Safety, toleration, and pharmacokinetics of intravenous azithromycin.

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.     

Drug policy, intravenous drug use, and heroin addiction in the UK

In order to fully understand and appreciate today's drug problem in the UK, the foundations of drug legislation and the history of drug evolution require exploration. This paper critically examines the history of drug policy and the growth of heroin addiction from the perspective of a novice researcher who works closely with intravenous drug users in relation to leg ulceration and wound care in the acute setting. Today's drug policy has come a long way in understanding the problems of heroin addiction and establishing services to meet intravenous drug users' needs and the needs of society. This paper highlights the early warning signs of drug addiction and growth within the UK from an early stage with key areas such as who the early users were and how addiction grew so rapidly between 1920 and 1960. Current policy and decision makers as well as clinicians and researchers in this field must understand the impacts of past policy and embed it within their decisions surrounding drug policy today.     

A double-blind, randomised, parallel study comparing intravenous dolasetron plus dexamethasone and intravenous dolasetron alone for the management of fractionated cisplatin-related nausea and vomiting

 Fractionated cisplatin-containing regimens are routinely used for chemotherapy in certain types of cancer. Dolasetron has been shown to be effective in preventing acute emesis related to high-dose cisplatin chemotherapy over 24 h; its effectiveness has not been evaluated in fractionated cisplatin-containing chemotherapy. This trial was designed to assess the efficacy of dolasetron alone or dolasetron plus dexamethasone in preventing nausea and vomiting related to fractionated cisplatin chemotherapy. The patients were 210 cancer in-patients, who were randomised to receive 100 mg dolasetron i.v. or 100 mg dolasetron i.v. plus 20 mg dexamethasone before chemotherapy primarily with cisplatin (15–50 mg/m²) infused over ≤4 h for at least 2 but not more than 5 consecutive days. Dolasetron was administered to all patients 30 min before cisplatin. Dexamethasone was administered in double-blind fashion 5 min before cisplatin. Efficacy was measured at hour 24 of each study day using complete response (no vomiting and no rescue medication) and maximum severity of nausea, self-assessed by patients using a 100-mm visual analogue scale. Most (198) of the patients completed the study and were evaluable. Overall complete response rates were significantly higher in the dolasetron plus dexamethasone group than in the dolasetron only group (72.9% vs 40.8%, respectively; P<0.0001). Complete response rates on each study day were also significantly higher with dolasetron plus dexamethasone than with dolasetron alone (P<0.029), with an attenuated efficacy in the delayed phase in both groups. Chi-square test and logistic regression applied to daily response rates indicated a significant influence of treatment (day 1: P=0.0002, day 2: P<0.0001, day 3: P=0.0007, day 4: P=0. 0007, day 5: P=0.029). Treatment and duration of chemotherapy exerted the only statistically significant subgroup effects on complete response (P<0.0001). Both treatments were administered safely. As seen with other 5-HT₃ receptor antagonist antiemetics, the addition of dexamethasone to dolasetron significantly increases effectiveness in preventing nausea and vomiting related to fractionated cisplatin chemotherapy. Both dolasetron and dolasetron plus dexamethasone were well tolerated. Published online: 19 August 1999     

不同部位静脉给药在静脉麻醉诱导中的时效差异

[目的]比较上、下肢静脉给药在静脉诱导麻醉中的时效差异,为临床护士静脉麻醉时选择穿刺静脉提供依据。[方法]选择采用静脉麻醉的住院手术病人60例,分为上肢静脉给药(上肢组)和下肢静脉给药(下肢组),按1.5 mg/kg的剂量静脉注射丙泊酚,观察病人意识消失的时间、疼痛的主诉、血压及心率的变化。[结果]上肢组诱导时间短于下肢组(P<0.001);两组病人疼痛、血压及心率变化无统计学意义(P>0.05)。[结论]在静脉麻醉诱导中选择上肢静脉给药,意识消失时间短于下肢静脉给药。     

Comparing the efficacy of intravenous tenoxicam,lornoxicam, and dexketoprofen trometamol for the treatment of renal colic

Study Objective

The aim of this study was to compare the efficacy and safety of 3 nonsteroidal anti-inflammatory drugs—intravenous tenoxicam, lornoxicam, and dexketoprofen trometamol—for the treatment of patients with renal colic.

Methods

We conducted a prospective double-blind randomized trial of consecutive adult patients who presented to the emergency department with a chief complaint of acute flank pain and had a clinical diagnosis of suspected acute renal colic. Patients were randomly allocated to receive an intravenous bolus of tenoxicam, lornoxicam, or dexketoprofen trometamol in a blinded fashion. Primary outcome measure of the study was visual analog scale (VAS) score difference at 30 minutes. Secondary outcome measures were VAS scores at 5, 15, and 120 minutes as well as rescue analgesic need at 30 minutes and adverse events during the follow-up period.

Results

A total of 445 patients were screened, and 123 patients were enrolled in the study. The mean age was 36 ± 10 years. The mean reduction in VAS pain scores at 30 minutes was 42 ± 26 mm for tenoxicam, 57 ± 23 mm for lornoxicam, and 52 ± 25 mm for dexketoprofen (P = .047). Lornoxicam demonstrated the fastest rate of VAS score reduction over the first 30 minutes. The mean reduction values in VAS pain scores at 5, 15, and 120 minutes were similar among the 3 groups. Rescue analgesics at 30 minutes were required by 16 patients (39%) receiving tenoxicam, 10 patients (24%) receiving lornoxicam, and 8 patients (19%) receiving dexketoprofen (P = .121). No serious adverse events were observed.

Conclusions

Intravenous tenoxicam, lornoxicam, and dexketoprofen are all effective in the treatment of renal colic, although lornoxicam appears to reduce VAS pain scores with the fastest rate in this comparison.     

Does intravenous methadone provide longer lasting analgesia than intravenous morphine? A randomized, double-blind study

A prospective, randomized, double-blind trial was designed to compare the duration of analgesia produced by intravenous morphine and methadone. Patients with intractable cancer-related pain were studied for 5-6 days. One-eighth of the patient's daily opiate requirement was supplied as an i.v. infusion of either morphine or methadone over a period of 15 min. when initiated by the patient using a patient-controlled analgesia device. Dosing intervals, pain intensity assessments and toxicity were evaluated. Twenty-three patients were randomized; 18 were fully evaluable. Ten of the evaluable patients received morphine, 8 received methadone. Dosing intervals did not change over the 5 days for either group. The mean dosing interval for the last 10 doses was 3.9 +/- 0.85 h for patients receiving morphine and 3.9 +/- 1.6 h for patients receiving methadone (P = NS). One patient receiving morphine and one taking methadone required only 2-3 doses/day for pain control. Pain intensity and relief were similar for both groups. All patients had adequate analgesia as determined by at least a 50% difference in pain intensity at peak relief. The duration of pain relief when repeated intravenous doses of these analgesics were given was similar throughout the entire study period although morphine and methadone have different serum half-lives (3 vs. 25 h). Parenteral methadone does not offer a clinically significant increase in the duration of analgesia in patients with severe pain secondary to cancer.     

Cost-effectiveness of oral clodronate compared with oral ibandronate, intravenous zoledronate or intravenous pamidronate in breast cancer patients

This study aimed to identify the effects of different bisphosphonates in reducing skeletal-related events, and to determine whether there are any differences in their cost-effectiveness, taking into account their efficacy, safety profile and administration routes. A systematic literature search of databases, such as PubMed and the Cochrane Controlled Trials Register, supplemented by the latest congress abstracts from meetings of the European Hematology Association and the American Society of Clinical Oncology was conducted up to November 2006. Important references in reviews published by peer-reviewed journals were also taken into consideration. Our base-case cost-effectiveness analysis for Germany and the UK showed cost savings for oral clodronate therapy compared with other bisphosphonate therapies. In Germany, costs per patient of treatment with oral clodronate were euro1092.38, euro2360.40 and euro2500.29 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively. The UK results were similar, the costs per patient of treatment with oral clodronate being euro841.79, euro2989.99 and euro3669.19 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively.     

Pharmacokinetics, pharmacodynamics, and minimum effective clinical dose of intravenous nicardipine

Nicardipine hydrochloride was administered intravenously to two groups of hypertensive patients: one group of 37 patients with mild to moderate hypertension and one group of 20 patients with severe hypertension. In the first group, doses of 0.5, 1, 2, and 4 mg/hr, as well as placebo, were infused for 48 hours in a double-blind fashion. Blood pressure and heart rate were monitored for this period and for the 24 hours after the infusion was discontinued. Significant decrements in blood pressure were noted with all doses; 4 mg/hr produced lowering that was greater than all other doses; 1 and 2 mg/hr produced lowering that was greater than 0.5 mg/hr but that were not different from each other. Excellent correlation of blood pressure reduction and plasma level was observed and linear kinetics existed. In the severe hypertensive patients, 1, 2, 4, 5, and 8 mg/hr were infused to established minimal and ineffective doses. One milligram per hour was an ineffective dose; 4, 5, and 8 mg/hr all produced significant reductions over the course of the study that were undistinguishable from each other. Two milligrams per hour produced modest reductions in blood pressure. Blood pressure reduction also correlated with plasma levels in the severe hypertensive group.     

Pharmacokinetics of intravenous acyclovir,zidovudine, and acyclovir-zidovudine in pregnant rats

The pharmacokinetics and placental transfer of acyclovir and zidovudine monotherapies and acyclovir-zidovudine combination therapy were compared in the pregnant rat. Timed-pregnancy Sprague-Dawley rats were used for the study. Doses of 60 mg of each drug/kg of body weight in monotherapy and in combination therapy were given by intravenous bolus, and samples of maternal plasma, amniotic fluid, fetal tissue, and placental tissue were collected over a period of 8 h postdose. Concentrations of each drug in the various matrices were measured by high-performance liquid chromatography. All data were analyzed by using WinNonlin. A one-compartment model with first-order elimination was used to fit the AZT plasma data from the combination therapy rats, but the plasma data from the other groups were fit to a two-compartment model. Tissue data were analyzed by noncompartmental analysis to generate area-under-the-concentration-time-curve values. Implementation of the combination therapy altered the pharmacokinetics of each drug compared to its monotherapy pharmacokinetics. The combination of these two drugs may potentiate fetal and amniotic fluid exposures to each drug.     

Disposition of nasal,intravenous, and oral methadone in healthy volunteers

OBJECTIVE: Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers. METHODS: The study was approved by the Institutional Review Board of the University of Washington, Seattle. Eight healthy volunteers (6 men and 2 women) aged 19 to 33 years were enrolled after informed written consent was obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or intravenously on 3 separate occasions in a crossover design. Nasal methadone (50 mg/mL in aqueous solution) was given as a 100-microL spray in each nostril (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography-mass spectrometry analyses of methadone and the metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was measured by noninvasive infrared pupilometry coincident with blood sampling. RESULTS: Nasal uptake of methadone was rapid, with maximum plasma concentrations occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral methadone, on the basis of dark-adapted pupil diameter, were reached in about 15 minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24, 10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects reported that nasal methadone caused a burning sensation. CONCLUSIONS: Nasal administration of methadone results in rapid absorption and onset of effect and high bioavailability, which was greater than that reported for other nasal opioids, with a similar duration of effect. Nasal administration may be an alternative route of methadone administration; however, improved formulations are desirable to reduce nasal irritation.     

Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1-minute infusion in a double-blind, three-way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half-life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and +21.3%, respectively).     

Physicochemical properties of ferumoxytol, a new intravenous iron preparation

Background  Intravenous iron is a critical component of anaemia management. However, currently available preparations have been associated with the release of free iron, a promoter of bacterial growth and oxidative stress.
Materials and methods  We determined the molecular weight, dialysability and capacity for free iron release of ferumoxytol, a semi-synthetic carbohydrate-coated superparamagnetic iron oxide nanoparticle. Ferumoxytol was compared with three intravenous iron preparations in clinical use: iron dextran (low molecular weight), sodium ferric gluconate and iron sucrose. Intravenous iron preparations were also incubated in rat, and pooled human sera (at concentrations of 600 μM and 42 μg mL⁻¹ respectively) from healthy subjects.
Results  The molecular weight of ferumoxytol was 731 kDa. The relative order of molecular weight was as follows: ferumoxytol > iron dextran > iron sucrose > sodium ferric gluconate. The least ultrafilterable iron was observed with ferumoxytol and the most with ferric gluconate. The least dialysable free iron was observed with ferumoxytol and the most with ferric gluconate. Incubation of intravenous iron preparations in rat or pooled human sera demonstrated minimal free iron release with ferumoxytol. The order of catalytic iron release as detected by the bleomycin detectable iron assay was as follows: ferumoxytol < iron dextran < iron sucrose < ferric gluconate. A similar trend was observed for the in vivo serum concentration of free iron in rats.
Conclusions  In vitro observations from these experiments suggest that ferumoxytol has a favourable profile in terms of tendency to release free iron, in comparison with currently available intravenous iron preparations.     

Enalaprilat, an intravenous angiotensin-converting enzyme inhibitor, in hypertensive crises

The effect of enalaprilat (MK-422), a newly synthesized, intravenous, nonsulfhydryl, angiotensin-converting enzyme inhibitor, was studied in seven patients with either severe or malignant hypertension. All subjects initially received a 1 mg bolus injection of enalaprilat followed in 30 minutes by 10 mg. Five subjects received an additional 40 mg. Mean (+/- SE) pretreatment blood pressure for the group was 226 +/- 9/141 +/- 7 mm Hg. Five minutes after the 1 mg enalaprilat dose, blood pressure decreased to 211 +/- 10/131 +/- 9 mm Hg and further fell to 201 +/- 14/123 +/- 11 mm Hg at 30 minutes. The maximal reduction in blood pressure to 169 +/- 14/112 +/- 10 mm Hg occurred 30 minutes after the 10 mg dose. No further blood pressure reduction was observed in those subjects who received the additional 40 mg dose. Within the entire group, five subjects exhibited sustained blood pressure reduction. No adverse side effects or symptomatic hypotension occurred in any subject.