acquired immunodeficiency syndrome with a reversed-phase high-pressure liquid chromatography assay. The mean clearance following bolus injection was 38 ml/min per m2, with a range of 15 to 55 ml/min per m2. The postdistributive half-life ranged from 6 to 16 h. With oral administration, the mean bioavailability was 44% (range, 19 to 67%). An oral dose of 60 mg/m2 (162 mumol/m2) resulted in concentrations in plasma that approximated those achieved with a 30-mg/m2 (81-mumol/m2) intravenous dose. The toxicity of this combination regimen was minimal. It appears that the oral route is a practical route of administration for trimetrexate in patients with acquired immunodeficiency syndrome requiring long-term outpatient treatment or prophylaxis for P. carinii pneumonia.     

The change in zoster-associated pain treated with oral valaciclovir in immunocompetent patients with acute herpes zoster

We have analysed zoster-associated pain treated with valaciclovir (VCV) in immunocompetent patients with acute herpes zoster over 6 months, and evaluated the safety of VCV. We know of no reports that evaluate postherpetic neuralgia (PHN) treated with VCV for 6 months. Predisposing factors that influence PHN were age (over 60 years), clustered vesicles, severity of eruption, sleep disturbance, and hypesthesia. Timing of the administration of VCV before or after the onset of rash did not influence the incidence of PHN. No serious adverse reactions were observed during the administration of VCV.     

Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C(max)) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C(max) values of 2.56 and 2.55 microg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-beta-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.     

口腔氧气吹拂法预防骨肉瘤患者大剂量甲氨蝶呤化疗后口腔溃疡的效果

目的 观察口腔氧气吹拂法预防骨肉瘤患者大剂量甲氨蝶呤化疗后口腔溃疡的效果.方法 选取接受静脉化疗的骨肉瘤患者52例作为研究对象,按照随机数字表法将患者分为对照组和观察组,每组26例.对照组化疗时采用亚叶酸钙漱口,观察组化疗开始时即给予24 h间断口腔氧气吹拂.观察并比较2组患者化疗后7d内口腔溃疡发生率、口腔溃疡程度分...     

碱性成纤维细胞生长因子治疗恶性血液病化疗后口腔黏膜炎的效果观察

口腔黏膜炎（OM）是恶性血液病病人化疗后常见的并发症，具有潜在危险性，且缺乏有效防治手段，不仅给病人带来疼痛，影响病人的生存质量，也是致死性感染的重要原因之一。本组观察2004年6月-2005年6月在我科住院的74例次恶性血液病病人化疗所致的溃疡性OM的临床表现，比较了碱性成纤维细胞生长因子（bFGF）治疗和常规漱口液、软膏治疗对OM的疗效。     

Bioavailability of oral and intramuscular molindone hydrochloride in schizophrenic patients

This study was designed to assess the bioequivalence of intramuscular molindone hydrochloride and marketed oral molindone. Ten schizophrenic patients (mean age, 30.2 years) received oral molindone in single daily doses of 100 or 150 mg for four to eight days followed by intramuscular molindone in single daily doses of 50 or 75 mg for four days. On the last day each molindone formulation was given, plasma samples were collected at baseline and at 0.5, 1, 2, 4, 6, 8, and 12 hours after administration. The pharmacokinetic measures of area under the curve and maximum concentration show that intramuscular molindone is 1.49 to 1.67 times more bioavailable than oral molindone. This finding indicates that once a patient's acute psychotic episode has been stabilized with intramuscular molindone, therapy can continue without interruption by substituting 1.5 mg of oral molindone for every 1 mg of intramuscular molindone. The time to maximum concentration occurred significantly earlier (P = 0.05) with intramuscular molindone (0.6 hours) than with oral molindone (1.1 hours). Elimination half-life values were approximately two hours for both formulations.     

消化道肿瘤患者化疗后发生口腔感染的影响因素研究

目的探讨消化道肿瘤患者化疗后发生1：7腔感染的危险因素,以期为临床防治提供依据。方法选取2010年1月至2012年12月收治的120例消化道肿瘤化疗患者作为研究对象,进行前瞻性监测研究,对19项口腔感染的可能危险因素进行单因素卡方检验及多因素Logistic回归分析。结果120例消化道肿瘤患者中口腔炎的发生率为37．5％,经单因素分析结果发现年龄、1：2腔环境、口腔自洁习惯、口腔pH值：吸烟、口腔疾患史、含5-Fu／MTX方案、病期、白细胞计数降低度、侵入性操作、化疗周期、义齿与口腔感染发生率有显著相关性（P〈0．05）,而性别、Kamofsky评分、焦虑抑郁、有无使用抗生素、上呼吸道感染、职业、文化程度与口腔感染发生率无显著相关性（P〉0．05）,以口腔感染发生为因变量,采用非条件Logistic多因素回归分析,结果显示年龄、口腔环境、口腔自洁习惯、白细胞计数、含5-Fu／MTX、病期是消化道瘤患者化疗后口腔感染发生的危险因素（P〈0．05）。结论年龄、白细胞计数、口腔环境、口腔自洁习惯、化疗方案、病期是引发化疗后口腔感染的重要危险因素,临床上可通过正确含漱、科学饮食控制等干预,降低消化道肿瘤患者化疗后口腔感染的发生率。